UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASI--IfNGTON D.C., 20460 

PC Code: 086002 

DP Barcode: 426576 

Date: 12/8/2015 

MEMORANDUM 

Subject: 

To: 

From: 

Reviewed: 

Through: 

Registration Review -Preliminary Problem Formulation for Ecological Risk, 

Environmental Fate, and Drinking Water Assessments for Warfarin. 

Caitlin Newcamp, Chemical Review Manager 

Neil Anderson, Branch Chief 

Risk Management and Implementation Branch I 

Pesticide Re-evaluation Division (7508P) 

Office of Pesticide Programs 

Elizabeth 

Ibrahim Abdel-Saheb

Donovan, M.S. 

, Ph.D.

Bio

, 

l

Chemist 

ogist 2.J1---

~-~~ 

~ 

Environmental Risk Branch 6 

Environmental Fate and Effects Division (7507P) 

Office of Pesticide Programs 

Michael Wagman, Biologist Jii/ #~~ .. , ~ / 0 

Mon

William 

ica Wait

Eckel

, RAPL 

, Ph.D., Senior 

~ 

sl~ce A~sor W ~ V~f \ 2-/ &'" /\ ~ 

5 Environmental Risk Branch 6 

Environmental Fate and Effects Division (7507) 

Office of Pesticide Programs 

Mark Corbin, Branch Chief 

Environmental Risk Branch 6 

Environmental Fate and Effects Division (7507) 

Office of Pesticide Programs 

The Environmental Fate and Effects Division (EFED) has completed the preliminary problem 

formulation for the ecological risk, environmental fate, and drinking water assessments to be 

conducted as part of the registration review of the rodenticide warfarin. 

The problem fonnulation draws on information from both open literature and studies submitted 

by the technical registrants. This document is intended to provide an overview of what is 

currently known regarding the environmental fate and ecological effects associated with warfarin 

Page 1 of51 
Page 2 of 51

and outlines uncertainties regarding attributes of the parent compound and its transformation 

products. It describes the preliminary ecological risk hypothesis and the processes that will be 

used during the completion of drinking water and ecological risk assessments in support of 

registration review. This document also recommends studies that should be included in a data 

call-in (DCI) to address uncertainties surrounding the environmental fate and potential ecological 

effects of warfarin.
Page 3 of 51

Preliminary Problem Formulation for the Environmental 

Fate and Ecological Risk, Endangered Species, and Drinking 

Water Assessments in Support of the Registration Review of 

Warfarin

Warfarin

4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one

(CAS 81-81-2)

(PC Code 086002)

Environmental Risk Branch VI

Environmental Fate and Effects Division

Elizabeth Donovan, M.S., Biologist

Ibrahim Abdel-Saheb, Ph.D. Environmental Scientist

Reviewed by:

Michael Wagman, Biologist

William Eckel, Ph.D., Senior Science Advisor

Monica Wait, RAPL

Mark Corbin, Branch Chief

U. S. Environmental Protection Agency

Office of Pesticide Programs

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington, DC 20460
Page 4 of 51

Table of Contents

1 Executive summary................................................................................................................. 5

2 Introduction............................................................................................................................. 5

3 Use Characterization............................................................................................................... 6

4 Conclusions from Previous Risk Assessments....................................................................... 7

4.1 Endangered Species Assessments........................................................................ 7

4.2 Reregistration Eligibility Decision....................................................................... 7

4.3 Drinking water assessment................................................................................... 8

5 Environmental Fate and Transport.......................................................................................... 9

5.1 Transformation Products.................................................................................... 10

6 Receptors............................................................................................................................... 10

6.1 Toxicity Summary.............................................................................................. 10

6.2 Secondary Toxicity ............................................................................................ 12

6.3 Incident Database Review.................................................................................. 15

7 Exposure Pathways of Concern ............................................................................................ 16

8 Analysis Plan ........................................................................................................................ 16

8.1 Stressors of Concern........................................................................................... 16

8.2 Measures of Exposure ........................................................................................ 17

8.3 Measures of Effect ............................................................................................. 24

9 Endangered Species Assessment .......................................................................................... 24

10 Endocrine Disruptor Screening Program.............................................................................. 25

11 Preliminary Identification of Data Gaps............................................................................... 25

11.1 Fate ..................................................................................................................... 25

11.2 Effects................................................................................................................. 27

12 References............................................................................................................................. 32

Appendix A: Summary of Ecotoxicity Data for Warfarin............................................................ 43

Appendix B. Screening Level Models to Evaluate Potential Importance of Drinking Water and 

Inhalation Exposure Pathways...................................................................................................... 48

Appendix D. Wildlife Mortality Incidents Attributed to Use of Warfarin .................................. 51
Page 5 of 51

1 Executive summary

The Environmental Fate and Effects Division (EFED) has completed the preliminary problem 

formulation for the ecological risk, environmental fate, and drinking water assessments to be 

conducted as part of the registration review of warfarin. The problem formulation describes the 

methods planned to be used during the completion of drinking water and ecological risk 

assessments in support of registration review and provides an overview of the environmental 

fate, ecological effects, and potential risks associated with the use of warfarin as well as 

uncertainties unique to risk assessment of warfarin. This document also identifies additional 

studies that would be beneficial to the conduct of an ecological risk assessment. 

Data needs for ecological effects are:

• Avian acute oral toxicity test (850.2100), one passerine species

• Avian reproduction toxicity (850.2300), for an upland game bird (e.g., bobwhite quail 

(Colinus virginianus)) and waterfowl species (e.g., mallard duck (Anas platyrhynchos)).

• Earthworm Subchronic Toxicity Test (850.3100), one species.

Data needs for environmental fate are:

• Environmental Chemistry Methods and Associated Independent Laboratory Validations: 

Water & Soil (850.6100)

2 Introduction

Warfarin is a first generation coumarin anticoagulant rodenticide. It uncouples oxidative 

phosphorylation depressing hepatic synthesis of prothrombin and clotting factors VII, IX and X 

and cause direct damage to capillary permeability. The ultimate effect is widespread internal 

hemorrhage (World Health Organization, 2010). The warfarin chemical case historically 

included both warfarin (PC code 086002) and its sodium salt (PC code 086003), but there are 

currently no active products registered under the sodium salt.

Anticoagulants are vitamin-K antagonists that disrupt normal blood-clotting mechanisms and 

induce capillary damage. Typically, death is delayed for four to ten or more days after a lethal 

dose is ingested, and animals may continue to feed and move about until shortly before death. 

Death results from hemorrhage, and exposed animals may exhibit behavior that may make them 

more susceptible to predation (Cox and Smith, 1992). This may result in secondary exposure to 

predatory animals. Warfarin is metabolized by vertebrate animals that have eaten bait, but some 

is sequestered in various body tissues for days or weeks. First generation anticoagulants tend to 

be less toxic and persistent in biological tissue than second generation anticoagulant rodenticides

and usually require several days of consecutive feedings to deliver a lethal dose.

EFED evaluated the most recent ecological risk assessments for warfarin in association with the 

updated toxicity, exposure, and usage information to determine if sufficient data are available 

and if further updates are needed to support registration review. In addition, EFED considered 
Page 6 of 51

the latest Agency science policies and risk assessment methodologies. The structure of warfarin

and its sodium salt, as well as the chemical names and other identifiers can be found in the 

chemical identity table in Section 5 of this document. 

3 Use Characterization

There is no national level usage data for for warfarin (086002). Table 1 lists the maximum use 

patterns (application rates, number of reapplications, etc.) for the labeled use sites for warfarin. 

The table is based on the Label Usage Report Package created by the Biological and Economics 

Analysis Division (BEAD) in support of Registration Review (USEPA, 2015). 

There are currently 23 Section 3 labels for warfarin. Warfarin is formulated as granules,

pellets/tablets, microencapsulated pellets and gel solution. The target pests include: Norway rat 

(Rattus norvegicus), black rat (R. rattus), house mouse (Mus musculus), meadow vole (Microtus 

pennsylvanicus), pine vole (M. pinetorum), montane vole (M. montanus), Eastern mole 

(Scalopus aquaticus), star-nosed mole (Condylura cristata), hairy-tailed mole (Parascalops 

breweri), coast mole (Scapanus orarius), broad-footed mole (S. latimanus), Townsend’s mole (S. 

towsendii), and deer and white-footed mouse (Peromyscus spp.). Concentrations in bait are 

0.025% warfarin.

Table 1. Label Use Information for warfarin based on BEAD’s summary report

Use

Single Max 

Application Rate Application 

Methods

Agricultural/Farm Premises; Agricultural/Farm Structures/Buildings and 

Equipment; Airports/Landing Fields; 

Commercial/Institutional/Industrial/Equipment (Indoor); 

Commercial/Institutional/Industrial/Equipment (Outdoor); 

Commercial/Transportation Facilities-Nonfeed/Nonfood; 

Household/Domestic Dwellings; Household/Domestic Dwellings Indoor 

Premises; Household/Domestic Dwellings Outdoor Premises; 

Nonagricultural Outdoor Buildings/Structures; Public Buildings/Structures 

(Vert. Pest Control); Ships and Boats

0.00025 

lb/placement

Bait station/ 

By hand

Animal Burrows, Harborages or Dens of Plague Reservoir hosts 0.00025 

lb/placement

Bait station/ 

Gel syringe/ 

By hand

Automobiles, Taxis, Limousines, Recreational Vehicles, & Tires; 

Commercial/Institutional/Industrial floors; Commercial Transportation 

Vehicles (All or Unspecified); Railroad Boxcars; Wide Area/General Indoor 

Treatment; Wide Area/General Outdoor Treatment (Public Health use)

0.00025 

lb/placement

Bait station

Golf Course Turf; Ornamental Lawns and Turf 0.00021 

lb/placement

Bait station/ 

Gel syringe
Page 7 of 51

4 Conclusions from Previous Risk Assessments

The Agency has conducted previous ecological risk assessments on warfarin that serve as a basis 

for this problem formulation. They are briefly summarized below. 

4.1 Endangered Species Assessments

An endangered species risk assessment for San Francisco Bay Species was completed for 

warfarin in 2011 (USEPA 2011) to address potential risk to the Salt marsh harvest mouse 

(SMHM) (Reithrodontomys raviventris), and Alameda Whipsnake (AW) (Masticophis lateralis 

euryxanthus) for which warfarin was alleged to be of concern in a complaint made by the Center 

for Biological Diversity against United States Environmental Protection Agency on May 30, 

2007 (Case No: 07-2794-JCS). Based on the best available information, the Agency made a 

“May Affect, and Likely to Adversely Affect” determination for the SMHM and AW from the 

uses of warfarin. Additionally, the Agency determined that there was the potential for 

modification of designated critical habitat for the AW from the use of warfarin.

4.2 Reregistration Eligibility Decision 

The Reregistration Eligibility Decision (RED) for warfarin was published in 1991 (USEPA, 

1991). The RED found that all uses of warfarin were eligible for reregistration with additional 

restrictions, such as expanded label language regarding use of protective bait stations, consistent 

label formats for residential use patterns, and restricted use of the 1% tracking powder 

formulations. 

