### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D.C

. 20460

OF F IC E OF CH EMI C AL SAF E TY A ND P O LLUTION PRE V ENTION



### MEM ORA NDUM

D A T E: March 16

, 2016

SU B JEC T : Dif e n aco um

. 

### R evise d Human Health Assessment Scoping Docum ent in Support of R eg i strat ion Review.

P C Co d e: I 1990 l D ec i s i o n No. : ..f/>070 P e tition No .: NA DP B a r co d e: 0 43229 1 R eg i s tr a ti o n N o .: NA R eg ulat o r y Action: 

### Registra t i o n Rev i ew Case No. : 7630 Ri s k Assess m e nt T y p e : 

### Single ChemicaVe TXRNo.: NA CAS No.: 56073-07

- 5 

### 4 0 CFR : NA 

### MRID No.: NA



### F ROM :

THRO UG H :

T O : Margarita C

. 

### ollantes, M. S

. , Biolo gist

## ~?~i/t-· 

# !°d'fc»iL!:z..-.-
Jaim e D" Agostino

, Ph.D.

, Toxicologist**~** 

### Risk Assessme nt Branch II (RA B 2) Health Effects Division (7509 P )

Christina Swartz, Branch Chie f

# c:S:l~-- Ri s k Assessment Branch 

### II (RAB2) \**~** 

### Jes s Rowland, Deputy Division Dir ec tor 

# <:]--- ::;;.**~** 

### Je ff Dawson

, Acti ng Deput y Division Director Health Effects Division (7509 P) Office of P est i cide Programs

Ricardo Jones, Che mical R eview Manager R i sk Management and I mplementation Branch I 

### (RMIB l ) Pe s ticide Reevaluat i on Divi s ion (PRO) (7508P)

As part of R eg istrati on Review

, the Pe st icide Ree va luation Di visio n ( PRO ) has requested that the Hea l th Effec ts Divi s ion (HED) provide a human h ea l th risk assess ment sco ping document for the

r o denticid e agent difenacoum to s upport Registrati o n Review. This document was revised to include the correct d ate of the Hazard Assessment and Science Policy Cou ncil (HASPOC) decision m e mo a s well as the current methodology u se d to determine the dermal abso rption for cl i fenacoum. The mo st recent ri s k assessment fo r dif e nacoum was conducted in July

, 20, 2007 (K. Sc humach er, 0 330185).

Pa ge I of24

### Exec uti ve S umm ary



### H ED has p r epared a scoping document to support Registration R ev i ew for di fenaco um (3-(3- bipheny l- 4-yl- 1

, 2 ,3,4

- t et r ahydro- 1

- n aphthy l)-4

- hydroxycoumarin ). Difenacoum is a second generation anticoagulant rod e nticide. Di fe nacoum i s re g i s tered to co ntrol hou se mice

, a variety of rats as well as subterranea n co ntr o l of rats and voles in burrows inside and within 50 to 10 0 feet of agricultural buildings

, man

- made agricu ltural s tructure s , residential hom es, processing facilities, indu s tria l and commercial buildin gs, trash receptacles

, public buildings

, transport vehicles (ships

, trains and aircraft), dock s , ports and terminal build i n gs. Ther e are curren tl y s ix d i fe na coum e nd-u se products comprised of 0.005 % 

### ac ti ve ingredient (ai) and formulated as p e ll ets, blocks

, and ready-to-use place p acks. Second-generation anti-coagulant rodenticides

, consumer-use products (i.e., products 

### '.S I lb ) containing difethial o ne are prohibited. Profe ssional/ commercial us es of second-generation anticoagulants

, require ba i t st at i o n s for a ll o u tdoors and above-ground placements and/or indoor placements where children

, wildlife or domestic animals
may be exposed. Furthermore, commerc i a l l abels prohibit broadcast ap plication of pellet baits. Products that are intend ed primaril y for use in and around agricultural st ru ctures are packa ge d in i nd i vid u al containers ho l din g no less than 8 pounds (lbs) of bait. Products int e nded for

co mmercial / professiona l u se a r e packaged in individual containers holding no le ss than 1 6 pounds (l b s) of bait.

D i fe nacoum i s a racemic mi x ture ; both th e 

### cis- and 

### tran s- isomer s are pesticida ll y active. To eva luate t h e scope of work necessary to support Re g i s trat i on Rev i ew, HED h as conside r ed
recent risk assessments fo r difenacoum

, updates to its to x icity, exposure , and u sage databa ses , and the late st Age nc y science policy and risk assessment methodologies.

Th e toxicology database for dif e nacoum i s cons i dered adequate for risk asse ss ment except fo r t h e la ck of an inha l ation and a d e rmal study (00573 84, U. Habiba

, 3/1 / 20 16 ) which a r e required at t h i s tim e. An 

### alternative to cond u cting an inhalation study wou ld be to add addit i onal PP E ( i. e., u se of r esp irator s) to registered labels which woul d address ri sks of co n ce rn r es ultin g from inhal at i o n

ex p os ures to a point where th e margin s of expos ure (MO E s) ba sed o n the H aza rd Assessment and Science Po li cy Co uncil ( H ASPOC) screening criter i a wou l d no lon ge r be of concern. Ba se d on th e low MOEs calculated for dermal exposure , lab e l changes are not an o ption instead of

co nductin g a dermal stu d y. H ED also determ ined that a 2

- ge nerati on reproduction stu d y , an acute

n e urotoxicit y battery, a s ub chro ni c neurotoxicity battery

, an d an immunot ox i c it y st ud y are not
requ i red for dif e nacoum (005 7 3 84

, U

. Habiba

, 3 / 1

/2 016). Dur i n g Regi s tration Review

, the Agency m ay update POD s and tox ic o l og i ca l e ndpoint s based o n updated policies for e ndp o int

se l ec ti on.

Dif e nacoum inhibits the r ege n e ration of v itam i n K

, w h ich d ec r eases th e sy nthesis of blood
coag u l ation factors and can l ead to hem o n-hag i n g and death. Evidence of th ese a n t i coagu l ant effects

, consisting of clinical s i gns , effec t s on clotting tim e, hemorrhaging, and s ub s equent death

were o bserv ed in a ll spec ie s t es t e d in the ava il ab l e mammalian studies. Since difenacoum affects the syn the s i s of n ew clotting factors, rather than directly affecting the circulating factors, a l a t e nc y p e ri od typically ex ists between the t i me of exposu r e and the t i m e of effect that i s depende n t upon th e half

- li ves of the circulating clotting facto r s. No o ther types of adverse effects were observed in the datab ase. including neurotoxicity. immunotoxicity, or developmental effects. Th e acute

Pa ge 2 of24

### Page 3 of 24

toxicity of difenacoum is severe via the oral, dermal, and inhalation routes of exposure (Category I). Difenacoum is not an eye or dermal irritant, nor is it a dermal sensitizer.

