Warfarin Human Health Risk Assessment 0426574 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December 8, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Wa rfarin and Warfarin Sodium Salt. Human Health Assessment Scoping 

Document and Draft Human Health Risk Assessment in Support of Registration 

Review. 

PC Code: 086002, 086003 

Decision No.: 502966 

DP Barcode: 0426574 

Registration Nos.: 0011-1 

Petition No.: NA Regulatory Action: Registration Review Risk Assessment 

Risk Assessment Type: Single Chemical Case No.: NA 

TXR No.: A CAS No.: 81-81-2 

MRID No.: 

FROM: 

A .iOCFR: NA 

Monica 

Yung Yang. 

Hawk

Ph.D.

ins, 

, 

Ph.D.

Toxicol

, M. 

og

P.H.

ist 

, Epy

~-er 

ironmental 

6-. g;-;r Heal> 

th ~cientist // ,,,..____ Risk Assesso /~ 

Mohsen Sahafeyan, Chemist • . L c.,, / - .../, /1. · '""e::.--7 

Risk Assessment Branch VI · 

Health Effects Division (7509P) I /. 

THROUGH: Donna S. Davis, Acting Branch Chief \ p)~ Q.pRisk Assessment Branch vr NJ ' 

TO: 

I lealth Effects Division (7509P) 

Caitlin Newcamp. Chemical Review Manager 

Melissa Grable, Team Leader 

Neil Anderson, Branch Chief 

Pesticide Re-Evaluation Division (PRD/7508P) 

This memorandum serves as HED"s scoping document and draft human health risk assessment 

(DRA) under registration review for the registered uses of warfarin and warfarin sodium salt. 

1.0 Executive Summary 

HED has evaluated the most recent human health risk assessment for warfarin (and warfarin 

sodium salt) to determine if sufficient data are available and if updates are needed to support 

registration review. The latest risk assessment was conducted in 2008 (D34773 l , M. Dow, 

7/30/2008). HED has also considered updates to its toxicity, exposure and usage databases, and 

the latest Agency science policy and risk assessment methodologies. This memorandum serves 

as HED's scoping document and draft human health risk assessment for warfarin. 

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Warfarin Human Health Risk Assessment 0426574 

Warfarin, a synthetic analogue of vitamin K. is a member of the coumarin family of blood 

anticoagulants. It is currently registered for use to control rodents in and around homes and 

other residential buildings, commercial buildings, industrial/agricultural buildings. similar manmade structures, inside transport vehicles (ships. trains, aircraft). and underground to control 

mol es in turf areas, golf courses, and other non-grassy areas. Warfarin is marketed as a bait 

block. a gel bait with a syringe applicator. and microencapsulated pellets on the inside of bait 

stations. The registered products can be applied as a bait for rats and mice or applied as a gel bait 

that is injected into the ground. The bait stations must be resistant to destruction by pets and 

children under six years of age and must be used in a manner that prevents such children from 

reaching into compartments and obtaining bait. The labels state if a bait can be shaken from 

stations when they are lifted, units must be secured or otherwise immobilized. 

No data deficiencies were identified for the toxicology, residue chemistry, or occupational/ 

residential exposure databases. Warfarin's toxicity, mechanism of action, and methods for 

treatment of overdose in humans are well established given its broad use as a pharmaceutical. No 

animal toxicology studies are required for warfarin at this time. Dietary exposure is not expected 

and occupational/residential exposures are anticipated to be negligible from the currently 

registered uses of warfarin (bait in bait stations or packaged in tamper-resistant bait stations). 

Based on the negligible exposure potential of the currently registered uses of warfarin, no 

toxicological points of departure have been established. As a result, quantitative risk 

assessments are not necessary to conclude with reasonable certainty that exposures to the 

currently registered uses of warfarin do not pose a significant human health risk. 

2.0 HED Recommendations 

2.1 Data Deficiencies 

o None. 