4.3 Comparative Risk Assessment

“Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative 

Approach” (USEPA 2004) evaluated primary and secondary exposure of warfarin, among other 

rodenticides, to birds and mammals. The assessment determined that the greatest risk of 

warfarin use to non-target animals is via primary and secondary exposure to mammals. Risk 

associated with primary and secondary exposure to birds is not of concern. The 2004 assessment

also specified a number of factors contributing to uncertainty in assessing anticoagulant 

rodenticides. Those factors that contributed the most uncertainty were: (1) missing data, 

including acute, chronic, and secondary toxicity as well as data regarding retention of some 

active ingredients in the liver, blood, and other body tissues; (2) the variable quality and quantity 

of existing data on metabolism and retention times in rodents and non-target species; (3) specific 

use information by formulation, including typical amounts applied by use site, seasonally, and 

annually; distances applied from buildings; amounts used in rural versus urban areas; use by 

Certified Applicators versus homeowners and other non-certified applicators; and other such 

relevant information; (4) information on the number and species of birds and non-target 

mammals frequenting baited areas and the likelihood of their finding and consuming bait or 

poisoned primary consumers in the various use areas; (5) methods to determine liver 

concentration(s) and total body burdens of rodenticide that would corroborate death or even if
Page 8 of 51

such a cause-effect relationship is appropriate (e.g., the “threshold of toxicity” concentration); 

(6) not accounting for the impacts of sub-lethal effects on reproduction and non-target mortality 

(e.g., clotting abnormalities, hemorrhaging, stress factors including environmental stressors, such 

as adverse weather conditions, food shortages, and predation); (7) not accounting for 

bioaccumulation of repeated sub-lethal exposures to bait or poisoned rodents utilized as food by 

predators and scavengers; and (8) lack of incident reporting. 

4.4 Risk Mitigation Decision and Notice of Intent to Cancel

In 2008, EPA released the Risk Mitigation Decision for Ten Rodenticides (RMD) (EPA 2008, 

Docket ID EPA-HQ-OPP-2006-0955 at www.regulations.gov). Warfarin products were included 

in the list of ten rodenticides addressed in the 2008 document. The focus of the decision was:

1) To minimize children’s exposure to rodenticide products used in homes by requiring 

that all rodenticide bait products marketed to general and residential consumers be 

sold only with bait stations, with loose bait (e.g., pellets and meal) as a prohibited bait 

form. 

2) To reduce wildlife exposures and ecological risks, by requiring sale and distribution 

limits intended to prevent general consumers from purchasing residential use bait 

products containing four of the ten rodenticides that pose the greatest risk to wildlife 

(the second generation anticoagulants – brodifacoum, bromadiolone, difenacoum, and 

difethialone). Moreover, bait stations will be required for all outdoor, above-ground 

uses of these second generation anticoagulants.

EPA updated its previous risk assessment findings conducted in support of the May 2008 RMD 

through the application of additional effects and exposure data, use of additional exposure 

modeling, and quantitative risk assessment techniques for the four rodenticides subject to the 

Notice of Intent to Cancel (NOIC) (brodifacoum, difethialone, warfarin and bromethalin) and for 

two rodenticides that are likely alternatives (i.e., active ingredients included in products with 

RMD-compliant registrations for commensal rodent control, specifically, chlorophacinone and 

warfarin; bromethalin has both compliant and non-compliant registrations). To support the 

NOIC, EPA conducted an extensive assessment of the potential for primary and secondary 

effects of the rodenticides under evaluation. This work was brought before the Science Advisory 

Panel (SAP) in 2011 for review; meeting materials are available under docket number EPA-HQOPP-2011-0718 at www.regulations.gov. 

4.5 Drinking Water Assessments

Warfarin is applied as a bait; it tends to bind to organic matter, and little is expected to partition 

or runoff into drinking water sources; therefore, this route of exposure was not assessed during 

reregistration. Due to the limited use pattern (bait applications only) and the relatively low 

environmental exposure of warfarin, no drinking water assessment is anticipated during 

registration review unless use rates increase significantly or if a new use is proposed in the 

future.
Page 9 of 51

5 Environmental Fate and Transport 

Table 2 summarizes the physicochemical properties of warfarin based on data available in open 

literature. Warfarin is considered moderately mobile in the environment (based on FAO 2000 

mobility classification) and persistent in groundwater (USEPA, 2006). Volatilization from moist 

soil surfaces is not expected to be an important route of dissipation given an estimated Henry's 

Law constant of 2.8 X 10-9 atm-cu m/mole. Wafarin in soluble (17 mg/L). If released into 

water, warfarin is expected to adsorb to suspended solids and sediment based upon the Koc. 

Volatilization from water surfaces is not expected to be an important route of dissipation based 

upon this compound's estimated Henry's Law constant. An estimated bioconcentration factor

(BCF) of 24x suggests a low potential for bioconcentration in aquatic organisms. With respect to 

abiotic routes of degradation, warfarin is stable to hydrolysis with a half-life (pH 7, 25 °C) of 16 

years (Hazardous Substances Data Bank, HSDB).

Warfarin absorbs UV radiation to approximately 330 nm (Gore et al., 1971) and may therefore 

be susceptible to direct photolysis in the environment; however, no data were found concerning 

the possible photolysis rate.

With respect to biotic routes of degradation, warfarin (sodium salt) was considered stable with 

only13% degradation over a 28-day incubation period using activated sludge (Brorson et al., 

1994).

Warfarin was not detected (detection limit of 0.001 ppb) in the 84 water samples which were 

analyzed (Kolpin et al., 2002).

In California, groundwater samples were collected from 1231 sites between May 2004 and March 

2010 and analyzed for a broad suite of water quality constituents, including pharmaceutical 

compounds (warfarin included). The sites were located in 28 study units that represent a reasonably 

complete sampling of the range of hydrogeologic conditions and land-use patterns encountered in 

California. Seven compounds were not detected in groundwater samples in this study: albuterol, 

cotinine; dehydronifedipine, diltiazem, diphenhydramine, thiabendazole, and warfarin (Miranda and 

Belitz, 2011). 
Page 10 of 51

Table 2. Physical-chemical Properties of Warfarin 

Study Value and units Source

CAS Number 81-81-2 ASTER

SMILES Code c(ccc1C(O)=C2C(-

c(ccc3)cc3)CC(=O)C)cc1OC2=O

ASTER

Molecular weight 308.33 ASTER

Hydrolysis 16 years (pH 7, 25 oC) Ellington 1989

Solubility 17 mg/L at 20 oC Tomlin (ed.). 1997

Biodegradation Not readily biodegradable with only a 13% 

degradation (COD reduction) over a 28-day 

incubation period. Warfarin is reduced by 

Nocardia and Arthrobacter spp. to the alcohol.

Brorson et al. (1982)

Organic carbon Partition 

Coefficient (Koc)

701 L/kgoc (estimated) Lyman et al., 1990 

Based on measured log 

Kow of 2.70, and a 

regression-derived 

equation

Vapor pressure 1.16X10-7 mm Hg at 210C Hartley D, Kidd H, 

eds.1983

Henry’s law constant 2.8X10-9 atm-cu m/mole Calculated

Octanol-water partition 

coefficient (Kow)

2.70 Hansch et al.; 1995

Warfarin has the potential to move offsite through food consumption by target species, which 

travel away from the application site. Other than direct consumption of bait and secondary 

poisoning, other routes of environmental exposure are expected to be minimal. Although, 

warfarin is moderately adsorbed, movement of residues by means of leaching through the soil 

profile to an aquatic environment is possible. Further, warfarin is unlikely to volatilize, unlikely 

to move offsite due to method of application (mainly in bait stations), and due to the relatively 

low application rates (maximum of 0.003 lb a.i./placement), unlikely to runoff or leach 

substantially.

5.1 Transformation Products

Warfarin is reduced by Nocardia and Arthrobacter spp. to the alcohol.

6 Receptors

6.1 Toxicity Summary

Table 3 provides a summary of the taxonomic groups and the surrogate species tested to 

characterize the potential acute and chronic ecological effects of warfarin. In addition, the table 

provides a preliminary overview of the potential acute toxicity of warfarin by providing the acute 

toxicity classifications. No ecotoxicity data are available for any degradates of warfarin.
Page 11 of 51

Warfarin is slightly toxic to birds on an acute oral basis, moderately toxic to birds on a subacute 

dietary exposure basis, and very highly toxic to mammals on an acute oral and subacute dietary 

exposure basis. Studies evaluating chronic toxicity of warfarin to birds and mammals have not 

been submitted to the Agency. In addition, data on the toxicity of warfarin to terrestrial 

invertebrates and terrestrial plants have not been submitted to the Agency. 

Technical grade warfarin is classified as moderately toxic to freshwater fish and invertebrates on 

an acute exposure basis. Acute estuarine/marine fish and invertebrate data as well as chronic 

exposure effects data to warfarin for fish and invertebrates have not been submitted to the 

Agency. In addition, no toxicity data for aquatic plants were submitted to the Agency. 

Table 3. Most Sensitive Test Species Evaluated for Assessing Potential Ecological Effects of 

Warfarin.

Taxonomic 

Group

Study 

Type Tested Species Toxicity Endpoint

Acute Toxicity 

Classification/

NOAEC most 

sensitive 

endpoint(s)

MRID and 

Classification

Birds1

Acute oral 

(primary 

bait 

consumer)

Anas 

platyrhynchos

(Mallard)

LD50 = 621 mg/kg-bw Slightly toxic

00248782

(Acceptable)

Dietary

Colinus 

virginianus

(Northern 

bobwhite)

LC50 = 625 mg/kg-diet

Moderately toxic. 

15 day study, 

most deaths days 

3-7, one day 10

00153365

(Acceptable)

Chronic No data

Mammals

Acute oral 

(single 

dose)

Laboratory Rat LD50 = 3.0 mg/kg-bw Very highly toxic

05002272

(Acceptable)

Dietary 

(5-day 

exposure)

Laboratory Rat LC50 = 4.41 ppm

Very highly toxic. 

Observed 14 

days, mortalities 

days 3-9

Teeters 1981

(TMN 126)4

(Supplemental)

Chronic No data

Terrestrial 

invertebrates

Acute 

contact No data

Freshwater 

fish2 Acute

Rainbow trout 

(Oncorhynchus 

mykiss) 

96-hr LC50 > 16 mg/L 3 00156284

(Acceptable)

Chronic No data

Freshwater 

invertebrates

Acute

Water flea 

(Daphnia 

magna)

48-hr LC50 > 17 mg/L Slightly toxic3 00153368

(Acceptable)

Chronic No data

Estuarine/

marine fish

Acute and 

Chronic No data

Estuarine/

marine 

invertebrates

Acute and 

Chronic No data
Page 12 of 51

Table 3. Most Sensitive Test Species Evaluated for Assessing Potential Ecological Effects of 

Warfarin.