In th e previous 200 7 assessment dietary ( f ood and drinking water ) exposures were not quantified because of the limited use pattern (strictly non

- food rodenticide use with no dietary exposure). A quantitative assessment was performed for commercial and residenti al exposure only. T herefore an aggregate risk assessment was not conducted

.

A short term (ST) dermal and inhalation occupational and commercial handler exposure assessment will be required during Registration Review based on the potential exposure to ha ndlers (loaders, applicator, etc.) during the use of di fenacoum

. Applicator/handler e xposure to products formulated as blocks, and ready

- to

- use placement packs is considered to be negligible. However, applicator/handler assessments will be conducted for the loose pellet formulation only. Occupational post

- application exposure is not expected due to the expectation of no significant surface residue from solid formulation applications nor worker contact with surfaces containing residues in areas treated with dife nacoum products

. Consumer use products may not contain second generation anticoagulants. Therefore, residential applicator/ handler exposure will not be assessed. Re sidential p ost

- applic ation exposure is not anticipated as product s must be placed in tamper resistant packaging if used above ground or where children, may be exposed

. There have been recent changes in occupational and commercial assessment assumptions since the previous

asse ssments that will need to be incorporated during Registration Review along with any changes to reevaluate the points of departure , toxicity endpoints, and uncertainty factors u sed for risk assessment purposes

. Exposure from s pray drift and volatilization is not anticipated for the current di fenacoum use pattern

.

I ntroduction

Difenacoum (3

- (3

- biphenyl

- 4

- yl

- 1,2,3,4

- tetrahydro

- 1

- naphthyl)

- 4

- hydroxycoumarin) is a second generation rodent control agent registered for the control of house mice, a variety of rats as well subterranean burrows control of voles in and around agricultural , man

- made agricultural structures, residential homes, processing facilities, industrial and commercial buildings, trash receptacles, public buildings, transport veh icles (ships, trains and aircraft), docks, ports and terminal buildings

. It is a warfarin

- like compound that acts as an anticoagulant and is formulated as paraffin pellets, bait ready

- to

- use place packs, and paraffin blocks. All products contain 0.005
pe rcent active ingredient

. The most recent human health risk assessment was finalized in July 2007 ( K . Schumacher ; D330185 ).

In 2008, the Agency issued a risk mitigation decision for ten rodenticides, of which di fenacoum was included. The mitigation decisi on set restrictions in order to minimize 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. However, it should be noted that difenacoum has no tracking powder end use 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.

### Page 4 of 24

Consumer

- use products (≤ 1 lb.)

 Second

- generation anticoagulants are proh ibited as well as loose treated whole

grain/pellets/meal as a form for indoors and above ground outdoor uses.

Professional

- use products

 Must be sold in quantities of ≥ 4 lbs. (first

- generation anticoagulants/non

- anticoagulants), ≥ 8 lbs. (second

- genera tion anticoagulants; agricultural building areas) and ≥ 16 lbs. (second generation anticoagulants; above ground outdoors)

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

 Must also be placed within 100 feet of a structure (fence and perimeter baiting beyond 100’ of a man

- made structure are prohibited) when used outdoors and above ground, see 50 foot Document Clarification Letter to Bell (03.20.12) (signed) in docket number EPA

HQ

- OPP

- 2006

- 0955

- 0820 found at www.regulations.gov.

 For uses of first

- generation anticoagulants or non

- anticoagulants, product labels require bait stations if children, wildlife or domestic animals may be exposed.

 For uses of second

- generation anticoagulants, labels require bait stations for all outdoors and above

- ground placements and/or indoor placements where children, wildlife or domestic animals may be exposed.

The majority of di fenacoum products are applied u sing tamper resistant bait stations, which are required for all rodenticides where children and pets may be present per 2008 anticoagulant rodenticide mitigation. However, tamper resistant bait stations are not required for below

ground burr ows

. If below

- ground application of bait is performed properly according to product labels, no bait should be available above ground for exposure to children or non

- target animals. See use profile table in the a ppendix (attachment 3) for more information on application rate and application methods of di fenacoum products

. Hazard Identification/Toxicology

D ifenacoum is a vitamin K antagonist. Vitamin K is essential for the blood to clot, which prevents the loss of significant amounts of blood resulting from internal b leeding that occurs under normal circumstances, such as with breached blood vessels, or as a result of injury. Difenacoum and the other anticoagulant rodenticides inhibit vitamin K epoxide reductase, blocking the regeneration of vitamin K to its active form. Because the amount of vitamin K in the body is finite, blocking the regeneration of vitamin K leads to depletion of the clotting factors, which causes the coagulation process to become progressively less effective and can lead to massive internal he morrhaging and, ultimately, death.

The toxicology database for dif enacoum includes: the acute six

– pack of studies, a non

- guideline 6

- week oral study in dogs, a developmental study in both rats and rabbits, a mutagenicity battery of studies, and a metaboli sm study in rats. B ased on a weight of evidence approach considering all the available hazard and exposure information, HED determined that the reproduction, acute and subchronic neurotoxicity, and immunotoxicity studies are not required at this time ( 005 73 84

, U. Habiba, 3 /1/201 6 )

. Using the same approach, HED determined that a subchronic dermal

### Page 5 of 24

study and a subchronic inhalation study are required at this time for difenacoum ( 00573 84 , U. Habiba, 3 /1/201 6 )

. An alternative to conducting an inhalation study would be to add additional PPE (i.e., use of respirators) to registered labels which would address risks of concern resulting from inhalation exposures to a point where the margins of exposure (MOEs) based on the H ASPOC screening criteria would no longe r be of concern. Based on the low MOEs calculated for dermal exposure, label changes are not an option instead of conducting a dermal study.

