Warfarin Human H ea lth Ri sk Assessment 04 26574



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460

MEMORANDUM Dat e: Dece mb er 8 , 2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SU BJECT : Wa rfarin and Warfarin So dium Sa lt. Human Hea lth Assessment Scoping Document and D raft Human Health Risk Assessment in Support of Registration Review. PC Code: 0 860 02, 0 86003 D

ec i s io n No.: 502966 DP Barco de: 0426574 R

egis tr a ti o n Nos
. : 0011-1 Pe titi o n No
. : NA Reg ul ato ry Action: Regi stration Revi ew Ri s k Assessment C a se No.: NA Ri s k Assess me n t Type: Single Ch e mical TXR No.: A CAS No.: 81-81-2 MRID No.: 

### F ROM: A .i OCFR : NA 

### Monica Hawk ins , Ph.D. , M. P.H. , Epy iro nmental H ea lth

# ~cientist**Risk Assesso** **/~** Yung Yang. Ph.D. , Toxicol og ist

### ~-er 

### 6-. 

# g;-;r > // ,,,..____ Mohsen Sahafeyan, Chemist • . L c.,, /

- .../, 

### /1. · 

## '""e::.--7 Ri sk Asses s me nt Branch V I · H ea lth Effect s Division (7509P) 

### I /. THROUGH : Donna S. Dav is, Ac ting Branc h Chief \

# p)~Q.pRi s k Assessment Branch 

## vr 

# NJ '
TO: I lealth Effects Division ( 7509P) Ca itlin Newcamp. Chemical Review Man age r Melissa Grabl e, Team Lead e r Neil Anderso n , Branch Chief P es ticide Re- Eva l uation Division ( PRD/7508 P) This me morandum serves as HE D"s scoping document and draft human health risk assessment ( DRA ) under reg is tration rev iew for th e registered us es o f warfarin and warfarin so dium sa lt. 

### 1. 0 Exec utiv e S ummary H E D has evaluated the most r ece nt human he alth risk assessment for wa rfarin ( and warfarin so dium salt) to determine if s ufficient data are availabl e and if updates are needed to support regi s tratio n review. The latest ri sk assessment was co nducted in 2008 (D3 477 3 l , M. Dow , 7/ 30 / 2008). H E D has also cons idered updates to its toxicity , expo s ure and u sage databases , and the late st Agency sc ience p o licy and risk assessment me thodologi es. This mem o randum serves as HED's scoping document and draft human health ri sk assessment for warfarin. Page 1of9Warfarin Hum an H ea lth Ri s k Asse ss ment 0426574 Warfarin, a synthe ti c analogue of v itamin K. is a member of the coumarin family of blood anticoagu l ants. It is currently r egis te red for u se to contro l rodents in and a round home s a nd other reside n tia l bu il dings , commerc ia l buildings , industrial/agricultural building s . similar man mad e st ructures, inside transport vehicles (s hip s. trains , airc raft). and underground to control mol es in turf areas, go lf co urses, and ot he r non- g rass y a r eas . Warfa rin is marketed as a bait block. a gel bait with a syringe applicator. and microencapsulated pellets on the in s ide of bait stations. Th e reg istered products can be ap pli ed as a bait for rats and mice or applied as a gel bait that is in jected into the grou nd. The bait sta ti ons must be res istant to destructio n by pet s and children und e r six years of age and mu st be used in a manner that prevent s such c h ildren from reaching into co mpartm ents and obtaining bait. The labels state if a ba it can be shaken from stations w he n they are li fted, units must be secu r ed or o th e rw ise immobili zed
. No data deficiencies were id entified for the toxicology , residue chemistry , or occupational / resid e ntial exposure databases. Warfa ri n 's toxicity, m echanis m of ac t ion , an d method s for treatment of overdose in human s are well established given its broad use as a pharmaceutical. No animal toxicology stud ies are required fo r warfarin at this time. Dietary exposure is not expected and occupa ti onal/re s id ent ial expos ures are anticipated to be negligib l e from the current ly registe red uses of warfarin (bait in bait s tation s or packaged in tamper-re s is tant bait stations). Based on the negligible exposure potential of the currently reg istered u ses of warfarin, no toxicological points of d eparture ha ve been estab li s hed. As a result , quantitative ri sk assessments are not necessary to conclude with reasonab le cer tainty that exposures to the c urre n tly registered u ses of warfarin do not po se a significant human health r isk. 