Taxonomic 

Group

Study 

Type Tested Species Toxicity Endpoint

Acute Toxicity 

Classification/

NOAEC most 

sensitive 

endpoint(s)

MRID and 

Classification

Terrestrial 

plants

Seedling 

emergence

No data

Vegetative 

vigor No data

Aquatic 

plants and 

algae

Vascular No data

Nonvascular No data

1 Birds represent surrogates for terrestrial-phase amphibians and reptiles. 2 Freshwater fish are used as surrogates for aquatic-phase amphibians. 3 Not acutely toxic below the reported level of solubility in distilled water (17 mg/L)

4 Teeters, W.R. (1981) Warfarin technical: Toxicity to Laboratory Rat: Test No. 126. (U.S. Environmental Protection Agency, 

Pesticides Regulation Div., Agricultural Research Center, Animal Biology Laboratory, unpublished report.)

6.2 Secondary Toxicity

In the available studies, birds and mammals were exposed to warfarin in whole or ground 

carcasses, which were usually those of rats or mice, or in fortified meat. Most prey animals were 

fed treated bait, although some were dosed orally. Mortality was included as a measurement 

endpoint in all studies. Some studies also reported signs of toxicosis (e.g., bleeding, prolonged 

blood-coagulation time, abnormal behavior, or regurgitation) in surviving test animals. Although 

exposure scenarios, test species, and the number of test animals varied among the studies, 

collectively these studies provide useful information to characterize secondary hazards from 

short-term exposure. Though these types of secondary exposure studies provide information on 

the potential effects from warfarin exposure that may occur under field conditions, it is often not 

possible to quantify the level of exposure (rodenticide residues in primary consumers or food 

consumption by secondary consumers) or the sensitivity of the exposed animals to the 

rodenticide.

The few studies available for warfarin indicate that there are few adverse secondary effects for 

birds at the concentrations that were tested (50 or 500 mg a.i. kg-bait). In a review of the open 

literature warfarin studies examining secondary effects to birds (4 studies), 2 (5%) out of a total 

of 25 individuals died; no adverse signs were reported in the survivors (Table 4). Test species 

were tawny owl (Strix aluco), black-billed magpie (Pica pica), barn owl (Tyto alba), and 

Eurasian buzzard (Buteo buteo). Laboratory studies for secondary toxicity to mammals suggest 

that warfarin is more toxic to mammals than birds. In 7 studies, 9 (9%) of 100 individuals died 

after eating warfarin-treated rodents (Table 5). Dead animals included 3 mink, 3 least weasels 

(Mustela nivalis), and 3 dogs while raccoons and European ferrets did not exhibit any mortality 

or other adverse toxic symptoms typically associated with warfarin. 
Page 13 of 51

Table 4. Observed Effects of Warfarin on Birds Consuming Contaminated Carcasses

Predator/scav

enger species Prey offered to birds No. prey offered daily per bird

No. days birds 

exposed

No. birds 

exposed

No. birds 

dead

No. survivors 

with signs of 

warfarin 

toxicitya

Reference

(MRID)

Tawny owl Mice fed bait for 3 

days 1 every other day 9028

4

2c

0

0

0

0

Townsend et al. 

1981

Black-billed 

magpie

Rats fed 0.05% baitc

for 4-7 days Ad libitum 5 14 0 0 Mach 1997

Barn owl Rats fed 0.005% baitc 4 total 5-7 4 2 nr Lee 1994b

Eurasian 

buzzard Rat/mouse Ad libitum 18 1 0 nr Telle 1955b

a eb = external bleeding; ih = internal hematoma; bl = bleeding (unspecified); ct = increased blood coagulation time; nr = not reported b Cited in US EPA (2004) Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative Approach

c rat and mouse registered baits in the U.S. are 0.025% a.i. and 0.054% a.i
Page 14 of 51

Table 5. Observed Effects of Warfarin on Mammals Consuming Contaminated Carcasses

Predator/scav

enger species

Prey offered to 

mammals

No. prey offered 

daily per 

mammal

No. days 

mammals 

exposed

No. 

mammals 

exposed

No. 

mammals 

dead

No. survivors 

with signs of 

warfarin 

toxicitya

Reference

(MRID)

Mink Nutria fed 0.025% bait 

for at least 7 days Ad libitum 8-15 3 3 No survivors Evans and Ward 1967b

Mink

Rabbits fed 25 or 67 

mg a.i./kg baitc for 5 

weeks

Ad libitum 28 50 0 0 Aulerich et al 

1987

Least weasel

Mice fed 0.001% bait,

0.005% bait,

Or 0.02% bait for 3 

daysc

Ad libitum

90

29-90

12-57

2

2

2

0

1

2

2 (ct)

1 (ct)

No survivors

Townsend et al. 

1984

European 

ferret

Prairie dogs fed 0.05% 

baitc for 15 days 1 7 10 0 0

Carlet and Mach 

1997

MRID# 

44995003

European 

ferret

Prairie dogs fed 0.05% 

baitc for 15 days Ad libitum 5 10 0 0

Mach 1998

MRID# 

44820001

Racoon Rats fed 0.025% bait 

for 5 days

1

3

5

5

8

10d

0

0

0

0 EPA 1982

Dog 

(domestic)

Nutria fed 0.025% bait 

for at least 7 days Ad libitum 8-16 3 1 2 (eb/ct) Evans and Ward 1967b

Dog 

(domestic)

Mice fed 0.025% bait,

0.05% bait,

Mice dosed with 2.5 

mg a.i.,

10 mg a.i.,

40 mg a.i.

4-10

10

1

1

1

56

56

56

25

17

4

1

1

1

1

0

0

0

1

1

0

0

0

No survivors

No survivors

Prier and Derse 

1962b

a eb = external bleeding; ih = internal hematoma; bl = bleeding (unspecified); ct = increased blood coagulation time; nr = not reported b Cited in US EPA (2004) Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative Approach

c rat and mouse registered baits in the U.S. are 0.025% a.i.

d the 10 test animals included the 8 individuals from the first trial plus 2 additional untested individuals
Page 15 of 51

6.3 Incident Database Review

A thorough incident collection and analysis for all anticoagulant rodenticides was completed in 

2013. A summary of the 10 warfarin wildlife incidents reported with a certainty classification of 

“possible”, “probable”, or “highly probable” is included in Table 6. These classifications mean

that, at a minimum, there was supporting evidence (e.g., hemorrhaging) and/or residue data to 

indicate that the wildlife involved in the incident were adversely affected by exposure to an 

anticoagulant rodenticide and/or an independent wildlife specialist, based on findings of a 

necropsy examination and toxicological analysis, identified an anticoagulant rodenticide as the 

cause of death in the incident report. The reported avian species include a bobwhite quail and 

carnivore/scavenger birds that include the bald eagle, peregrine falcon, great horned owl, and 

Cooper’s hawk. The reported mammalian species include squirrels. 

Although most of the reported wildlife incidents involve animals found dead, there are several 

rodenticide incidents that involve incapacitated animals (most of which died after being found). 

They demonstrate that animals exposed to rodenticides may be incapacitated in ways that would 

almost certainly make them more vulnerable to predators and accidental deaths (e.g., car or 

window strikes). If an animal dies due to predation or an accident, their death may not 

necessarily be attributed to a pesticide, even if it is a contributing factor.

Table 6. Wildlife Mortality Incidents for Warfarin Reported in the EIIS Database

Incident 

ID Year Legality Certainty State Land Use

Generic 

Species 

(Number 

Affected)

Comments

CEE-TV 

# 61108 1998 N/R Probable NY N/R Cooper’s 

Hawk (1)

Warfarin detected in liver at 0.73 

ppm

I003350-

001 1995 N/R Probable NY Residential Bald Eagle 

(1)

Warfarin detected in liver at 1.4 

ppm. Second year male 

diagnosed with warfarin 

intoxication. Gross pathologyhemorrhage in alimentary canal.

I004169-

001 1981 Registered Possible VA Agricultura

l

Bobwhite 

Quail (3)

Gross pathology found lesions in 

the birds consistent with 

warfarin poisoning; no analytical 

data were included in the report.

I006306-

016 1986 N/R Highly 

Probable NJ N/R Peregrine 

Falcon (1)

Warfarin detected in the liver at 

1.48 ppm

I008146-

001 1998 Registered 

Use Probable NY N/R

Great 

Horned Owl 

(1)

Warfarin detected in liver at 0.73 

ppm

I011130-

001 2000 N/R Probable GA Agricultura

l

Bald Eagle 

(1)

Chemical residues were found in 

the gut contents, or bait material 

and biological or biochemical 

evidence
Page 16 of 51

Table 6. Wildlife Mortality Incidents for Warfarin Reported in the EIIS Database

Incident 

ID Year Legality Certainty State Land Use

Generic 

Species 

(Number 

Affected)

Comments

I013810-

014 1971 N/R Probable NY N/R Squirrel (1) --

R000-02-

054 1981 N/R Probable NY N/R Squirrel (1)

Warfarin detected in the liver at 

0.22 ppm. Gross pathologypallor of muscle and/or internal 

organs, inter- and intramuscular 

hemorrhages, hemorrhage and/or 

serum in pericardial sac. 

7 Exposure Pathways of Concern

The environmental fate properties and use patterns of warfarin indicate that non-target 

consumption of bait, consumption of individuals that have consumed bait, represent potential 

transport mechanisms of warfarin to terrestrial organisms. 

Drinking water and inhalation exposure pathways were screened using the SIP (Screening 

Imbibition Program) and STIR (Screening Tool for Inhalation Risk) screening methods SIP and 

STIR are described in detail at: http://www2.epa.gov/pesticide-science-and-assessing-pesticiderisks/models-pesticide-risk-assessment#terrestrial. The drinking water pathway was found not to 

be an exposure pathway of potential concern for acute risks to birds due to low solubility of 

warfarin relative to toxicity. However, the drinking water pathway is an exposure pathway of 

potential concern for acute risks to mammals. Chronic risks to mammals and birds cannot be 

excluded because there is insufficient data on chronic toxicity. The inhalation exposure pathway 

was found not to be an exposure pathway of concern for birds due to the low volatility of 

warfarin. SIP and STIR results are presented in Appendix B.

8 Analysis Plan

8.1 Stressors of Concern

8.1.1 Ecological Risk Assessment

For this registration review, the stressor of ecological concern for terrestrial organisms is the 

parent compound, warfarin.
Page 17 of 51

8.1.2 Drinking Water Assessment

A drinking water assessment isn’t expected to be conducted during the registration review because

bait is contained in stations, and therefore not available for runoff.

8.2 Measures of Exposure 

Bait is contained in stations, and therefore not available for runoff, thus exposure of aquatic

environment is unlikely. Available toxicity data indicates that warfarin is not toxic to aquatic 

receptors up to the limit of solubility. In addition, the use pattern is baits only and not large scale 

broadcast treatments. For these reasons, EFED does not expect to conduct a quantitative aquatic 

risk assessment during registration review.