In the previous risk assessment, HED recommended that an in vivo dermal absorption study in rats be required as a condition of registration. The study has not been submitted ; however, HED has determined that the study is not required at this time because the dermal absorption can be determined using a weight of the evidence approach considering the currently availab le data. The physical chemical properties of difenacoum (molecular weight of 444.5 g/mol and log Kow of 6 .1 ) support a low dermal absorption. In addition, the European Food and Safety Authority (EFSA), as part of their evaluation of difenacoum in 2008, us ed a dermal absorption factor of 3% based on an in vitro study conducted with human skin. Furthermore, using the National Institute for Occupational Health and Safety (NIOSH) F inite D ose Sk in P ermeation C alculator ( http://www.cdc.gov/niosh/topics/skin/finiteSkinPermCalc.html ) and the physical chemical properties of difenacoum (see appendix 7 for a full list ), a predicted dermal absorption fact or of 0.5 % was obtained over an 8 hour period with a dermal load of 0. 52 μg/cm 2



### . The dermal load of 0. 52 μg/cm 2 

### was derived by taking the expected daily exposure (0. 572 mg) and dividing by the entire surface area of the hands (~ 1100 cm 2 

### )

. The Finite Dose Skin Permeation Calculator was developed through support of a Center of Disease Control/National Institute for Occupational Safety and Health (CDC/NIOSH) grant, and provides an estimation of fluxes, skin concentrations, and amounts absorbed from any size dose applied to partially or fully hydrated skin, using the physicochemical properties of the test compound and defined exposure parameters (Kasting, G.B. 2006; Wang, T.F. 2007; Kasting, G.B. 2008; Miller, M.A. 2010). Currently, OPP does not rely on (Q)SA R modeling alone to derive a Dermal Absorption Factor (DAF) for risk
assessment. However, estimates from the Finite Dose Skin Permeation Calculator may be used with read across data to support a weight of the evidence evaluation. Based on a weight of t he evidence approach, the dermal absorption of difenacoum is likely less than 4%; however, HED chose a dermal absorption value of 4% as a conservative estimate based on the available data.

D ifenacoum inhibits the regeneration of vitamin K, which decreases the synthesis of blood coagulation factors and can lead to hemorrhaging and death. Evidence of these anticoagulant effects, consisting of clinical signs (pallor, lethargy, decreased activity, subdued appearance, and piloerection, effects on clotting time (increased prothrombin and Kaolin

- cephalin times)

, hemorrhaging, and subsequent death were observed in all species tested (dogs, rats, mice, and rabbits) in the available mammalian studies. Since difenacoum affects the synthesis of new clotting factors, rather than directly affecting the circulating factors, a latency period typically exists between the time of exposure and the time of effect that is dependent upon the half

- lives of the circulating clotting factors. For example, death and clinical signs were not observed until 5

- 8 days following an acute oral exposure. Similarly, effects in repeat dosing studies did not occur until late in the studies; effects on clotting time w ere first seen at around day 30 in the 6

- week dog study. The delayed effects of the chemical were to some extent related to dose; in the 6

- week dog study the effects on clotting time were seen earlier in dogs that received higher doses. No other types of adverse effects were observed in the database , including neurotoxicity, immu notoxicity,

### Page 6 of 24

or developmental effects

. The acute toxicity of difenacoum is severe via the oral, dermal, and inhalation routes of exposure (Category I). Difenacoum is not an eye or dermal irritant, nor is it a dermal sensitizer.

At the time of Registration Review or the next risk assessment, the Agency may update PODs and toxicological endpoints based on updated policies for endpoint selection

. Additionally, the uncertainty factors will be reassessed in the context of the updated PODs and endpo ints. Please refer to Attachment 4 for a summary of the toxicity endpoints and points of departure ( PODs ) from the previous risk assessment and Attachment 6 for the c omplete toxicity profile table.

Conclusions : The toxicity database is adequate for the p urpose of registration review, except for the lack of an inhalation study and a dermal study which are required at this time

. An alternative to conducting an inhalation study would be to add additional PPE (i.e., use of respirators) to registered labels which would address risks of concern resulting from inhalation exposures to a point where the margins of exposure (MOEs) based on the Hazard Assessment and Science Policy Council screening criteria would no longer be of concern. Based on the low MOEs calc ulated for dermal exposure, label changes are not an option instead of conducting a dermal study. At the time of Registration Review

, the Agency may update PODs and toxicological endpoints based on updated policies for endpoint selection.

Residue Chemistry and Dietary Exposure

There are no agricultural field crop uses of di fen a coum , nor are there any tolerances established or needed. Furthermore, based on difenacoum’s physicochemical properties, no measurable concentrations are expected i n drinking water.

Conclusions : A new dietary (food and water) exposure assessment is not anticipated to be needed during Registration Review.

Residential Exposure

Residential Handlers Consumer use products may not contain second generation anticoagulants. Therefore, all Sublabel A Consumer Use labels expired June 4, 2011 and are thus no longer actively registered.

Residential Post

- Application Post application exposure to products placed in t amper resistant bait stations or below ground are not anticipated. Tamper resistant b ait stations are mandatory for any bait placed above ground where childr en and/or pets may be present.

Non Occupational Spray Drift or Volatilization Since difenacoum i s applied as a solid formulation by hand, largely in tamper

- resistant bait stations, neither exposure via drift or volatilization is expected.

### Page 7 of 24

Conclusions: N e ither a residential handler nor post

- application assessment will be required during Registration Review. A dditionally, neither exposure via drift or volatilization is expected.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act , HED must consider and aggregate pesticide exposures and risks from three major sources: food, d rinking water, and residential exposures. B ased on the registered uses, HED does not anticipate dietary ( food or drinking water ) or residential exposure due to the lack of consumer product use and requirement for bait stations where children are present

. Therefore, an aggregate risk assessment is not anticipated for children or adults

.

Conclusions : A n aggregate risk assessment is not required for children or adults during Registration Review based on the current difenacoum use pattern and formulations

. Occupational Exposure

O ccupational Handler Exposure In the previous 2007 assessment , d ifenacoum pellets and place packs were formulated as ready

to

- use; therefore, an assessment of mixer/loader exposure was not conducted. HED used PHED (Granular Bait Dispersed by Hand) to assess occupational applicator exposure. Applicator exposure was assessed for the maximum application rate ( i.e. , 7 oz of product) and 4 treatment sites. The level of concern (LOC) is equal to a margi n o f exposure ( MOE ) of 100 or greater. The

r isk estimates for all applicator scenarios result in MOEs equal to or greater than 870 and were not of concern.