### 2 . 0 H E D Reco mmend ations 2.1 Data Deficiencies


### o No n e. 

### 2.2 Tolerance Co ns ideration s Warfarin i s not a food-use chemical. The r e are no 

### U.S. toleranc es established for warfarin ; therefore tolerance considerations are not relevant to thi s action. 

### 2.3 Lab e l Recommendation s 

### HE D ha s r ev iewe d the warfar in labe ls and concludes that the y are adeq u ate and has no label r evisio n s recommendat ion s at this time. 

### 3.0 Introduction Warfarin [3-(alpha-ac e tonylbenzyl)

- 4-hydroxycoumarin] is reg i stered for use as a rode nti cide. Warfa rin be lo ngs to the coumarin family of bl ood anticoagulants. The sod ium sa lt of warfarin i s used as 

### an anticoagu lant in the treatment of individuals w ith hyper-coagu l ation p r ob lem s . The structure, chemical name, and other identifiers are fo und in the chemical identity table (Tab le 

### 3.l.l). 3.1 Chemical Id e ntity Page 

### 2 of9Warfarin Hum an H ealth Ri sk A ssess ment 0426574
Tab l e 3. 1.1. No m e n cla tu re of W arfar in 0

C h e mical st ructure

CAS name ran - 2 - one CAS registry number



### Pag e 3of 9Warfarin Human H ealth Risk Assess ment 042 6574 

### 3.2 Phys ic a l/C hemic a l C h a r a cteri s tic s

Tabl e 3.2.1. Ph ys icochemic a l Properti es of Warfarin
. P ara mete r Valu e R eference Ph ysical description White powder or crystal with no odor Melting point 159 to 165 ° C 0. 1 96 

### mg /

mL water at 25 ° C up to 8% in acetone up to 2% in e thanol. Re -registration Eligibility Water solubility The sodium salt Document , May 1991 formu lation is readi ly soluble in water. Octano l/water partition 2
. 37 coefficient , Lo g Kow 

### pH 7
. 2 to 8.3 in water 

### 3.3 Pe s ti cid e Use P a tte rn Warfarin is current ly reg istered for use to control rodent s i n and arou nd homes and other residential buildings , comm e rcial bu i lding s, industria l /agricultural buildings , similar man - made structures , in s ide transport ve hicles (s hip s. trains , aircraft) , and und e rground to control mol es in turf areas, golf courses, and o ther non- gra ss y areas . Warfarin i s m arketed as a bait block, a ge l ba it w ith a syringe applicator , and microencapsu lated pe llets on the inside of bait s tations. The labels state to apply the bait b l ock and gel ba it in bait s tations , as packaged bait stations containing microencapsulated pellets , or as packaged in tamper
- re s is tant bait s tation s if pet s . dome s tic animal s . non-target wildlife, and children m ay access th e bait. The reg i s tered produ c t s can be applied a s a 4 to 16 ounce bait at eac h placement location for rats and mic e, V4 to 

### Yz o unces or up to 2 ou nces (fo r a lot of mo u se act iv ity) bait at each p lacement location for m ice , or applied as a gel bait with up to 1 syringe that is injecte d into the g round at each ba i t placement location per l 0.000 square feet. The bait s tations mu st be resistant to destruction by pets a nd children under s ix years of age and must be u sed in a manner that prevents such children from reach i ng into compartme nts and obtain i ng bait. The lab e ls state if a bait can be s haken from stations when they are li fted , units must be se cured or otherw ise immobilized
. In 2008. th e Agency issued a Ri sk Mitigation Deci s io n ( RMD ) for te n rodenticide s . of which warfarin was inc luded. The mitigation decision set restrictions in order to minimi ze rod e nticide exposu r e to c h i ld ren , wi ld li fe a nd domest ic anima ls . The risk m it igation decision does no t apply to rodenticide fi e ld ( non-commensal rodents) uses or tracking powd e r products. A brief summary i s below. The d e tails of the RMD can be fou nd in docket number E PA -HQ-OPP- 2006

- 0955- 0764 at www.regulations.gov.