For the warfarin registration review risk assessment, it will be assumed that terrestrial animals 

could be exposed in two different pathways. Animals may directly consume bait (primary 

consumption), or animals may consume contaminated carcasses either killed or scavenged by the 

consumer (secondary consumption). Both approaches and the expected exposure levels are 

detailed below. It is important to note that these methods differ from what is typically done in 

EFED risk assessments, but they are appropriate for warfarin based on the use parameters and 

environmental exposures described previously and consistent with other EFED risk assessments 

for rodenticides.

8.2.1 Estimating Primary Terrestrial Exposure

EFED’s exposure assessment for the rodenticides differs from that for most other pesticides. For 

a rodenticide, the bait itself is the potential food item of concern. Thus, the amount of active 

ingredient in the formulated bait is used as an estimated environmental concentration (EEC). 

This information is used to estimate the amount of grain bait that birds and mammals of various 

sizes need to consume to obtain a dose expected to be lethal to 50% of the individuals in the 

population (i.e., LD50 dose). Estimates of food-ingestion rates (g dry matter per day) are 

determined from established allometric equations presented in the Wildlife Exposure Factors 

Handbook (USEPA 1993). The concentration of warfarin in grain bait is also used to estimate 

initial dietary exposure (mg a.i. per kg in bait) which in turn is used to calculate avian and 

mammalian dietary RQs. 

8.2.1.1 Expected Warfarin Accumulation through a Single Feeding on Bait 

Exposure through bait consumption will be calculated using two methodologies. For the first 

method, warfarin exposure is calculated as mg a.i./kg-bwt, where kg-bwt is the kilograms of the 

consuming individual for three standard weight classes of passeriforms and rodents. Exposure 

(food dry weight consumption) estimates were derived using allometric equations from USEPA 

(1993). The allometric equations for passeriform birds and rodent mammals were used as these 

would best approximate those individuals with high potential for consuming grain and they 
Page 18 of 51

would give the most conservative exposure estimates. Food dry weight was converted to wet 

weight assuming the bait contained 10% water, similar to the assumption that seeds for wildlife 

consumption contain 10% water (USEPA 1993). Formulas for calculation of dose estimates are 

provided in Table 7, and warfarin exposure estimates (on a dose basis) are provided in Table 8. 

RQs are generated by dividing these exposure estimates of warfarin (mg a.i./kg-bwt) for a given 

weight class by the most conservative toxicity endpoint for the relevant taxa scaling adjusted for 

the default body weights. RQs using these exposure estimates were generated for acute bird and 

mammal (using LD50 data) non-targets.

Table 7. Formulas for Calculation of Daily Warfarin Intake based on Consumption of Bait.

Passeriform bird food intake (g, dry weight): FI (g dry-wt/day) = 0.398 * Wt(g)0.850

Rodent mammal food intake (g, dry weight): FI (g dry-wt/day) = 0.621 * Wt(g)0.564

Food intake (g, wet weight): FI (g wet-wt/day) = FI (g dry-wt/day) / 0.90

Warfarin intake (mg a.i./kg-bwt/day) = FI (g wet-wt/day) * mg a.i./kg-bait / Wt(g)

Where: Wt(g) = weight (in grams) of the bird or mammal consumer

mg a.i./kg-bait = 50 or 100 depending on warfarin concentration in bait

Table 8. Expected Daily Warfarin Intake for Default Bird and Mammal Weights based on 

Consumption of Bait.

Weight 

(g)

Food intake 

(g drywt/day)

Food intake 

(g wetwt/day)

Warfarin intake (mg a.i./kg-bwt/day)

Bait concentration = 

250 mg a.i./kg-bait

Passeriform 

Birds*

20 5.1 5.6 63.5

100 19.9 22.2 49.9

1000 141.2 156.9 35.3

Rodent 

Mammals

15 2.9 3.2 47.7

35 4.6 5.1 32.9

1000 30.6 34.0 7.6

*surrogate for reptiles and terrestrial-phase amphibians

8.2.1.2 Expected Warfarin Accumulation through Multiple Feedings on 

Bait 

Available data on the retention times for warfarin are provided in Table 9. In contrast to the 

other anticoagulants, warfarin is extensively metabolized, and the major route of excretion is in 
Page 19 of 51

the urine. Meehan (1984) states that approximately half the warfarin consumed by a rat remains 

in the body after 6 hours, suggesting that up to 50% may be eliminated in this time period. EPA 

(1982) noted that only 7.6% of the warfarin consumed in bait by 11 rats remained in the carcass 

after a 5-day feeding period. Ford (1993; cited in Poché and Mach 2001) reported a half-life of 

42 hours in the gastro-intestinal tract, which supports the conclusion that a portion of the 

consumed warfarin dose is rapidly eliminated from the body. However, there is evidence that 

warfarin residues that are not excreted though urine and fecal matter may accumulate in various 

body tissues, especially the liver. Though warfarin concentrates in the liver, measurable amounts 

have also been found in the adrenal glands, lungs, bone marrow, kidneys, and lymph nodes 

(Machlin 1984). 

Vandenbroucke et al. (2008) orally dosed groups of mice with 5,985 μg a.i./mouse wafarin, 

which is approximately one-half of the LD50 dose. Warfarin was then assayed in liver tissue and 

blood plasma from euthanized mice at various times up to 21 days after dose administrations. 

The study authors estimated the elimination half-life of warfarin in liver tissue to be 66.8 days 

and the half-life in blood plasma to be 14.9 days. 

Fisher et al. (2003) orally dosed 20 rats by gastric intubation with a single dose of 1.0 mg a.i./kg 

warfarin. Rats were monitored for 5 days after dosing for symptoms of anticoagulant poisoning. 

Groups of six or seven rats were euthanized at week 1, 18, and 24. The livers were removed 

post-mortem for analysis of warfarin residue by HPLC. Warfarin elimination half-life in rat liver 

tissue was estimated to be 26.2 days. 

The discrepancies between the half-lives estimated in Vandenbroucke et al. (2008) and Fisher et 

al. (2003) may be partially a result of the different test organisms as there is some indication that 

elimination times for warfarin may vary among species. For example, O’Brien et al. (1987; cited 

in Eason et al. 2001) found comparatively rapid clearance of warfarin in pigs, with 

concentrations declining to very low levels after approximately 30 days. In addition, Wantabe et 

al. 2010 examined the differences in metabolism of warfarin in birds in order to study differences 

in species sensitivities to this rodenticide. Liver samples from domestic chickens (Gallus gallus), 

osteriches (Struthio camelus), mallard ducks (Anas platyrhunchos), snowy owls (Bubo 

scandiacus) and a great horned owl (B. virginianus) were used to measure the metabolism of 

warfarin to its hydroxylated degradates. Results of the study indicated that owls had the lowest 

metabolism of warfarin. Therefore, relative to the other species tested, owls may have a limited 

ability to detoxify warfarin. This could potentially lead to increased warfarin sensitivity in owls, 

relative to EPA's typical test species (e.g., mallard ducks). 

Half-life values for blood plasma also vary greatly among species. Breckenridge et al. (1985) 

intravenously dosed male New Zealand white rabbits with 20 μmol/kg warfarin. Blood samples 

were taken at regular intervals and analyzed for wafarin concentration. The study authors 

reported a plasma elimination half-life for warfarin of 5.6 hours in rabbits. 
Page 20 of 51

Table 9. Retention of Warfarin in Blood and Liver

Rodenticide Species Dose (mg 

a.i./kg) # doses Blood t1/2a(days)

Liver 

retentiona,b

(days)

Reference 

(MRID)

Warfarin Mouse 5985 

μg/mouse 1 14.9 66.8 (t1/2) Vandenbroucke et al. 2008

Warfarin Rat unknown unknown

0.7 (male)

1.2 

(female)

NA Pyrola 1968f

Warfarin Rat 1.0 1 NA 26.2 (t1/2) Fisher et al. 2003 

(48190801)

Warfarin Rabbit unknown unknown 0.2 NA Breckenridge et al 

1985f

Warfarin Possum unknown unknown 0.5 NA Eason et al. 1999d

Warfarin Pig unknown unknown NA 30-40 O’Brien et al 1987f

a t1/2 for plasma and liver is the elimination half-life b liver retention is expressed as either the time period for which residues persist or as the elimination half-life c the elimination half-life of 350 days is for a single oral dose of 0.02 or 0.15 mg a.i./kg; elimination was not biphasic d the elimination half-life of 128 days is the terminal phase for a single oral dose of 0.35 mg a.i./kg; elimination was 

biphasic

e Cited in US EPA (2004) Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative 

Approach

f cited in Eason et al. 2001

As indicated previously, warfarin typically causes mortality several days after ingestion, which 

may allow target animals consume bait for several days before dying. This can lead to doses that 

far exceed the lethal dose. A compound that accumulates in body tissues may pose greater risk to 

primary and secondary consumers, especially if repeated sublethal exposure results in the 

accumulation of a lethal dose or if additional exposures occur before the lethal dose has taken its 

effect (i.e., leading to a dose that is beyond what is sufficient to cause mortality). 

Cumulative rodenticide doses for animals consuming bait for six consecutive days were also 

calculated using formulae in Table 10. This analysis assumed that 100% of the daily diet of the 

animals is represented by the rodenticide bait and that they eliminate the warfarin with a half-life 

of 66.8 days based on the highest definitive liver half-life value (Table 9). In the formula, the 

variable “C” represents the concentration of the pesticide in the bait. The elimination rate 

constant (k) was calculated using the estimated warfarin half-life (t1/2 = 66.8 days), and food 

intake (FI) was calculated according to the allometric equation for each taxonomic group (Table 

7). The resulting cumulative body burden concentrations of warfarin are presented in Table 11. 

Different half-life assumptions based on available data may be used to further characterize risk in 

the assessment.
Page 21 of 51

Table 10. Formulas for Calculation of Warfarin Body Burden based on Consumption of 

Bait for Six Consecutive Days.

D D e FI C k

t t

* * = ( 1) + −

−

( ) 1/ 2 k = ln 2 t

Table 11. Calculated warfarin body burden in avian and mammalian consumers 

of bait after six days of exposure

Body weight 

(g)

Bait concentration = 250 mg a.i./kg-bait

Passerine Generic Bird

20 371.2 330.0

100 291.6 189.9

1000 206.4 85.0

Rodent Generic Mammal

15 278.7 212.1

35 192.8 182.4

1000 44.7 100.5

8.2.1.3 Expected Warfarin Exposure based on Bait Concentration

The second exposure method for primary consumption of bait results in a diet concentration of 

250 mg a.i./kg-bait (concentrations of warfarin as packaged in bait). RQs are calculated using 

this estimate of dietary concentration and the LC50 (mg a.i./kg-diet) available from dietary 

toxicity studies. RQs using these exposure estimates were generated for acute bird and mammal 

(using LC50 data) non-targets.

8.2.2 Estimating Secondary Terrestrial Exposure

Secondary exposure analysis (from consumption of contaminated individuals) requires 

consideration of residues in tissues of target and non-target organisms that are commonly 

consumed by predators and scavengers. Moreover, it is important to know how long the residue 

persists in body tissues. Residue concentrations for non-target animals fed warfarin are available 

in open literature. Design and methodology vary among studies, adding unknown variability to 

the results and analysis. Pending development of additional methods and testing requirements for 

such studies, these tests provide the best data available. 