Occupational handlers are anticipated to have short

- term dermal and inhalation exposures from apply ing difenacoum products

. Occupational dermal and inhalation exposure to bait blocks , and disposable placement packs is considered to be negligible. Intermediate

- and l ong

- term occupational exposure is not expected. The registered end use di fenacoum products require occupational handlers to wear long sleeved shirts, long pants, shoes, socks, and in some cases water proof gloves. Currently r egistered labels for pelleted products do not provide sufficient guidance regarding a method or use of container for measuring specified amount of bait per refillable station, nor a maximum number of refillable bait stations within the 100 foot perimeter of agricultural and commercial buildings. An u pdated occupational handler exposure assessment will be conducted during Registration Review. The revised assessment will include updated policies and body weight assumptions as well as any additional information provided by the registrant regarding methods for applying bait to refillable stations and maximum number of bait stations per 100 foot perimeter.

Occupational Post

- Application Exposure There is no anticipated occupational post

- application exposure to the current use pattern of di fenacoum

. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application exposure assessment for di fenacoum

.

### Page 8 of 24

Occupational Handler and Post

- Application Exposure Conclusions : An u pdated occupational handler exposure assessments will be conducted during Registration Review. Additional information regarding the maximum number of refillable trap/bait stations within the 100 foot perimeter of agricultural buildings could be beneficial in estimating potential handler exposure and risk. Occupational post

- appl ication exposure is not anticipated for Registration Review.

Public Health and Pesticide Epidemiology Data

As part of the Rodenticide Risk Mitigation Decision (RMD), and the subsequent Notice of Intent to Cancel (NOIC), the Environmental Protection Agenc y’s Office of Pesticide Programs’ Pesticide Re

- evaluation Division requested an analysis of human incidents involving exposure to rodenticides in 2011 (S. Recore, 10/28/2011, D395567) and updated in 2015 ( S. Recore

, D 430176, 11/17/2015 )

. For this evaluati on, the Agency consulted the OPP Incident Data System (IDS), t he National Pesticide Information Center ( NPIC ), Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH), Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) , and Agricultural Health Study (AHS) databases for pesticide incident data on the active ingredient difenacoum

.
For the Main IDS, which contains incidents resulting in higher severity outcomes (i.e., death, major and moderate incidents ) from January 1, 2010 to May 27, 2015, there were no incidents reported involving difenacoum. In Aggregate IDS, which contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes) , there was one incident reported involving difenacoum. The incident was classified as having no or unknown effects. Overall, there are few incidents reported to IDS involving difenacoum. A query of SENSOR

Pesticides from 1998

- 2011, identified no cases involving difenacoum. Difenacoum is not included in the AHS; therefore, that study does not provide information for this document.

T he Agency will continue to monitor the incident information and provide an updated review of incident, considering pre

- and post

- miti gation incidents separately, when the information becomes available.

Tolerance Assessment and International Harmonization

There are no tolerances for di fenacoum

.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possibl e, 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.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according t o 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

### Page 9 of 24

for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated.

Cumulative

Unlike other pesticides for which EPA ha s followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to di fenacoum and any other substances and di fenacoum does not appear to produce a toxic metabolite produced by 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 Pesticid e 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/cumula tive/.

Human Studies

The risk assessments which have been previously conducted for di fenacoum rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Ha ndlers Exposure Database (PHED), and the Outdoor Residential Exposure Task Force (ORETF)

. EPA has reviewed all the st udies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and
t here is no regulatory barrier to continued reliance on these studies

.

Data Deficiencies and Label Revisions

The following studies are required to support Registration Review of difenacoum:

870.3200 21/28

- day dermal toxicity 870.3465 90

- day inhalation study

Due to the expected short

- term nature of occupational exposure, a shor ter term inhalation study (21/28

- day inhalation study) is appropriate

.

No residue chemistry, or occupational and residential exposure data are needed to support the registered uses of di fenacoum at this time

. HED recommends that PRD ensure that all expired difenacoum Sublabel A Consumer Use labels be removed from the Pesticide Product Label System ( PPLS ). Furthermore, HED recommends that bait pellets are packaged with a measuring cone container and instruction s for refillable bait stations.

### Page 10 of 24

References

Recent Memoranda Relevant to Registration Review of Di fenacoum

Author DP/TXR # Date Title

Risk Assessment

K. Schumacher D330185 July 20

, 200 7 Difenacoum: H uman Health Risk Assessment for Proposed Uses on Commensal Rodents

. Not available May 28, 2008 (revised June 24, 2008) Risk Mitigation Decision for Ten Rodenticides
Occupational and Residential Exposure Assessment

M. Collantes D 3 3 8316 June 2007 OCCUPATIONAL AND RESIDENTIAL EXPOSURE ASSESSMENT for Section 3 Registration Use of Difenacoum Incident Report

J. Blondell EPA

- HQ

OPP

- 2006

- 0955

- 0010 June 3, 1999 Updated Review of Rodenticides Incident Report s Primarily Concerning Children

M. Hawkins D 332563 January 9, 2006 Rodenticide: Tier I (Scoping) Review of Human Incidents and Epidemiology Assessment S. Recore, D430176, November 17

, 2015



### Attachments

1. Chemical Identity Table 2. Physicochemical Properties of Technical Grade Di fenacoum Table 3. Use Profile Table for Di fenacoum 4 . Endpoint Selection Table s 5. Toxicology Data Requirements 6 . Toxicity Profile Tables 7. Physical and Chemical Properties for Assessing Dermal Absorption

### Page 11 of 24

Attachment 1

Chemical Identity Table

Table A .1. Difenacoum Nomenclature. Chemical Structure

Common Name Difenacoum, diphenacoum Molecular Formula C 31 H 24 O 3 Molecular Weight 444.5 IUPAC Name 3

- (3

- biphenyl

- 4

- yl

- 1,2,3,4

- tetrahydro

- 1

- naphthyl)

- 4

- hydroxycoumarin CAS Name 3

- [3

- (1,1′

- biphenyl)

- 4

- yl

- 1,2,3,4

- tetrahydro

- 1

- naphthalenyl]

- 4

- hydroxy

- 2H

- 1

- benzopyran

- 2

- one CAS Registry Number 56073

- 07

- 5 End

- use Products Difenacoum Rat and Mouse Block IV (0.005% w/w), Difenacoum Rat and Mouse Place Packs IV (0.005% w/w), Difenacoum Rat and Mouse Pellets IV (0.005% w/w), Difenacoum Rat and Mouse Pellets (0.005% w/w), Difenacoum Rat and Mouse Place Packs (0.005% w/w), Difenacoum Rat and Mouse Blocks ( 0.00 5% w/w) Chemical Class Anticoagulant Rodenticide

### Page 12 of 24

Attachment 2

Physicochemical Properties of Technical Grade Difenacoum Tabl e

. Table 2.2. Physicochemical Properties of Technical Grade Difenacoum.