2.2 Tolerance Considerations 

Warfarin is not a food-use chemical. There are no U.S. tolerances established for warfarin; 

therefore tolerance considerations are not relevant to this action. 

2.3 Label Recommendations 

HED has reviewed the warfarin labels and concludes that they are adequate and has no label 

revisions recommendations at this time. 

3.0 Introduction 

Warfarin [3-(alpha-acetonylbenzyl)-4-hydroxycoumarin] is registered for use as a rodenticide. 

Warfarin belongs to the coumarin family of blood anticoagulants. The sodium salt of warfarin is 

used as an anticoagulant in the treatment of individuals with hyper-coagulation problems. The 

structure, chemical name, and other identifiers are found in the chemical identity table (Table 

3.l.l). 

3.1 Chemical Identity 

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Warfarin Human Health Risk Assessment 0426574 

Table 3.1.1. Nomenclatu re of Warfarin 

0 

Chemical structure 

CAS name ran-2-one 

CAS registry number 

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Warfarin Human Health Risk Assessment 0426574 

3.2 Physical/Chemical Characteristics 

Table 3.2.1. Physicochemical Properties of Warfarin. 

Parameter Value Reference 

Physical description White powder or crystal 

with no odor 

Melting point 159 to 165 °C 

0. 196 mg/mL water at 25 °C 

up to 8% in acetone 

up to 2% in ethanol. Re-registration Eligibility Water solubility The sodium salt Document, May 1991 formulation is readily 

soluble in water. 

Octanol/water partition 2.37 coefficient, Log Kow 

pH 7.2 to 8.3 in water 

3.3 Pesticide Use Pattern 

Warfarin is currently registered for use to control rodents in and around homes and other 

residential buildings, commercial buildings, industrial/agricultural buildings, similar man-made 

structures, inside transport vehicles (ships. trains, aircraft), and underground to control moles in 

turf areas, golf courses, and other non-grassy areas. Warfarin is marketed as a bait block, a gel 

bait with a syringe applicator, and microencapsulated pellets on the inside of bait stations. The 

labels state to apply the bait block and gel bait in bait stations, as packaged bait stations 

containing microencapsulated pellets, or as packaged in tamper-resistant bait stations if pets. 

domestic animals. non-target wildlife, and children may access the bait. The registered products 

can be applied as a 4 to 16 ounce bait at each placement location for rats and mice, V4 to Yz 

ounces or up to 2 ounces (for a lot of mouse activity) bait at each placement location for mice, or 

applied as a gel bait with up to 1 syringe that is injected into the ground at each bait placement 

location per l 0.000 square feet. The bait stations must be resistant to destruction by pets and 

children under six years of age and must be used in a manner that prevents such children from 

reaching into compartments and obtaining bait. The labels state if a bait can be shaken from 

stations when they are lifted, units must be secured or otherwise immobilized. 

In 2008. the Agency issued a Risk Mitigation Decision (RMD) for ten rodenticides. of which 

warfarin was included. The mitigation decision set restrictions in order to minimize rodenticide 

exposure to children, wildlife and domestic animals. The risk mitigation decision does not apply 

to rodenticide field (non-commensal rodents) uses or tracking powder products. A brief summary 

is below. The details of the RMD can be found in docket number EPA-HQ-OPP-2006-0955-

0764 at www.regulations.gov. 

• Consumer-use products(~ I lb.), 

o Each product must include at least one bait station and may include bait 

refills. 

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Warfarin Human Health Risk Assessment 0426574 

o When applied outdoors above ground and in areas accessible to children, 

non-target wildlife or domestic animals, baits must be contained in bait 

stations. 

o Products for use outdoors and above-ground must be placed within 50 feet 

of a building. 