The determination of warfarin intake by individuals consuming warfarin poisoned animals or 

carcasses is calculated in a manner similar to the approach for individuals consuming bait 

(Section 8.2.2.1). Empirical residue data are used instead of bait concentration of warfarin 

(Table 11). Warfarin body burdens in carcasses collected from field and laboratory studies were 

determined in mammals, after exposure to warfarin bait. Data are available for a variety of 

small- and medium-sized mammalian granivores and omnivores. No data were identified for 

other exposed taxonomic groups (e.g., birds and reptiles). For all studies, it was assumed the 

concentrations were reported using wet weights of the mammals. 
Page 22 of 51

In laboratory studies, mean warfarin residues in mammalian carcass ranged from 0.038 to 104 

mg a.i./kg-bw. The relatively high mean residue values are most likely a result of the study 

design where Aulerich et al. (1987) fed rabbits low doses of warfarin bait for an extended period 

of time. This study indicates that mammals consuming small amounts of warfarin bait over an 

extended period are able to survive poisoning, perhaps because they are capable of building a 

tolerance to warfarin in this situation, or because they become more effective at metabolizing the 

compound. This study also suggests that these mammals have the potential to accumulate large 

amounts of warfarin residue (82-104 mg a.i./kg-bw, Table 12) which may make them 

significantly more toxic to secondary consumers than a mammal that consumed a single lethal 

dose. Because of the lack of data on warfarin residues in birds, terrestrial-phase amphibians and 

reptiles, it is assumed the mammalian body burden data would be relevant for all the evaluated 

taxonomic groups. Since the registered bait blocks contain 0.025% (250 mg a.i/kg-bait), the low 

dose values found in the majority of the residue studies, aside from the Aulerich data, likely do 

not reflect true field conditions either. For the registration review assessment, the body residue 

level of 2.95 mg a.i./kg-carcass (Townsend et al. 1984) will be used because the bait 

concentration used in the Towsend et al. study (200 mg a.i./kg bait) is the closest approximation 

of the concentration found in the registered warfarin baits. Different assumptions of body residue 

levels in primary consumers based on the available data may be used to further characterize risk 

in the assessment. 

Table 12. Warfarin Residue Levels in Mammalian Primary Consumers.

mg ai/kg 

bait

Target 

species Site Sample size Days exposed

Mean wholecarcass residue 

(mg a.i./kg-bw)

Reference

200a Mouse Laboratory 17 3 2.95 ± 0.26 (SE) Townsend et al. 

1984 

67a Rabbit Laboratory Not reported 35 104 Aulerich et al. 1987

50a Mouse Laboratory 62 3 1.63 ± 0.1 (SE) Townsend et al. 

1981

50a Mouse Laboratory 18 3 1.58 ± 0.1 (SE) Townsend et al. 

1984

25a Rabbit Laboratory Not reported 35 82 Aulerich et al. 1987

10a Mouse Laboratory 15 3 0.42 ±0.04 (SE) Townsend et al. 

1984

Warfarin exposure through carcass consumption is calculated as mg a.i./kg-bwt, where kg-bwt is 

the kilograms of the consuming individual for three weight classes of birds and mammals. For 

this analysis, bird weight classes of 50, 1000, and 2000 g individuals and mammal weight classes 

of 50, 1000, and 3000 g individuals are used to better represent the larger size of carnivores and 

scavengers relative to the full range of bird and mammal weights. The measured maximum body 

burden in the prey is then used to estimate rodenticide exposure in the secondary consumer using 

the general food intake allometric equations described in Section 8.2.1 above. Secondary 

consumers are assumed to be mammals weighing 50g, 1000g, or 3000g, or birds weighing 100g, 

1000g, or 5000g. For example, American kestrels range from 100-150g, red-tailed hawks range 

from 900-1000g and bald eagles range from 4000-5000g (Dunning 1984). Exposure (food dry 
Page 23 of 51

weight consumption) estimates are derived using the generic bird and mammal allometric 

equations from (EPA 1993). Food dry weight was converted to wet weight assuming the 

consumed prey/carcass contained 68% water (USEPA 1993). Formulas for calculation of dose 

estimates are provided in Table 13, and warfarin exposure estimates (on a dose basis) are 

provided in Table 14. RQs using these exposure estimates will be generated for birds and 

mammals (using LD50 data).

Table 13. Formulas for Calculation of Daily Warfarin Intake for Birds and Mammals 

based on Consumption of Carcasses.

Bird food intake (g, dry weight): FI (g dry-wt/day) = 0.648 * Wt(g)0.651

Mammal food intake (g, dry weight): FI (g dry-wt/day) = 0.235 * Wt(g)0.822

Food intake (g, wet weight): FI (g wet-wt/day) = FI (g dry-wt/day) / 0.32

Warfarin intake (mg a.i./kg-bwt/day) = FI (g wet-wt/day) * 2.95 mg a.i./kg-carcass / 

Wt(g)

Where: Wt(g) = weight (in grams) of the bird or mammal consumer

Table 14. Expected Daily Warfarin Intakes for Carnivorous Birds and Mammals based on 

Consumption of Contaminated Carcasses

Weight (g) Food intake 

(g dry-wt/day)

Food intake 

(g wet-wt/day)

Warfarin intake 

(mg a.i./kg-bwt/day)1

Birds* 50 8.3 25.8 1.55

1000 58.2 181.7 0.55

2000 91.3 285.4 0.43

Mammals 50 5.9 18.3 1.10

1000 68.7 214.7 0.64

3000 169.5 529.8 0.53

*surrogate for reptiles and terrestrial-phase amphibians 1 See Table 14 for derivation.

The second exposure method for consumption of contaminated carcasses results in a carcass 

concentration of 2.95 mg a.i./kg-carcass (maximum measured concentration of warfarin in 

carcasses). RQs using these exposure estimates will be generated for birds and mammals (using 

LC50 data) exposures.

8.2.3 Estimating Additional Environmental Exposures

Screening level calculations suggest that the drinking water pathway and inhalation pathways 

will not pose significant risks to birds and mammals (Appendix B). If additional information 

indicates there may be concerns, these pathways will be re-evaluated at the time of the risk 

assessment. 
Page 24 of 51

No monitoring data in surface water, in groundwater or in air were found from the USGS 

NAWQA program (http://water.usgs.gov/nawqa), the California Department of Pesticide 

Regulation CDPR (http://www.cdpr.ca.gov/docs/emon/surfwtr/surfcont.htm) or from the USEPA 

STORET program. Water monitoring programs such as these generally monitor for agricultural 

pesticides and typically do not include analysis for rodenticides such as warfarin. If water 

monitoring data are identified at the time the risk assessment is conducted, these data will be 

used for additional exposure characterization

8.3 Measures of Effect 

Toxicity data presented in Section 6 of this problem formulation will be used to calculate risk 

quotients. Any additional information submitted by the registrant or found in the open literature 

prior to conduct of the risk assessment will also be considered. The open literature studies are 

identified using EPA’s ECOTOXicology database (ECOTOX) (USEPA, 2007), which employs a 

literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and 

wildlife. The evaluation of both sources of data can also provide insight into the direct and 

indirect effects of pesticides on biotic communities from loss of species that are sensitive to the 

chemicals and from changes in structure and functional characteristics of the affected 

communities.

9 Endangered Species Assessment

Consistent with EPA’s responsibility under the Endangered Species Act (ESA), the Agency will 

evaluate risks to federally listed threatened and endangered (listed) species from registered uses 

of pesticides in accordance with the Joint Interim Approaches developed to implement the 

recommendations of the April 2013 National Academy of Sciences (NAS) report, Assessing 

Risks to Endangered and Threatened Species from Pesticides. The NAS report outlines 

recommendations on specific scientific and technical issues related to the development of 

pesticide risk assessments that EPA and the Services must conduct in connection with their 

obligations under the ESA and FIFRA. EPA will address concerns specific to warfarin in 

connection with the development of its final registration review decision for warfarin. 

In November 2013, EPA, the U.S. Fish and Wildlife Service, National Marine Fisheries (the 

Services), and USDA released a white paper containing a summary of their joint Interim 

Approaches for assessing risks to listed species from pesticides. These Interim Approaches were 

developed jointly by the agencies in response to the NAS recommendations, and reflect a 

common approach to risk assessment shared by the agencies as a way of addressing scientific 

differences between the EPA and the Services. Details of the joint Interim Approaches are 

contained in the November 1, 2013 white paper, Interim Approaches for National-Level 

Pesticide Endangered Species Act Assessments Based on the Recommendations of the National 

Academy of Sciences April 2013 Report.
Page 25 of 51

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, this ecological problem formulation supporting the Preliminary Work 

Plan for warfarin does not describe the specific ESA analysis, including effects determinations 

for specific listed species or designated critical habitat, to be conducted during registration 

review. While the agencies continue to develop a common method for ESA analysis, the 

planned risk assessment for the registration review of warfarin will describe the level of ESA 

analysis completed for this particular registration review case. This assessment will allow EPA to 

focus its future evaluations on the types of species where the potential for effects exists, once the 

scientific methods being developed by the agencies have been fully vetted. Once the agencies 

have fully developed and implemented the scientific methods necessary to complete risk 

assessments for listed species and their designated critical habitats, these methods will be applied 

to subsequent analyses of warfarin as part of completing this registration review.

10 Endocrine Disruptor Screening Program

Warfarin was not included in the first group or the second group of chemicals issued an order to 

conduct Tier 1 EDSP testing. For additional information the EDSP program, visit

http://www2.epa.gov/endocrine-disruption/endocrine-disruptor-screening-program-edspoverview. 

11 Preliminary Identification of Data Gaps 

11.1 Environmental Fate

Since the data used in this assessment were derived from open literature and were not based on 

USEPA-guideline studies, warfarin’s persistence and mobility have not been fully 

characterized. Should the use rate increase significantly or if a new use is proposed in the future, 

guideline studies may be necessary for a better understanding of warfarin’s persistence and 

mobility.
Page 26 of 51

Available Environmental Fate Data for Warfarin.

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies (MRID)

Study 

Classification

Are data needed 

for risk 

assessment?

Current Additional Data 

Need

835.2120 Hydrolysis (None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.2240 Aqueous 

photolysis

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.2410 Soil photolysis (None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.4100 Aerobic soil 

metabolism

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.4200 Anaerobic soil 

metabolism

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.4300 Aerobic aquatic 

metabolism

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.4400 Anaerobic 

aquatic 

metabolism

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.
Page 27 of 51

Available Environmental Fate Data for Warfarin.

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies (MRID)

Study 

Classification

Are data needed 

for risk 

assessment?

Current Additional Data 

Need

835.1230

835.1240

Adsorption/ 

desorption and 

leaching

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

835.6100 Terrestrial field 

dissipation

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

Storage Stability 

Study (TFD)

(None) (N/A) No

850.1730 Fish 

bioconcentration

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap was 

not identified as these data 

are not necessary for risk 

assessment at this time.