Parameter Value Reference Melting Point/Range 211.0

– 215.0oC (98.7% w/w) MRID 46750965 pH Not available Relative Density (20.5oC) 1.27 (98.7% w/w) Water Solubility (20oC) <0.05 mg/L at pH 4 1.7 mg/L at pH 7 61 mg/L at pH 9 Solvent Solubility (g/L at 20oC) Acetone 7.6 Propan

- 2

- ol 1.5 Ethyl acetate 3.7 Toluene 1.2 Methanol 1.2 Hexane 0.01 Dichloromethane 19.6 Vapor Pressure (25oC) 6.7 x 10

- 9

– 5.4 x 10

- 14 Pa Dissociation Constant (pK a ) 4.5 Octanol/Water Partition Coefficient (Log[P OW ]) 7.6 UV/Visible Absorption Spectrum

Wavelength of peak (nm) 310.6 259.4

Absorbance 0.267 0.664
Molar Extinction Coefficient 17,100 46,600Page 13 of 24



### Attachment 3. Preliminary Use Profile Table for Di fenacoum

Table A.3. Preliminary Use Profile Table for Di fenacoum (PC 119901 )

Company Formulation

[EPA Reg. No.] % ai Formulation Type Net

Contents Packaging Target

Pest Tamper

Resistant Bait Stations Application Rate PPE RUP Use Directions and Limitations

Woodstream Corporation Difenacoum

Rat and Mouse Block IV Reg istration # 36488

- 63

Sub

- label A: Agriculture Use

0. 005 Bait Block 8 lb/128oz (128 x 1.0 oz block )
to 20 lb/320 oz (320 oz

- 1.0 oz block) Rat s,

house mice and meadow voles

. Yes , for all placements where children, pets non

target mammal or birds may

access bait.

However, for all outdoor placements , product is to be placed in bait stations RATS: 3 to 10

blocks/placement using bait stations, placed at intervals of 15 to 30 ft

( 0.0625 lbs x 0.005% ai = 0. 000003 1 26 lb ai/block

0. 000003 1 lb ai x 10 blocks = 0.00003126 lb ai/10 blocks

MICE: 1 block placement using bait station placed at 8 to 12 ft intervals SL/G Yes Apply within 100 feet of agricultural buildings and man

- made agricultural structures. Burrow bating with this product is p rohibited. Fence and perimeter baiting beyond 100 feet from structure is prohibited

. . Do Not Use in Homes or Other Residential Settings

. Do Not Use in sewers. Do not broadcast bait. Do not sell this product in individual containers holding less than 8 po unds of bait

.

Difenacoum Rat and Mouse Block IV Reg istration # 36488

- 63

Sub

- label B: Profession Use 16 lb/256 oz (128 x 1 oz block) To 20 lb/320 oz (320 x 1 oz block) Use in and within 100 feet of man

- made
structures such as homes, food

processing facilities, industrial and commercial buildings, trash receptacles

, agricultural, and public buildings, transport vehicles, docks and port of terminal buildings

. Do not sell less than 16 pounds of bait. Burrow baiting is prohibited . Do not use in sewer. Do not broadcast. Fence and perimeter baiting beyond 100 feet from structure is prohibited.

Woodstream Corporation Difenacoum

Rat and Mouse Place Packs IV Reg istration # 36488

- 64

Sub

- label A: Agriculture Use 0.005 Place Packs 8 .06 lb/129oz (86 x 1.5 oz place pack, bait pack or bait bags)
to 51.56 lb/825 oz (550 x 1.5 oz place pack, bait pack or bait bags) Rat s,

house mice

, and meadow voles Yes RATS: 3 to 10 place

packs /placement using bait stations, placed at intervals of 15 to 30 ft

( 0.09375 lbs x 0.005% ai = 0. 00 0004 6 8 lb ai/place pack

0. 0.00 000468 lb ai x 10 place pack = 0.0000468 lb ai/10 place pack Apply within 100 feet of agricultural buildings and man

- made agricultural structures. Burrow bating with this product is prohibited. Fence and perimeter baiting beyond 100 feet from structure is prohibited

. . Do Not Use in Homes or Other Residential Settings

. Do Not Use in sewers. Do not broadcast bait. Do not sell this product in individual containers holding less than 8 pounds of bait

.

### Page 14 of 24

Table A.3. Preliminary Use Profile Table for Di fenacoum (PC 119901 )

Company Formulation

[EPA Reg. No.] % ai Formulation Type Net

Contents Packaging Target

Pest Tamper

Resistant Bait Stations Application Rate PPE RUP Use Directions and Limitations

Difenacoum Rat and Mouse Place Packs IV Reg istration # 36488

- 64

Sub

- label B: Profession Use 16.03 lb/256.5 oz (171 x 1.5 oz place pack, bait pack or bait bags) To 51.56 lb/825 oz (550 x 1.5 oz place pack, bait pack or bait bags) MICE: 1⁄4 to 1⁄2 oz of bait per placement using bait stations placed at intervals of 8 to 12 feet.

(0.03125 lb x 0.00005 ai = 0.0000015 lb ai/placement Use in and within 100 feet of man

- made
structures such as homes, food

processing facilities, industrial and commercial buildings, trash receptacles

, agricultural, and public buildings, transport vehicles, docks and port of terminal buildings

. Do not sell less than 16 pounds of bait. B urrow baiting is prohibited. Do not use in sewer. Do not broadcast. Fence and perimeter baiting beyond 100 feet from structure is prohibited.

Woodstream Corporation Difenacoum

Rat and Mouse Pellets IV Reg istration # 36488

- 65

Sub

- label A: Agriculture Use 0.005 Pelleted 8 lb/128oz (3628.74g) to 50 lb/800

oz (22670.62g) Rat s,

house mice, and meadow voles Yes RATS: 4 to 16 oz of

pellets/placement using bait stations placed at intervals of 15 to 30 ft

(1 lb x 0.00005 ai = 0.00005 lb ai/placement)

MICE: 1⁄4 to 1⁄2 oz of bait per placement using bait stations placed at intervals of 8 to 12 feet.