• Professional-use products 

o Must be sold in quantities of::: 4 lbs. (first-generation anticoagulants/nonanticoagu ants)~ 

o May not be offered for sale in consumer stores (hardware, grocery, etc.). 

o Must also be placed within l 00 feet of a structure (fence and perimeter 

baiting beyond l 00' of a man-made structure are prohibited) when used 

outdoors and above ground, see 50 foot Documenr Clarification Leifer to 

Bell (03.20. 12) (signed) in docket number EPA-HQ-OPP-2006-0955-0820 

found at ·.vww.regulations.gov. 

o For uses of first-generation anticoagulants or non-anticoagulants, product 

labels require bait stations if children, wildlife or domestic animals may be 

exposed. 

3.4 Consideration of Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible. were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.archives.gov/fcderal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment. OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to pesticide 

exposures that are based on activities in and around the home that involve pesticide use in a 

residential setting. Whenever appropriate. these non-dietary exposures are calculated based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. 

4.0 Haza rd Characterization and Dose-Response Assessment 

4.1 Toxicology Analysis 

Warfarin, a synthetic analogue of vitamin K, is a member of the coumarin family of blood 

anticoagulants. The sodium salt of warfarin is used as an anticoagulant in the treatment of 

individuals with hyper-coagulation problems. There are no guideline animal studies available in 

the warfarin database; however, its toxicity, mechanism of action, and treatment of overdose in 

humans are well established given its broad use as a phannaceutical. Guideline studies are 

required for non-food use pesticides in accordance with the current 40 CFR Part 158 Toxicology 

Data Requirements; however, the HASPOC concluded based on a weight-of-evidence approach 

that these studies are not required at this time due to the limited exposure pattern of warfarin and 

the qualitative nature of the risk assessment. [f the use pattern were to change, or new 

policies/procedures are put into place, then the need for these studies may be revisited. The 

TOXLINE (National Library of Medicine) database literature search did not identify any new 

toxicological information not already considered. 

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Warfarin toxicity is manifested as an increase in prothrombin and partial thromboplastin times 

and a decrease in the vitamin K-dependent clotting factors, II, VII, IX and X. Bleeding time, clot 

retraction, platelet counts, thrombin time, and euglobulin lysis times are usually no1mal. Signs 

of toxicity include cutaneous bleeding, hematuria, melena or hematochezia, hematomas, uterine 

bleeding in women, and epistaxis and gingival bleeding. Death follows excessive external 

and/or internal bleeding. As a member of the coumarin family, warfarin has been established as a 

human teratogen in clinical doses since coumarin derivative use or abuse in mothers (human) 

during gestation has been reported to result one-sixth of pregnancies ending in abortion or 

stillbirth and about two-thirds ending with a relatively normal outcome. 

Technical grade warfarin has high acute toxicity via oral or inhaJation (dust aerosol) routes of 

exposure (Toxicity Category I) and low acute toxicity via dermal route (Toxicity Category Ill). lt 

is not an eye or skin irritant. A skin hypersensitivity study was not available; however, human 

data indicate that warfarin does not induce an allergic reaction. 

4.2 Consideration of Toxicity to Children 

Food Quality Protection Act (FQPA) considerations do not apply to warfarin for the currently 

registered (non-food) use patterns described in this risk assessment. 

4.3 Endocrine Disruption 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility. pregnancy rates, reproductive loss. 

and sex ratios in offspring. For ecological hazard assessments. EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for warfarin, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), warfarin is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate." The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen. androgen. or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

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October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or li kely endocrine disruptors. 

For further infom1ation on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery. please visit our 

website. 2 

5.0 Dietary Exposure and Risk Assessment 

Based on the registered rodenticide use, residue data are not required and none have been 

submitted. Warfarin is strictly a non-food use rodenticide. The end-use product packaging and 

use (bait in bait stations or packaged in tamper-resistant bait stations) result in negligible 

exposure to human food or drinking water. Furthermore, warfarin has very low water solubility 

( 17 mg/I) and no measureable concentrations of warfarin are expected in drinking water; 

therefore, a quantitative drinking water assessment was not conducted by the Environmental Fate 

and Effects Division (EFED). 