• Consumer-use**product s(** **~** I lb.) , o E ach product mu s t include at le as t o ne bait s tation and may include bait refill s. Page 4 of9Warfarin Human Health Ri sk Assessment 0426574

o Wh e n applied outdoors above ground a nd in areas accessible to children, non-ta rge t w il dlife o r domest ic anima ls, baits must be contained in ba it s tati ons . o Products fo r u se o utdoors and above-ground must be pl aced wi thin 50 feet of a bu ildin g. • Profe ss io na l-u se product s o Mu s t be so ld in quant it i es of ::: 4 lb s. (first-generation anticoagulants/ non**anticoagu ants)~**  o M ay not be offe red fo r sa le in con s um e r s t o re s (hard war e, g rocery , etc.). o Must also be placed w ithin l 00 feet of a structure (fence and perimeter baiting beyond l 00' of a man-made struc ture are prohibited) w he n u sed o utdoo rs and above gro und , see 

### 50 foot Documenr Clarifica tion Le if e r to 

### Bell (03.20. 12 ) (sig ned) in docket numb e r E PA- H Q-OPP- 2 006

- 0955-08 2 0 fo und at · .vww.reg ul at ions . gov . o For uses of first

- ge neratio n anticoagulants o r no n- anticoagu lant s, produ ct label s require bait stat ions if children , wild li fe or domestic ani mal s may be exposed. 

### 3 .4 Co n s id erati on of E n v i r onm ental Ju s tice P otential areas of environmental justice concerns, to the extent possible
. were considered in this human health ri sk assessment , in accordance w ith U .S. Exec utive Order 12 8 98 , "Federal Ac ti o n s to Address E n v ironmental J u st i ce in Minority Pop ulation s and Low

- Income Populations ," ( http: //www.a rchi ve s . gov/ fcdera l-regi ste r / executive-orders/ pdf/ 12 898
. pdf). As a part of every pesticide ri s k assessment. OPP considers a l a rge variety of consumer subgroups according to well

- estab li s hed procedur es. In lin e w ith O PP policy, HED es tim ates ri sks to pesticide exposur es that are based on activit ies in and around th e home th at in vo lve p est ic ide use in a residential setting
. Whenever appropriate. these non - dietary exposures are calculated ba sed on home u se of pesticide products and associated ri sks fo r adult app licator s and for toddlers , yo uth s, and adu l t s e nte ring or p lay in g o n treated areas po st -applicati o n are evaluated. 

### 4
. 0 Ha za rd C h a racteriza tion a nd D ose -Res ponse Assess m ent 4
. 1 Tox ico logy An a l ys is Warfarin, a sy nthetic analogue of vitamin K, is a member of the coumarin fam il y of b l ood anticoagulants. The sodium sa lt of warfarin is u se d as an anticoagu lant in the treatme nt of individual s w ith hyper-coagulation problems. T here are no g uid e line animal studi es available in the warfar in database ; however , its toxicity , mechan ism of ac ti on, and tr eatme nt of overdose in humans are we ll es tabli shed given its broad use as a phannaceutical. Guideline st ud ies are r equired for no n-food use pesticides in accordance with the c urre nt 40 CF R Part 1 58 Toxicology Data Re quire m e nt s; ho weve r, the HAS P OC concluded ba se d on a we i g ht-of- ev id e nce approach that these st udi es are not req uire d at thi s time du e to the lim ited ex posure pattern of warfari n and t h e qualitative nature of the ri sk assessme nt. [f the use pattern were to change , o r ne w policies /procedures are put into place , then the need for these studies m ay be revisited. T he TOXLINE (Natio nal Library of Medicine) database literatur e search did not identify any n ew toxicological i nformati o n not a lready co n s id e r ed. Page 5of9Warfarin Human Health Ri s k Assessmen t 0426574 Warfar in toxicity is mani fested as an increa se in prothrombin and partia l thromboplastin times and a decrease i n the v itamin K-dependent clotting factors , II , VII , IX and X. Bleeding t i me , clot retraction , p latelet counts, thrombin time , and e ug lobulin lysis time s are usually no1mal. Signs of toxicity include cutaneous bleeding , hematuria , melena or h ematoc hezia , hematomas , uterine bleeding in wome n , and ep is taxis and gingival bleeding. Death follows excessive external and/or internal bleeding. As a member of the coumarin fa mily , warfarin has been established as a human teratogen i n clinical doses since coumarin derivative u se or abuse in mothe rs (human) duri ng gestation has been reported to re su lt one-sixth of pregnancies ending in abortion or s tillbirth and about two-thirds end ing with a relatively normal o utcome. 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 (Toxic ity Category Ill ). lt is not an eye or skin ir ritant. A skin hyperse n s itivity study was not available; however, human data indicate that warfarin does not i nduc e an allergic reaction. 