(0.03125 lb x 0.00005 ai = 0.0000015 lb ai/placement SL/G Yes Apply within 100 feet of agricultural buildings and man

- made agricultural structures. Burrow bating w ith this product is prohibited. Fence and perimeter baiting beyond 100 feet from structure is prohibited

. . Do Not Use in Homes or Other Residential Settings

. Do Not Use in sewers. Do not broadcast bait. Do not sell this product in individual containers h olding less than 8 pounds of bait

.

Difenacoum Rat and Mouse Pellets IV Reg istration # 36488

- 65

Sub

- label B: Profession Use Yes Use in and within 100 feet of man

- made
structures such as homes, food

processing facilities, industrial and commercial buildings, trash receptacles

, agricultural, and public buildings, transport vehicles, docks and port of terminal buildings

. Do not sell less than 16 pounds of bait. Burrow baiting is prohibited. Do not use in sewer. Do not broadcast. Fence and perimeter baiting

### Page 15 of 24

Table A.3. Preliminary Use Profile Table for Di fenacoum (PC 119901 )

Company Formulation

[EPA Reg. No.] % ai Formulation Type Net

Contents Packaging Target

Pest Tamper

Resistant Bait Stations Application Rate PPE RUP Use Directions and Limitations

beyond 100 feet from structure is prohibited.

Woodstream Corporation Difenacoum

Rat and Mouse Pellets Reg istration # 47629

- 14

Sub

- label B: Agriculture Use 0.005

% Pelleted 8 lbs to 5 0 lbs.

Rat and

Mouse Yes RATS: 4 to 16 oz of

pellets/placement using bait stations placed at intervals of 15 to 30 ft

(1 lb x 0.00005 ai = 0.00005 lb ai/placement)

MICE: 1⁄4 to 1⁄2 oz of bait per placement using bait stations placed at intervals of 8 to 12 feet.

(0.03125 lb x 0.00005 ai = 0.0000015 l b ai/placement Yes Apply within 5 0 feet of agricultural buildings and man

- made agricultural
structures. Do Not Use in Homes or Other Residential Settings

. Do Not Use in sewers. Do not broadcast bait. Do not sell this product in individual containers holding less than 8 pounds of

bait

Difenacoum Rat and Mouse Pellets Reg istration # 47629

- 14

Sub

- label C: Professional Use 16 lbs to 5 0 lbs. Use in and within 5 0 feet of man

- made
structures such as homes, food

processing facilities, industrial and commercial buildings, trash receptacles

, agricultural, and public buildings, transport vehicles, port o r terminal buildings

. Do not sell less than 16 pounds of bait.. Do not use in sewer. Do not broadcast.

Woodstream Corporation Difenacoum

Rat and Mouse Block Reg istration # 47629

- 16

Sub

- label B: Agriculture Use 0.005

% Block 8 to 20 lb s

Rat and Mouse Yes RATS: 3 to 10 blocks/placement using bait stations, placed at intervals of 15 to 30 ft

(0.0625 lbs x 0.005% ai = 0.000003126 lb ai/block

0.0000031 lb ai x 10 blocks = 0.00003126 lb ai/10 blocks

MICE: 1 block placement using bait SL/G

Yes Apply within 50 feet of agricultural buildings and man

- made agr icultural
structures. Do Not Use in Homes or Other Residential Settings

. Do Not Use in sewers. Do not broadcast bait. Do not sell this product in individual containers holding less than 8 pounds of bait

Difenacoum Rat and Mouse Block Reg istration # 47629

- 16 16 to 20 lb s SL/G

### Page 16 of 24

Table A.3. Preliminary Use Profile Table for Di fenacoum (PC 119901 )

Company Formulation

[EPA Reg. No.] % ai Formulation Type Net

Contents Packaging Target

Pest Tamper

Resistant Bait Stations Application Rate PPE RUP Use Directions and Limitations

Sub

- label C: Professional Use station placed at 8 to 12 ft intervals

Woodstream Corporation Difenacoum

Rat and Mouse Place Packs Reg istration # 47629

- 17

Sub

- label B: Agriculture Use

0.005

% Place Packs 8.06 lbs to

51.56 lbs

Rat and

Mouse Yes RATS: 3 to 10 place

packs/placement using bait stations, placed at intervals of 15 to 30 ft

(0.09375 lbs x 0.005% ai = 0.00000468 lb ai/place pack

0.0.00000468 lb ai x 10 place pack = 0.0000468 lb ai/10 place pack

MICE: 1⁄4 to 1⁄2 oz of bait per placement using bait stations placed at intervals of 8 to 12 feet.

(0.03125 lb x 0.00005 ai = 0.0000015 lb ai/placement SL/G NO This product may only be used inside and within 100 feet of buildings or inside of transport vehicles (ships, trains, or aircraft). This Product May Not Be Sold in Packaging that Holds Less Than 4 Pounds of Bait. Each bait pack is 2 ounces. Burrow baiting is prohibited Difenacoum Rat and Mouse Place Packs Reg istration # 47629

- 17

Sub

- label C: Professional Use 16.03 lb to 51.56 lbsPage 17 of 24



### Attachment 4. En dpoint Selection Table

Table A.4 . Toxicological Doses and Endpoints for Difenacoum for Use in Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Acute Dietary (All Populations) Dietary endpoints were not selected because difenacoum is strictly a non

- food use chemical.

Chronic Dietary (All Populations) Dietary endpoints were not selected because difenacoum is strictly a non

- food use chemical.

Dermal (Short

- Term) NOAEL=

0.005 mg/kg/day

Dermal absorption rate = 4% UF A = 10x

UF H = 10x Occupational LOC

for MOE = 100 Developmental toxicity study in

rabbits LOAEL = 0.015 mg/kg/day based on changes in blood coagulation (increased prothrombin and kaolin

cephalin times).

Inhalation (Short

- Term) NOAEL=

0.005 mg/kg/day

Toxicity by the inhalation route is considered to be equivalent to the estimated toxicity by the oral route of
exposure. UF A = 10x

UF H = 10x Occupational LOC

for MOE = 100 Developmental toxicity study in

rabbits LOAEL = 0.015 mg/kg/day based on changes in blood coagulation (increased prothrombin and kaolin

cephalin times).