6.0 Residential (Non-Occupational) Exposure and Risk Assessment 

Residential handler and post-appli cation exposures from warfarin are expected to be negligible 

since the registered product labels state to apply the bait in bait stations or packaged in tamperresistant bait stations if pets, domestic animals, non-target wildlife, and children may access the 

bait. These stations must be resistant to destruction by pets and children under six years of age 

and must be used in a manner that prevents such children from reaching into compartments and 

obtaining bait. Therefore. quantitative residential handler and post-application exposure 

assessments are not necessary to conclude with reasonable certainty that residential exposures to 

the cun-ently registered uses of warfarin do not pose a significant human health risk. 

6.1 Non-Occupational Bystander Post-Application Inhalation Exposure 

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report 

on March 2, 20103. The Agency has evaluated the SAP report and has developed a 

Volatilization Screening Tool and a subsequent Volatili zation Screening Analysis

4

• During 

1 See hnp://www.regulations.gov/#!documentDetail:D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 

2 h!m://www.epa.gov/endo/ 

3 http://www.epa.gov/scipolv/SA P/meetings/2009/ I 20 I 09mceting.htm I 

~ http://www.regulations.gov/#!dockerDetail;D=EPA-HO-OPP-2014-02 19 

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Registration Review. the Agency will utilize this analysis to determine if data (i.e .. route-specific 

inhalation toxicological studies) or further analysis is required for warfarin. 

7.0 Aggregate Exposure/Risk Characterization 

As quantitative dietary and residential exposure assessments are not required for warfarin 

because exposures are negligible and no toxicological points of departure have been established, 

a quantitative aggregate assessment is not required. lt can be concluded that aggregate exposures 

to the currently registered uses of warfarin do not pose a human health risk. 

8.0 Cumulative Exposure/Risk Characterization 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to warfarin and any other substances; and warfarin does not appear to produce a toxic metabolite 

produced by other substances. For the purposes of this action, therefore, EPA has assumed that 

warfarin does not have a common mechanism of toxicity with other substances. For information 

regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity 

and to evaluate the cumulative effects of such chemicals, see the policy statements released by 

EPA' s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA's website at http://www.epa.gov/pesticides/cumulative/. 

9.0 Non-Occupational Spray Drift Exposure 

The warfarin end use products are formulated as a bait block, a gel bait with a syringe 

applicator, and microencapsulated pellets on the inside of bait stations and will not result in spray 

drift due its application method in tamper-proof bait stations. 

10.0 Public Health and Pesticide Epidemiology Data 

For the Main IDS, from January 1, 2010 to May 27, 2015, there were no inc idents reported for 

the single chemical warfarin and its sodium salts in the database. There was one incident 

reported involving more than one chemical (including warfarin and its sodium salts) and was 

classified as moderate severity. 

In Aggregate IDS, from January l , 2010 to May 27, 2015, there was I incident reported 

involving warfarin and its sodium salts. This incident was classified as minor severity. Overall, 

there are few incidents reported to IDS involving warfarin and its sodium salts. 

The Agency will continue to monitor the incident information and provide an updated review of 

incidents, considering pre- and post-mitigation incidents separately, when the information 

becomes available. 

11.0 Occupational Exposure/Risk Characterization 

As mentioned in Section 3.3 .. warfarin is marketed as a bait block, a gel bait with a syringe 

applicator, and microencapsulated pellets on the inside of bait stations. The end-use products are 

packaged in bait stations or packaged in tamper-resistant bait stations (closed loading system). 

Occupational handler and post-application exposures are anticipated to be negligible since the 

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Warfarin Human Health Risk Assessment 0426574 

products are packaged in an enclosed system. Therefore, quantitative occupational exposure 

assessments are not necessary so it can be concluded that occupational exposures to the currently 

registered uses of warfarin do not pose a human health risk. 

12.0 References 

Memo, M. Dow et al., July 30, 2008; 0347731. 

Memo, S. Recore et al., November 24, 2015; 0426573, 0 426554 

Memo, M. Sahafeyan, et al., June 23, 2015, 0425410 

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