### 4 . 2 Co n s id e ra tion of T ox ici ty to C hildre n Food Quality Protection Act (FQPA) considerations do not apply to warfarin for the currently registered (non-food) u se patterns describ ed in this risk assessment. 

### 4.3 E ndocrine Di s rupti o n As required by FIFRA and FFDCA, EPA reviews numerous s tudi es to assess potential adverse outcomes from exposure to chemicals. Co ll ecti ve ly , these st udi es include acute, subchro nic and chronic toxicity , including assessments of carcinogenicity, ne urotoxicity , deve lopmental , reproduct ive, and ge nera l or systemic toxic ity. These studies include endpoints which may be susceptible to endocrine influence , includin g effects on endocrine target organ hi stopatho lo gy, organ weights , estrus cyclicity , sexual maturation, fertility. pregnancy rates , reproductive loss. and sex ratios in offspring. Fo r eco logic a l hazard assessments. EPA evaluates acute tests and chronic s tudi es that assess growth , developme ntal and reproductive effects in different taxonomic gro ups . As part of its most recent reg istrati on decision for warfarin, E PA review ed these data and selected the mo st sensitive e ndpoints for relevant risk assessment sce nario s from the existing hazard databa se. However, as req uired by FFD CA sec tion 408(p) , warfarin is subject to the endocrine screening part of the Endocrine Disruptor Screening Progra m (E DSP ). EPA has developed the EDS P to determine whether certain substances ( includin g pesticide active and other ingredient s) may have an effect in humans o r wi ldlife similar to an effect produced by a " naturally occurring estrogen, or other such e ndocrine effects as the Admi nistrator may designate." The EDSP employs a two-tiered approach to making the statutor il y required determinations. Tier 

### 1 consists of a battery of 

### 11 screening assays to identify th e potential of a chemical substance to interact with the estrogen. androgen. or th yroid (E , A, or T) hormonal systems. Chem icals that go through Tier 1 screening and are found to have th e potential to interact with E, A, or T hormonal systems will proceed to the next stage of th e EDSP where EPA w ill determine which, if any , of the Tier 2 te sts are nece ssa ry based on the avai lable data. Tier 2 testing is designed to identify any adverse e ndocrine-related effects caused by th e substance , and establish a dose-response re latio nship between the dose and the E, A , or T effec t. U nder FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between Page 6of9Warfarin Human Health Risk Assessment 0426574 October 2009 and February 2010, EPA issued t est orders / data call-ins for the first gro up of 67 chemicals, which contains 58 pesticide active i ngredients and 9 inert ingredients. A second l ist of chemicals identified for EDSP screening was published on J une 14 , 2013 1 and includes some pesticides schedu l ed for registration review and chemica ls found 

### in wate r. Neither of these li sts should be construed as a li st of known o r li kely endocrin e di srupto rs . For further infom1ation on the status of the 

### EDSP, the policies and procedures , the l i sts of chemicals, future list s, the test guidelines and the Tier 1 screening battery. please visit our website
. 2 

### 5. 0 Dieta ry Ex p os ure and Ri s k Ass ess ment Based on the registered rodenticide use, residue data are not r eq ui red and no ne have bee n submitted. Warfari n i s s tr ictl y a no n- foo d use r oden ti c ide. T he end- u se prod uct packag ing and use (bait in bait stat ions or packaged in tampe r-resistant bait s tations) res ul t i n neg li g i ble exposure to human food or drinking water. Furthermore, warfarin has very low water so l ubil i ty ( 17 mg/ I) and no measureable concentrations of warfarin are expected in drinking water; therefore , a quantitati ve drinking water assessment was not conducted by the Environmental Fate and Effects Di visio n (EFE D )
. 