Cancer Classification: N/A Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no obs erved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Page 18 of 24

Attachment 5. Toxic ology Data Requirements

The requirements (40 CFR 158.500) for non

- food uses are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.5: Toxicology Data Requirements for D ifenacoum
Guideline Study Type Required Submitted Satisfied 870.1100 Acute Oral Toxicity Yes Yes Yes
870.1200 Acute Dermal Toxicity Yes Yes Yes
870.1300 Acute Inhalation Toxicity Yes Yes Yes
870.2400 Acute Eye Irritation Yes Yes Yes
870.2500 Acute Dermal Irritation Yes Yes Yes
870.2600 Skin Sensitization Yes Yes Yes
870.3100 90

- Day Oral Toxicity in Rodents CR Yes Yes
870.3150 90

- Day Oral Toxicity in Non

- Rodents CR No NA
870.3200 21/28

- Day Dermal Toxicity NR No NA
870.3250 90

- Day Dermal Toxicity Yes Yes Yes
870.3465 90

- Day Inhalation Toxicity CR No Yes b

870.3700 Prenatal Developmental Toxicity Study (Rat) Yes Yes Yes

Prenatal Developmental Toxicity Study (Rabbit) Yes Yes Yes b

870.3800 Reproduction and Fertility Effects Yes No Yes b

870.4100 Chronic Toxicity (Rodent) CR No NA

870.4200 Carcinogenicity (Rat) CR No NA

Carcinogenicity (Mouse) CR No NA 870.5100 Bacterial Reverse Mutation Test Yes Yes Yes
870.5300 870.5375 i n vitro Mammalian Cell Gene Mutation Test

i n vitro Mammalian Chromosome Aberration Test Yes a Yes Yes Yes

870.5385 870.5395 Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test Yes a No Yes Yes

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen) CR No NA

Delayed Neurotoxicity of Organophosphorus Substances (28

- Day, Hen) CR No NA

870.6200 Neurotoxicity Screening Battery (Acute, Rat) Yes No Yes b

Neurotoxicity Screening Battery (90

- Day, Rat) Yes No Yes b

870.6300 Developmental Neurotoxicity Study CR No NA
870.7200 Companion Animal Safety CR No NA
870.7485 Metabolism and Pharmacokinetics Yes Yes Yes
870.7600 Dermal Penetration CR No NA
870.7800 Immunotoxicity Yes No Yes b CR = Conditionally Required. NA = Not Applicable.

a Either guideline study type may be used to satisfy the data requirement (e.g

. 870.5300 or 870.5375)

. b Study requirement waived (TXR 0057384 ).Page 19 of 24



### Attachment 6

. Toxicity Profile for Di fenacoum

Table A. 6 .1 Acute Toxicity Profile

– Difenacoum Technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

– rat 46750935 LD 50 = 1.8 mg/kg (♂) (95% C.I.= 1.5

- 2.1 mg/kg) I

870.1100 Acute oral

– rat 46750936 LD 50 = 2.6 mg/kg (♀) (95% C.I.= 2.1

- 3.7 mg/kg) I

870.1100 Acute oral

– rat and mouse 46766206 LD 50 (cis) Male Rats = 1.17 mg/kg, Female Rats = 1.625 mg/kg Male Mice = 0.45 mg/kg Female Mice = 1.0 mg/kg

LD 50 (trans) Male Rats = 7.33 mg/kg, Female Rats = 6.0 mg/kg Male Mice = 1.181 mg/kg Female Mice = 2.75 mg/kg I

870.1200 Acute dermal

– rat 46750938 LD 50 = 63 mg/kg (♀) (95% C.I. = 34

- 85 mg/kg) I

870.1300 Acute inhalation

– rat 46750939 LC 50 =>0.003646 mg/L ( ♂+♀) I

870.2400 Acute eye irritation

– rabbit 46750940 1/3 conjunctival irritation immediately after. No positive irritation at 24

- hours. IV

870.2500 Acute dermal irritation

– rabbit 46750941 No irritation at the 24

- hour observation. IV

870.2600 Skin sensitization

– guinea pig 46750942 Not a sensitizer N/A

### Page 20 of 24

Table A. 6 .2 Subchronic, Chronic and Other Toxicity Profile

– Difenacoum Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Non

guideline 6

- Week oral

toxicity (dog) 46750944 (1994)

Acceptable/nonguideline 0, 0.01, 0.025, 0.05, 0.1, 0.2 mg/kg/day NOAEL = Not determined LOAEL = 0.01 mg/kg/day based on changes in blood coagulation, particularly increased prothrombin time beginning on day 30.

All animals exposed to ≥ 0.025 mg/kg/day were sacrificed early due to i ncreased coagulation times and/or clinical evidence of hemorrhage. 870.3100 90

- Day oral

toxicity (rat) 46766207 (1991)

Unacceptable /guideline 0, 0.01, 0.02/0.09, 0.03 mg/kg/day NOAEL = Cannot be determined LOAEL = Cannot be determined

No effect on coagulation at 0.01 mg/kg/day

This study was classified unacceptable due to inadequate number of animals/sex/dose. There were no surviving males after day 78. The dose level for the 0.02 mg/kg/day animals was increased to 0.09 mg/kg/day on Day 65 (F) or 66 (M). Hematology data are not available for the low dose group. 870.3700a Prenatal

developmental in rodents (rat) 46766208 (1994)

Acceptable/guideline 0, 0.01, 0.03, 0.09 mg/kg/day Maternal NOAEL = 0.03 mg/kg/day Maternal LOAEL = 0.09 mg/kg/day based on vaginal bleeding and increased kaolin

- cephalin time.

Developmental NOAEL = 0.09 mg/kg/day Developmental LOAEL = Not observed 870.3700b Prenatal

developmental in

non

- rodents (rabbit) 46750947 (1994)

Acceptable/guideline 0, 0.001, 0.005, 0.015 mg/kg/day Maternal NOAEL = 0.005 mg/kg/day Maternal LOAEL = 0.015 mg/kg/day based on changes in blood coagulation (increased prothrombin and kaolin

- cephalin times).

All animals in the 0.015 mg/kg/day group were sacrificed to prevent or minimize fatal maternal hemorrhage.

Developmental NOAEL = 0.015 mg/kg/day Developmental LOAEL = Not observed 870.5100 Gene mutation

–

bacterial reverse mutation assay 46750948 (1995)

Acceptable/guideline Negative.

870.5100 Gene mutation

–

bacterial reverse mutation assay 46766209 (1986)

Acceptable/nonguideline Negative.

870.5300 Gene mutation

–

in vitro mammalian cell gene forward mutation assay 46750952 (1995)

Acceptable/guideline Negative.