Environmental

Chemistry

Method: Water

850.6100

Analytical 

method in water 

and independent 

laboratory 

validation 

(None) (N/A) Yes Enforcement analytical 

methods are being routinely 

requested in registration 

review for use by state lead 

agencies.

Environmental

Chemistry

Method: Soil

Analytical 

method in soil 

and independent 

laboratory 

validation

(None) (N/A) Yes Enforcement analytical 

methods are being routinely 

requested in registration 

review for use by state lead 

agencies.

11.2 Ecological Effects

Tables 15 and 16 identify ecological effects studies by MRID that offer data for each guideline 

requirement, as well as study classifications and whether or not further data are needed in order 

to support risk assessment. 

Currently, inadequate data are available to further characterize the differential toxicity among 

bird species. In addition, there is evidence of different or multiple modes-of-action of 

rodenticides in different taxa. Additional toxicity data on a wider range of species or data 

exploring mode-of-action would be beneficial to better understand the natural variation and to 

improve confidence in the assessment of risk to non-target species. 

No data are available to assess the effects of long-term, low-dose exposure of warfarin on avian 

reproduction (OCSPP 850.2300) or survival. Avian reproduction data are available for another 

registered anticoagulant rodenticide, chlorophacinone that highlights the potential for effects 

from long-term, low-dose exposure. For chlorophacinone, mallard ducks exposed to dietary 

concentrations for five days had an LC50 = 172 mg/kg-diet (MRID 41513103); however, nine of 
Page 28 of 51

16 (56%) adult females died exhibiting symptoms of anticoagulant poisoning during the avian 

reproduction study eating a diet containing only 0.96 mg a.i./kg-diet (MRID 489904002). EFED 

recommends that additional data on effects of long-term low-dose exposure of warfarin to birds 

through extended exposure dietary studies and avian reproduction studies be requested. 

No data are available to assess of the toxicity of warfarin to terrestrial invertebrates. EFED does 

not have concerns for warfarin exposure to pollinators such as bees and butterflies, as expected 

exposures would be low. Warfarin is not applied as a spray; therefore, expected exposure on 

plants, including flowers, would be low. Pollinators would not be expected to feed on live 

animals or carcasses that may have been contaminated with warfarin. Warfarin exposure to 

terrestrial invertebrates may occur if individuals feed on the bait, feed on live animals 

contaminated with warfarin residues, or feed on carcasses with warfarin residues. No terrestrial 

invertebrate incidents have been reported for warfarin.

The earthworm LC50 values for bromadiolone, a second generation rodenticide, at 24 h and 48 h 

were 145.70 μg/cm2 and 25.03 μg/cm2, respectively, and at 14 d and 28 d were 449.958 mg/kgsoil and 105.593 mg/kg-soil, respectively (Liu et al. 2015). Incidences of terrestrial invertebrates 

consuming bait containing an anti-coagulant rodenticide and subsequently excreting it have been 

documented (Fisher et al. 2007; Hernandez-Moreno et al. 2013). Toxicity of warfarin to 

terrestrial invertebrates is unknown; however, there is evidence to suggest that toxicity may 

occur and that the exposure pathway for secondary exposure is complete. EFED is not requesting 

the full suite of pollinator protection studies as outlined in recent guidance, at this time 

(http://www2.epa.gov/pollinator-protection/pollinator-risk-assessment-guidance). However, 

EFED does request an earthworm toxicity study for warfarin and any existing data that 

demonstrate toxicity, or lack of toxicity, to warfarin for terrestrial invertebrates. 

Although they are technically considered data gaps, EFED does not recommend requesting 

terrestrial plant, aquatic plant, chronic fish, or chronic aquatic invertebrate toxicity data for 

warfarin at this time since these data would not be expected to change the conclusions of the 

registration review risk assessment. There remains uncertainty in the level of risk for each of 

these taxonomic groups given the missing data; however, the expected exposures for the 

currently registered use patterns will be relatively low:

• Terrestrial plants - No data are available to assess of the toxicity of warfarin to 

terrestrial plants; however, exposure to plants is also expected to be low since there is no 

spray application and the material is applied as a formulated bait or a treated grain. 

Warfarin binds strongly to organic material (i.e., the formulated bait or grain) and little 

is expected to be available for runoff or leaching. No plant incidents have been reported 

for warfarin.

• Aquatic plants – No data are available to assess the toxicity of warfarin to aquatic plants; 

however, aquatic exposure is also expected to be low since there is no spray application 

and the material is applied as a formulated bait or a treated grain. Warfarin binds 

strongly to organic material (i.e., the formulated bait or grain) and little is expected to be 

available for runoff or leaching. No aquatic incidents have been reported for warfarin.
Page 29 of 51

• Chronic fish and aquatic invertebrates – No data are available to assess the chronic 

toxicity of warfarin to fish and aquatic invertebrates; however, aquatic exposure is 

expected to be low since there is no spray application and the material is applied as a 

formulated bait or a treated grain. Warfarin is moderately acutely toxic to fish and 

invertebrates, and chronic effects would not be unexpected. However, warfarin binds 

strongly to organic material (i.e., the formulated bait or grain) and little is expected to be 

available for runoff or leaching for this proposed use. No aquatic incidents have been 

reported for warfarin.

Table 15. Available ecological effects data for terrestrial organisms exposed to warfarin and 

remaining data gaps. 

OCSPP 

Guideline Data Requirement Submitted Studies (MRID)

Study 

Classification

Are data 

needed for 

risk 

assessment?

Current Additional 

Data Need

850.2100 Avian oral toxicity 00156284 acceptable Yes Data are requested for 

avian acute oral with 

00153369 passerine species acceptable

00248782 acceptable

05005716 supplemental

850.2200 Avian dietary toxicity 00153365 acceptable No --

00117979 supplemental

00161724 acceptable

00156283 supplemental

00153366 acceptable

00157812 acceptable

00156285 acceptable

850.2300 Avian reproduction (None) (N/A) Yes Data are requested for 

avian reproduction 

toxicity testing an 

upland game bird 

species and a waterfowl 

species. 

NonguidelineAvian inhalation (None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap 

was not identified as 

these data are not 

necessary for risk 

assessment at this time.
Page 30 of 51

Table 15. Available ecological effects data for terrestrial organisms exposed to warfarin and 

remaining data gaps. 

OCSPP 

Guideline Data Requirement Submitted Studies (MRID)

Study 

Classification

Are data 

needed for 

risk 

assessment?

Current Additional 

Data Need

850.3020 Honey bee acute 

contact toxicity

(None) (N/A) No Additional data on 

toxicity to terrestrial 

invertebrates other than 

honey bee may be useful 

for risk assessment but 

are not required at this 

time. 

850.3030 Honey bee residue on 

foliage

(None) (N/A) No Data have not been 

submitted to fulfill these 

guidelines. Data gaps 

were not identified as 

these data are not 

necessary for risk 

assessment at this time.

OECD TG 

213

Acute oral toxicity to 

adult honey bees

(None) (N/A) No

OECD TG 

237

Acute oral toxicity to 

larval honey bees

(None) (N/A) No

NonguidelineChronic oral toxicity 

to adult honey bees

(None) (N/A) No

NonguidelineChronic oral toxicity 

to larval honey bees

(None) (N/A) No

NonguidelineField trial of residues 

in pollen and nectar

(None) (N/A) No

OECD 

Guidance 75

Semi-field testing for 

pollinator

(None) (N/A) No

850.3040 Field testing for 

pollinator

(None) (N/A) No

850.3100 Earthworm 

Subchronic Toxicity 

Test 

(None) (N/A) Yes Data are requested for 

earthworm toxicity.

850.4100 Seedling Emergence 

and Seedling Growth

(None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap 

was not identified as 

these data are not 

necessary for risk 

assessment at this time.

850.4150 Vegetative Vigor (None) (N/A) No Data have not been 

submitted to fulfill this 

guideline. A data gap 

was not identified as 

these data are not 

necessary for risk 

assessment at this time.
Page 31 of 51

Table 16. Available ecological effects data for aquatic organisms exposed to warfarin and 

remaining data gaps. 

OCSPP

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classifications

Are data 

needed to 

conduct 

risk 

assessment?

Current Additional Data 

Need

850.1010 Freshwater 

invertebrate 

acute toxicity

00153368 Acceptable No --

850.1025

850.1035

850.1045

850.1055 

Saltwater 

invertebrate 

acute toxicity 

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1075 Freshwater fish 

acute toxicity 

00156284 Acceptable No --

00156287 Acceptable

850.1075 Saltwater fish 

acute toxicity 

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1300 Freshwater 

invertebrate 

life cycle 

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1350 Saltwater 

invertebrates 

life cycle 

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1400 Freshwater fish 

early-life stage

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1400 Saltwater fish 

early-life stage 

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.1500 Fish life cycle (None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 

data are not necessary for risk 

assessment at this time.

850.4400 Aquatic plant 

Toxicity Test 

using Lemna

(None) (N/A) No Data have not been submitted 

to fulfill this guideline. A data 

gap was not identified as these 
Page 32 of 51

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MRID Citation Reference

44995009 DER not 

located

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Constants for Evaluation of Hazardous Waste Land Disposal: Volume 1. Data 

on 32 Chemicals. Unpublished study prepared by Genesis Laboratories, Inc. 

13 p. 

161-3 Photodegradation-soil

MRID Citation Reference

44995011 DER not 

located

Mach, J. (1996) Photodegradation Studies on Soil Using Field Rodent Bait 

(0.025%) in Colorado. Unpublished study prepared by Genesis Laboratories, 
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Inc. 17 p. 

Non Guideline Selections

5001951 2076482

biodegradation

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Ikawa (1972) Effect of Mycotoyins and Coumarins on the Growth of Facillus 

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5005014 2076488

Residue 

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Detection in air

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Warfarin EcoEffects Bibliography 

71-1 Avian Single Dose Oral Toxicity

MRID Citation Reference

156284 2056028 Beavers, J. (1985) An Acute Oral Toxicity Study in the Bobwhite with 

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ACC 248782 2056009 Shapiro, R. (1982) Avian Single Dose Oral LD50. Report No. T-2488. 

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platyrhynchos~L_ a l'aide du coumafene et du chlorophacinone_ ?Trials of 

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71-2 Avian Dietary Toxicity

MRID Citation Reference
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117978 2056007 Roth, R.; Shapiro, R. (1982) Avian Dietary LC50 Study with Mallard Ducks: 

?Wincon|: Report No. T-2390. (Unpublished study re- ceived Sep 3, 1982 

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117979 2056008 Roth, R.; Shapiro, R. (1982) Avian Dietary LC50 Study with Bob White 

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3282-32; prepared by Nutrition International, Inc., submitted by D-Con Co., 

Inc., Montvale, NJ; CDL:248782-E) 

153365 2056023 Fletcher, D. (1985) 15-Day Dietary LC50 Study with Technical War- farin in 

Bobwhite Quail: Study No. 85 QC 55. Unpublished study prepared by BioLife Associates, Ltd. 40 p. 