### 6. 0 Re s idential ( No n-Occupational) E xpo s ure and Risk As sess ment Res i dential handler and post-app li cation exposures from warfarin are expected to be neg ligib le s ince the registered product labels state to apply the ba it 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 childre n under six years of age and must be used in a manner that prevent s s uch children from reaching into compartments and obtaining bait. Therefore. quantitative residential handler and post-app l ication exposure assessments are not necessary to conclude with rea so nable certainty that res idential exposures to the cun-ently registered u ses of warfarin do not pose a significant human health risk
. 

### 6
. 1 Non-Occupational By s tand e r Post-Application Inhalation E xpo s ure Volatilization of pesticides may be a source of post-app l ication inhalation exposure to individuals nearby pesticide applications. The Agency sought expert adv ice 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, 2010 3

. The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volat ili zation Screening Ana lys is 4 • Duri ng

1 See hnp: //www.regulation s .gov /# !documentDe t ail:D =EPA-HQ-OP PT- 2009

- 0477

- 0074 for the final second list of chemicals. 2 h!m: //www.epa.gov/endo /
3 http: //www.epa.gov/ scipo lv / SA P / meeting s/2009/ I 20 I09mceting.htm I**~** http: // www.regulations.gov/# !dockerDetail;D = EPA-HO-OPP-2014-02 1 9 Page 7of9Warfarin Human Health Ri sk A ssessment 0426574 Registration Review. the Age ncy will utilize this analysis to determine if data (i.e
.. route
- specific inhalation toxicological st udi es) o r further analysis is required for warfarin. 

### 7.0 Aggregate E xpo s ure/Risk Characteri za tion As quantitative dietary and residential expos ure 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. l t can be concluded that aggregate exposures to the currently registered uses of warfarin do not pose a human health risk. 

### 8
. 0 Cumulative Ex po s ure/Ri s k Characterization Un li ke other pestic id es for which EPA has fo ll owed a cumulative risk app roac h ba sed on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to warfarin and any othe r s ub stances; and warfarin does not appear to produce a toxic metabolite produced by other subs tances. 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 effor t s to determine w hi ch 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 P esticide Pro grams 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/ c umulative/
. 

### 9.0 Non-Occupational Spray Drift Ex po s ure The warfarin end use products are formulated as a bai t 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 P esticide Epidemio l ogy Data For the Main IDS , from January 1, 2010 to M ay 27 , 2015 , there were no in c ident s reported for the single chemical warfarin a nd 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 J anuary 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 in vo lv in g warfarin and its sod ium sa lt s. The Agency will continue to monitor the inc ident information and provide an update d re v iew of in cidents, considering pre- and post-mitigation incidents separately, when the information becomes available. 

### 11.0 Occupational Ex po s ure /Ri s k C har acteriza tion As mentioned in Sec ti on 3.3
.. warfarin is marketed as a bait block , a gel bait with a syringe app licator, and microencapsulated pellets on the inside of bait stations. The end-use products are packaged in bait stations o r packaged in tamper-resistant bait stat ion s (closed loadi ng system). Occupational handler and post-applicat ion expos ure s are anticipated to be neg li g ible s in ce th e Page 8of9Warfarin Human Health Risk Assessm e nt 0426574 

### products are packaged in an enclosed system . Th erefore, quantitative occupational exposure asse s sments are not necessary so it can be concluded that occupational exposures to the curre n tly regi s te re d u se s of warfarin do not pose a human health risk. 

### 12.0 Reference s Memo , M
. Dow 

### e t al. , July 30 , 2008 ; 0347731. Memo, S. Recore 

### e t al. , Novemb er 24 , 2015; 0426573, 0 426554 Memo , M
. Sahafeyan , et al. , 

### J une 23 , 2015 , 0425410

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