### Page 21 of 24

Table A. 6 .2 Subchronic, Chronic and Other Toxicity Profile

– Difenacoum Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5375 Cytogenetics

- in

vitro mammalian cell chromosome aberration test 46750950 (1995)

Acceptable/guideline Positive for chromosomal aberrations in cultured human lymphocytes with and without S9 activation, with a variable dose

- response.

870.5375 Cytogenetics

- in

vitro mammalian cell chromosome aberration test 46766210 (1986)

Acceptable/guideline Positive for chromosomal aberrations in Chinese hamster lung cells with and without S9 activation, with a variable dose

- response.

870.5395 Cytogenetics

–

mammalian erythrocyte micronucleus test (rat) 46766211 (1996)

Acceptable/guideline Negative.

870.5395 Cytogenetics

–

mammalian erythrocyte micronucleus test (mouse) 46766212 (1987)

Acceptable/guideline Negative.

870.5550 Other effects

–

unscheduled DNA synthesis in mammalian cells in culture 46773601 (1996)

Acceptable/guideline Negative.

870.5550 Other effects

–

unscheduled DNA synthesis in mammalian cells in culture 46766214 (1990)

Acceptable/guideline Negative.

870.7485 Metabolism and

pharmacokinetics (rat) 46766216 (1996)

Acceptable/guideline 0.051 or 0.54 mg/kg Groups of 4 female SD rats were given a single oral gavage dose of radiolabled difenacoum. Absorption: Rapid; reached mean peak blood level for each dose group 4 hours after dosing.
Distribution : Radioactivity was present in all tissues examined. At necropsy (168 hours), the majority of the unexcreted dose was present in the liver (37.6%/20.6% mean radioactivity from administered low/high dose), with smaller amounts in the carcass (17.2%/13.5%; low/high dose), the GI tract (4.0%/2.7%; low/high dose), and pancreas (1.1%/1.2%; low/high dose).
Metabolism: Absorbed difenacoum is extensively metabolized, with both parent compound and up to 4 metabolites present in the liver at 7 days after dosing. In the liver, 4 metabolites were found in low dose animals and 2 metabolites were found in high dose animals. Both the parent compound and two of the hepatic metabolites are eliminated in the faeces

### Page 22 of 24

Table A. 6 .2 Subchronic, Chronic and Other Toxicity Profile

– Difenacoum Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

within the first 24 hours, along with a polar metabolit e(s).
Elimination: At 24 hours, 17.7%/19.8% ( feces ), 1.4%/1.2% ( urine ), and 0.36%/0.06% ( expired CO 2 ) of the radioactivity from the administered low/high dose, respectively, was recovered. By 168 hours, 39.9%/50.9% ( feces ) and 1.9%/1.44% ( urine ) of the radioactivity from the administered low/high dose, respectively, was recovered. 870.7485 Metabolism and

pharmacokinetics (rat) 46766215 (2002)

Acceptable/nonguideline 0.57 mg/kg ( cis isomer) or 0.55 mg/kg ( trans isomer) Groups of 4 female SD rats were given a single oral gavage dose of radiolabled cis or trans

difenacoum. Absorption: Reached plateau in plasma 8

- 24 hours after dosing, followed by slow elimination phase. Peak blood level of the cis

- isomer ( 0.21
 g equiv /ml) was approximately 2.5 times greater than the trans

- isomer ( 0.08  g equiv/ml) at 8 hours.
Distribution: Radioactivity was present in all tissues examined. At 96 hrs, the highest levels were found in the liver (19

- 22% of the administered dose of cis

- isomer; 22

- 29% trans)

, carcass (13.9

- 16.3% cis ; 11.9

- 13.5% trans ),
pancreas (1.2

- 1.8% cis ; 1.3

- 1.4% trans ), and GI
tract , including stomach, intestines, cecum, and content (4

- 4.2% cis ; 3.1

- 4.3% trans ).
Metabolism: Not investigated in this study.
Eliminati on: Within 96 hours, the radioactivity was recovered mostly in the feces (41% of the administered dose of cis

- isomer; 44.5% trans ), with small amounts in urine (0.5% cis ; 0.6%
trans ).

### Page 23 of 24

Table A. 6 .2 Subchronic, Chronic and Other Toxicity Profile

– Difenacoum Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (rat) 46750957 (1987)

Acceptable/nonguideline 1.2 mg/kg 32 male Alpk:AP rats were given a single oral gavage dose of radiolabled difenacoum and were sacrificed in groups of three at 1, 4 and 8 days, and 2, 4, 8, 12 and 26 weeks after dosing. Absorption: The concentration of radioactivity in the blood and tissues was highest 24 hours after dosing, which was the earliest
measurement. Distribution: The highest concentration of radioactivity, expressed as % of the dose, was found in the liver (42%), follow ed by the pancreas (0.48%), kidney (0.22%), and salivary glands (0.09%), with lower concentrations in the blood and fat. Whole body autoradiography showed that radioactivity levels were similarly distributed and not significantly reduced (except for the G I tract) at 5 days after dosing.
Metabolism: The cis:trans ratio of difenacoum in the liver at 24 hours was 64:36, while the ratio of administered difenacoum was 44:56, which suggests that the tran

- isomer was being preferentially metabolized or eliminated . Five metabolites were found in the liver, accounting for 53% of the total radioactivity in the liver extract, but these were not identified.
Elimination: Elimination from the liver was biphasic, with a rapid phase during days 1

- 8 accompanied by a reduc tion in clotting factor synthesis (t 1⁄2 = 3 days), followed by a slower terminal phase during days 28

- 182 (t 1⁄2 = 118 days). Similar biphasic elimination was found in the kidney and salivary glands, but not the pancreas. The relative rate of elimination wa s liver, fat, and blood > kidney > salivary glands >
pancreas.

### Page 24 of 24

Attachment 7. Physical and Chemical Properties for Assessing Dermal Absorption

Input Value Reference

Log K ow 

### 6.1 , 20oC, pH 6.5 1 

### http://pubchem.ncbi.nlm.nih.gov/ Melting Point 216oC http://pubchem.ncbi.nlm.nih.gov/ Boiling Point 290oC http://pubchem.ncbi.nlm.nih.gov/ Vapor pressure 5.35 x 10

- 11 

### mm Hg

,

25oC http://pubchem.ncbi.nlm.nih.gov/

Simulation time 8 hours N/A
1 

### A value of 5.5 was used in the National Institute for Occupational Health and Safety finite dose skin permeation calculator because it was the highest acceptable value the program would allow.