153366 2056024 Fletcher, D. (1985) 19-Day Dietary LC50 Study with Technical War- farin in 

Mallard Ducklings: Study No. 85 DC 56. Unpublished study prepared by BioLife Associates, Ltd. 41 p. 

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International Ltd. 20 p. 

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Final Report: Project No. 205-102. Unpublished study pre- pared by Wildlife 

International Ltd. 16 p. 

157812 2056034 Shapiro, R. (1986) Avian Dietary LC50 Study with Mallard Ducks: Wincon 

(Warfarin): Report No. T-5513. Unpublished study pre- pared by Wildlife 

International, Ltd. 31 p. 

40818001 DER not 

located

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prepared by Bio-Life Associates, Ltd. 35 p. 

161724 2056035 Shapiro, R. (1983) Avian Dietary LC50 Study with Bob White Quail: 

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71-3 Wild mammal toxicity

MRID Citation Reference

2471? 2056049 Crabtree, D.G.; Robison, W.H. (19??) Warfarin and its effect on some 

wildlife species. Pages 167-173,~In~Seventeenth North American Wildlife 

Conference. N.P. (Also~In~unpublished sub- mission received May 30, 1972 

under unknown admin. no.; submit- ted by Velsicol Chemical Corp., Chicago, 

Ill.; CDL:230307-G) 

71-5 Simulated or Actual Field Testing

MRID Citation Reference
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40077201 2056037 Christopher, M.; Balasubramanyam, M.; Purushotham, K. (1984) Toxi- city 

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44820001 DER not 

locatedinvalid in 

reviews

Mach, J. (1998) Secondary Hazard Study Using Warfarin-Killed Prairie Dogs 

(Cynomys ludovicianus) Fed to Domestic Ferrets Mustela putorius furo): Lab 

Project Number: 96013. Unpublished study prepared by Genesis Laboratories, 

Inc. 64 p. 

44995003 DER not 

located

Mach, J.; Carlet, L. (1997) Secondary Hazard Study Using Warfarin-Killed 

Black-Tailed Prairie Dogs (Cynomys ludovicianus) Fed to Domestic Ferrets 

(Mustela putorius furo): Lab Project Number: N97001. Unpublished study 

prepared by Genesis Laboratories, Inc. 18 p. 

44995004 2076444 Mach, J.; March, K. (1997) Secondary Hazard Study Using Warfarin-Killed 

Black-Tailed Prairie Dogs (Cynomys ludovicianus) Fed to Black-Billed 

Magpies (Pica pica): Lab Project Number: N97003. Unpublished study 

prepared by Genesis Laboratories, Inc. 21 p. 

72-1 Acute Toxicity to Freshwater Fish

MRID Citation Reference

117976 2056005 Shapiro, R. (1982) Static Acute Bioassay for the Toxicity of Wincon ... to 

Bluegill Sunfish ...: Report No. T-2387. (Unpublished study received Sep 3, 

1982 under 3282-32; prepared by Nutrition International, Inc., submitted by 

D-Con Co., Inc., Montvale, NJ; CDL:248782-B) 

117977 2056006 Shapiro, R. (1982) Static Acute Bioassay for the Toxicity of Wincon ... to 

Rainbow Trout ...: Report No. T-2392. (Unpublished study received Sep 3, 

1982 under 3282-32; prepared by Nutrition In- ternational, Inc., submitted by 

D-Con Co., Inc., Montvale, NJ; CDL:248782-C) 

153363 2056019

2056020

McAllister, W.; Bowman, J.; Cohle, P. (1985) Acute Toxicity of Technical 

Warfarin to Bluegill Sunfish (Lepomis macrochirus): Report #33306. 

Unpublished study prepared by Analytical Bio- Chemistry Laboratories, Inc. 

54 p. 

153364 2056021

2056022

McAllister, W.; Bowman, J.; Cohle, P. (1985) Acute Toxicity of Technical 

Warfarin to Rainbow Trout (Salmo gairdneri): Study No. 33304. Unpublished 

study prepared by Analytical Bio-Chemistry Laboratories, Inc. 55 p. 

156286 2056030 McAllister, W.; Cohle, P. (1984) Acute Toxicity of Warfarin Techni- cal to 

Rainbow Trout(Salmo gairdneri): Report No. 32461. Unpub- lished study 

prepared by Analytical Bio-Chemistry Labs, Inc. 53 p. 

156287 2056031 McAllister, W.; Cohle, P. (1984) Acute Toxicity of Warfarin Techni- cal to 

Bluegill Sunfish(Lepomis macrochirus): Report No. 32460. Unpublished 

study prepared by Analytical Bio-Chemistry Labs, Inc. 53 p. 

40098001 2049421 U.S. Fish and Wildlife Service, Columbia National Fishery Research 

Laboratory (19??) Warfarin. (Unpublished study) Catfish study

No MRID 2056046 U.S. Environmental Protection Agency (1975) Biological Laboratories 

Report-Rainbow Trout Acute Toxicity, April 28.
Page 40 of 51

72-2 Acute Toxicity to Freshwater Invertebrates

MRID Citation Reference

117975 2056004 Shapiro, R. (1982) Static Acute Bioassay for the Toxicity of Wincon ... to 

Daphnia magna: Report No. T-2391. (Unpublished study received Sep 3, 

1982 under 3282-32; prepared by Nutrition In- ternational, Inc., submitted by 

D-Con Co., Inc., Montvale, NJ; CDL:248782-A) 

153368 2056025 Forbis, A.; Georgie, L.; Burgess, D. (1985) Acute Toxicity of Tech- nical 

Warfarin to Daphnia magna: Report #33305. Unpublished study prepared by 

Analytical Bio-Chemistry Laboratories, Inc. 44 p. 

156288 2056032 Forbis, A.; Georgie, L.; Burgess, D. (1984) Acute Toxicity of War- farin 

Technical to Daphnia magna: Report No. 32462. Unpublished study prepared 

by Analytical Bio-Chemistry Labs, Inc. 38 p. 

141-1 Honeybee Toxicity

18842 2056003 Atkins, Jr., E.L., L.D. Anderson, E.A. Greywood (1969) Effect of Pesticides 

on Apiculture: Project No. 1499; Research Report CF-7501. (Unpublished 

Study Received May 8, 1971 under 1F1174; Prepared by Univ. of CaliforniaRiverdale, Dept. of Entomology, Submitted by Ciba Agrochemical Co., 

Summit, NJ; CDL: 090973-B).

Non Guideline Selections

2459 0r 27031 

or 29649

2056010

2056011

2056048

Papworth, D.S. (1958) A review of the dangers of warfarin poisoning to 

animals other than rodents. Royal Society of Health Journal 78(? ):52-60. 

(Also~In~unpublished submission received Feb 7, 1963 under unknown 

admin. no.; submitted by McLaughlin Gormley King Co., Minneapolis, 

Minn.; CDL:221990-D) 

2469 2056002 Evans, J.; Ward, A.L. (1967) Secondary poisoning associated with 

anticoagulant-killed nutria. Journal of the American Veterinary Medical 

Association 151(7):856-861. (Also~In~unpublished sub- mission received 

May 30, 1972 under unknown admin. no.; submit- ted by Velsicol Chemical 

Corp., Chicago, Ill.; CDL:230307-E) 

2838 Referenced but 

no DER

Hein, L.; Koch, R.; Krieger, C.H. (1952) Tomorin, Cumopyrin, War- farin and 

the Methoxy Derivative of Warfarin: Biological Studies. (Unpublished study 

including second progress report, received Mar 17, 1952 under unknown 

admin. no., prepared by Wisconsin Alumni Research Foundation, submitted 

by Ciba-Geigy Corp., Greensboro, N.C.; CDL:104673-B) 

2839 Referenced but 

no DER

Hein, L.; Derse, P.; Krieger, C.H. (1952) Warfarin and Tomorin Biological 

Studies: Fourth Progress Report. (Unpublished study received Feb 20, 1952 

under unknown admin. no.; prepared by Wisconsin Alumni Research 

Foundation, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:104665-

A) 

5988 2056038 Brock, E.M. (1965) Toxicological feeding trials to evaluate the hazard of 
Page 41 of 51

secondary poisoning to gopher snakes, Pituophis cate - ?nifer ?. Copeia ? 

(2):244-245. (Also In unpublished submis- sion received Apr 23, 1976 under 

6704-78; submitted by U.S. Dept. of Interior, Fish and Wildlife Service, 

Washington, D.C.; CDL:224031-L) 

31300 DER not 

located- more 

of a report on 

incidents

Hayne, D.W.; Copple, H.; Thornton, G.W.; et al. (1976) (Letters Concerning 

Toxicity to Dogs following Accidental Ingestion). (Unpublished study 

received Mar 20, 1980 under 876-184; prepared in cooperation with North 

Carolina State Univ., Institute of Statistics and others, submitted by Velsicol 

Chemical Corp., Chicago, Ill.; CDL:242305-A) 

5001730 Open lit Warkany, J. (1976) Warfarin embryopathy. Teratology 14:205-209. 

5001784 Open lit Jennings, D.S. (1972) Warfarin poisoning in pigs ?letter| Veterinary Record 

90(4):110. 

146380 2056017 Beck, L. (1980) Primary Eye Irritation. Zoecon Rat and Mouse Bait: Project 

No. 1596-B. Unpublished Study Prepared by Elars Bioresearch Laboratories, 

Inc.

5001952 2056039 Phillips, D., J. Rowe (1976) Warfarin: A Question of Balance. New Scientist 

70(1001): 400-401.

5001953 2056040 Phillipson, J., D. Wood (1970) Poisoning Grey Squirrels: A Threat to 

Wildlife? New Scientist 70(1001): 398-400

5006274 2056042 Zatsepin, V.G., D.F. Trakhanov, N.I. Nikiforov (1977) Izuchenie toksichnosti 

deratizatsionnykn yaooy glya pushnykh zverei.

Study on Toxicity of Oeratization Poisons to Fur-bearing animals. All Union 

Scientific Research Institute of Veterinary Sanitation 57: 127-132.

5006278 2056043 Telle, H.J. (1954) Neue Rattenekaempfungsmittel – New Rodenticides 

Deutscne Gesundheitswesen 9(24): 769-771.

5008022 205044 Fowler, M.E. (1975) Toxicities in Exotic and Zoo Animals. Veterinary Clinics 

of North America 5(4): 685-698.

5009867 2056045 Uyeda, S. (1956) Bird Problems with use of Warfarin Cats. Pages 19-20. In 

Hawaiian Sugar Technologists Report No. 15. Honolulu, Hawaii: Hawaiian 

Sugar Technologists.

143276 2056012 Lorgue, G. (1984) Comparative Toxicity in the Pig after Repeated Oral 

Ingestion of Brodifacoum, Bromadiolone and Warfarin. Unpublished 

Translation of Toxicities Comparees Chez le Porc Par Ingestions Orales 

Repetees de Brodifacoum, Bromadiolone et coumafene Prepared by Lyon 

National Veterinary School Laboratory of Toxicology. Lipha Report No. 85-

012.

146377 2056013 Beck, L. (1980) Rat Acute Oral Toxicity. Zoecon Rat and Mouse Bait: Project 

No. 1596-D. Unpublished Study Prepared by Elars Bioresearch Laboratories, 

Inc.

146378 2056014 Beck, L. (1980) Acute Dermal Toxicity. Zoecon Rat and Mouse Bait: Project 

No. 1596-C. Unpublished Study Prepared by Elars Bioresearch Laboratories, 

Inc.

146379 2056015 Beck, L. (1980) Acute Dermal Irritation. Zoecon Rat and Mouse Bait: Project 

No. 1596-A. Unpublished Study Prepared by Elars Bioresearch Laboratories, 

Inc.
Page 42 of 51

148098 2056016 Shapiro, R. (1985) Letter Sent to S. Palmateer Dated July 1, 1985; Antidotal 

Effect of Warfarin used in Avian Toxicology Studies Performed for the d-Con 

Co., Inc.: (Antidotal Effect of Vitamin K in the Basal Diets to Counteract or 

Modify the Effects of Warfarin in Avaian Wildlife Studies). Prepared by

Product Safety Labs.
Page 43 of 51

Appendix A: Summary of Ecotoxicity Data for Warfarin

Table A-1. Aquatic Toxicity Profile for Warfarin

Assessment 

Endpoint

Tested Species Toxicity Value (95% CI) 

Used in Risk Assessment 

Acute 

Classification

Reference

(MRID)

Freshwater Organisms

Acute Toxicity to 

Fish and 

Aquatic-phase 

Amphibians

Rainbow trout 

(Oncorhynchus 

mykiss) 

96-hr LC50 > 16 mg/L Slightly toxic 00156284

Bluegill sunfish

(Lepomis 

macrochirus)

LC50 > 17 mg/L Slightly toxic 00156287

Acute Toxicity to 

Aquatic 

Invertebrates

Water flea 

(Daphnia magna)

48-hr LC50 > 17 mg/L Slightly toxic 00153368

Table A-2. Avian Acute Oral Toxicity Studies

Rodenticide/

 Species

% 

a.i.

 LD50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Study length 

and Time to 

death and 

(study length)

MRID/

Reference and 

classification

Comments

Northern 

bobwhite quail 100 >2000 156284, acceptable
Page 44 of 51

Table A-2. Avian Acute Oral Toxicity Studies

Rodenticide/

 Species

% 

a.i.

 LD50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Study length 

and Time to 

death and 

(study length)

MRID/

Reference and 

classification

Comments

Northern 

bobwhite quail 100 > 2150 153369, acceptable

Mallard duck

Tech. 621 248782, 

acceptable

Mallard duck

10 120 5005716, 

supplemental Not conducted with technical

Chicken 

(domestic)

942 Bai and 

Krishnakumari 

1986 , 

have paper, not reviewed
Page 45 of 51

Table A-3. Avian Acute Dietary Toxicity Studies

LC50 dietary

Rodenticide/

 Species

% a.i. LC50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Time to death 

and (study 

length)

MRID/Referen

ce and 

classification

Comments

Northern 

bobwhite quail 100 625 NA 33 g

15 day study, 

most deaths days 

3-7, one day 10

153365, 

acceptable

fed a diet described as ‘vit K-deficient (meaning no vit K in 

feed supplement), very ‘flat’ dose response curve

Northern 

bobwhite quail Tech. 3000 117979, 

supplemental

Northern 

bobwhite quail 100 3900 161724, 

acceptable

Northern 

bobwhite quail 100 6690 

(2537, 551690) 1.1 (0.3, 1.9) 21 g

15 day study, 

deaths from day 

3-9

156283, 

supplemental,

fed standard diet, contained 8.8 mg/kg of synthetic Vit K 

(menadione sodium bisulfate), may have been sufficient to 

mitigate effects of warfarin

Mallard duck

100 890 NA

19 day study, 

deaths from day 

3-16

153366, 

acceptable,

fed a diet described as ‘vit K-deficient (meaning no vit K in 

feed supplement), very flat dose response curve

Mallard duck Tech. 1726 157812, 

acceptable

Mallard duck 100 > 5000 156285, 

supplemental

Table A-4. Mammalian Acute Oral Toxicity Studies

Rodenticide/

 Species

% a.i. LD50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Time to death 

and (study 

length)

MRID/Refer

ence and 

classification

Comments

Laboratory 

rat 100 3.0 (male) 196

MRID 05002272 (Gaines 1960)

GS 0011-107, Acceptable

also included in Gaines 1969 

Laboratory 

rat

2.5-5.0(females) 00143093 mortality was not monotonic – suggestive of study issues. 
Page 46 of 51

Table A-4. Mammalian Acute Oral Toxicity Studies

Rodenticide/

 Species

% a.i. LD50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Time to death 

and (study 

length)

MRID/Refer

ence and 

classification

Comments

Laboratory 

rat

35.7

41.9 

EPA 1982 Beltsville report (variation in warfarin), not reviewed

Laboratory 

rat

NA 512 (male)

<10 (female)

NA 200 14 day 

observation

Deaths 1-10 

days

00146977 Animals fed lab chow

Male value originally 450-680, now calculated with binomial 

estimate

Cat 100 < 2.5 1.75-3.30 

kg

went to 14 days

mortalities btw 

1-10 days

00002461 

(Acceptable)

Only 2 cats per dose level, 1974 study. (100% mortality at 

2.5) (Til et al 1974)

Table A-5. Mammalian Acute Dietary Toxicity Studies

Rodenticide/

 Species

% 

a.i.

 LC50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Time to death and 

(study length)

MRID/Reference 

and classification

Comments

Laboratory 

rat (Albino) 

98 4.41 (3.43-5.64) 5.4 (2.8, 8.0) 60-74g Observed 14 days, 

mortalities days 3-9

Teeters 1981 

(TNM 126)

Supplementa1

Laboratory 

rat (Albino)

98 5.43 (4.23-7.00) 5.1 (2.8, 7.5) 91-120g Observed 14 days, 

mortalities days 3-10

Teeters 1981 

(TNM 68)

Supplementa1

Laboratory 

rat (Albino)

98 5. 91 (4.66, 7.51) 5.9 (3.9, 8.8) 61-75 g Observed 14 days, 

mortalities days 3-9

Teeters 1981 

(TNM 122)

Supplementa1

Laboratory 

rat (Albino)

98 6.03 (4.45-8.20) 3.6 (2.0, 5.3) 81-116 g Observed 14 days, 

mortalities days 4-9

Teeters 1981 

(TNM 50)

Supplementa1

Mink 11.7 (9.2, 15.0) 2.0 Aulerich et al. 

1987 (E039689)

Not in comparative
Page 47 of 51

Table A-5. Mammalian Acute Dietary Toxicity Studies

Rodenticide/

 Species

% 

a.i.

 LC50, mg/kg

 (95% CI)

Probit slope 

(95% CI)

Average 

Body 

Weight 

(day=0)

Time to death and 

(study length)

MRID/Reference 

and classification

Comments

Black-tailed 

prairie dogs 99 97.6 (23.7, 185.1) 1.38 (0.5, 2.3)

>675 g and 

775 g for 

adult 

females and 

males, 

respectively

15-day feeding 

exposure, observed 

total 25 days. 

Mortalities from 8-22 

days

E66881

Mach et al. 2002, 

Qualitative NEED TO B E SURE CAN FIND REVIEW
Page 48 of 51

13 Appendix B. Screening Level Models to Evaluate Potential Importance of Drinking Water 

and Inhalation Exposure Pathways

SIP (Screening Imbibition Program, v1.0) Inputs and Conclusions

Table 1. Inputs

Parameter Value

Chemical name Warfarin

Solubility (in water at 25oC; mg/L) 17

Mammalian LD50 (mg/kg-bw) 3

Mammalian test species laboratory rat

Body weight (g) of "other" mammalian species

Mammalian NOAEL (mg/kg-bw) 0

Mammalian test species

Body weight (g) of "other" mammalian species

Avian LD50 (mg/kg-bw) 621

Avian test species mallard duck

Body weight (g) of "other" avian species

Mineau scaling factor 1.15

Mallard NOAEC (mg/kg-diet) 0

Bobwhite quail NOAEC (mg/kg-diet) 0

NOAEC (mg/kg-diet) for other bird species 0

Body weight (g) of other avian species

NOAEC (mg/kg-diet) for 2nd other bird species

Body weight (g) of 2nd other avian species
Page 49 of 51

Table 2. Mammalian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 2.9240 2.9240

Adjusted toxicity value (mg/kg-bw) 2.3075 0.0000

Ratio of exposure to toxicity 1.2672 0.0000

Conclusion*

Exposure through drinking 

water alone is a potential 

concern for mammals

Due to insufficient data, risk 

cannot be precluded

Table 3. Avian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 13.7700 13.7700

Adjusted toxicity value (mg/kg-bw) 322.4390 0.0000

Ratio of exposure to acute toxicity 0.0427 0.0000

Conclusion*

Drinking water exposure 

alone is NOT a potential 

concern for birds

Due to insufficient data, risk 

cannot be precluded

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when 

aggregated with other routes (i.e., diet, inhalation, dermal), pesticide exposure through drinking water may contribute 

to a total exposure that has potential for effects to non-target animals.
Page 50 of 51

Welcome to the EFED 

Screening Tool for Inhalation Risk

This tool is designed to provide the risk assessor with a rapid method for determining the potential

significance of the inhalation exposure route to birds and mammals in a risk assessment.

Input

Application and Chemical Information

Enter Chemical Name warfarin

Enter Chemical Use rodent control

Is the Application a Spray? (enter y or n) n

If Spray What Type (enter ground or air) air

Enter Chemical Molecular Weight (g/mole) 308.33

Enter Chemical Vapor Pressure (mmHg) 1.16E-07

Enter Application Rate (lb a.i./acre) 0.025

Toxicity Properties

Bird

Enter Lowest Bird Oral LD50 (mg/kg bw) 621

Enter Mineau Scaling Factor 1.15

Enter Tested Bird Weight (kg) 1.58

Mammal

Enter Lowest Rat Oral LD50 (mg/kg bw) 3

Enter Lowest Rat Inhalation LC50 (mg/L) 0.005

Duration of Rat Inhalation Study (hrs) 4

Enter Rat Weight (kg) 0.35
Page 51 of 51

Output

Results Avian (0.020 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 1.92E-03

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 2.42E-04

Adjusted Inhalation LD50 4.16E+00

Ratio of Vapor Dose to Adjusted Inhalation LD50 5.82E-05 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) not applicable

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 not applicable not applicable

Results Mammalian (0.015 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 1.92E-03

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 3.04E-04

Adjusted Inhalation LD50 2.98E-01

Ratio of Vapor Dose to Adjusted Inhalation LD50 1.02E-03 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) not applicable

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 not applicable not applicable