# EPA Reg. No. 2382

-18775-Dliy**L~tt~rs** (ALERT) S: 907121 1111712011; N".

# Ii',"""
S: 904900 101512011;**N~w** R&gistrlition; S: 899655 6/2212011; N&w**R~gistMtiOI'l;** S: 897940 6/16/2011; New**R~Bistr!1tion; ,f~**  

### !iii DP391921;RDIfB; CompleteD!1te: 

# a s: 896235 511912011; New Registratiol'l;



### +: 

### !iii DP 399816;RDI IB; Complete**Dat~:** ,+: 

### Iii DP 390814;RDI IB; Complete Dlite:

'+; 

### I.iiI DP390818;RDIIB; Complete Date: _f 

### !iii DP 390819;RDI IB; Complete Date: 

### IE S: 894831 412&2,'''; N". 

## "'B""'''''';2'3<

## "5'"i9i2Oi 1; New Registration; 

### s: 894831 4128'2011; New Re{}istrIltiofl,·-

s: 896235 5119/2011; New Re!}!s/(;]tion; S: 894831 412f:12D11; New Registration"

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# 7/(irw

### DATA PACKAGE BEAN SHEET Date: 15-Jun-2011 Page 1 of2



### * * * Registration Information 

### * * 1< Registration:**~_~_~~~RrL:J~_ff!rl_){** 

### __**IR.ge!~Ab**

### __§qh_IJIIQN--':QR

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### PQG?

____ Company: 2382

- VIRBAC AH, INC.
Risk Manager:**~_ry'I10** -**~io:.h_~~_~**__**~_e:~~e:_~**

## __**~** 

## __**(!O~) _~~_?_~'!9_~** 

### __**R:9_~~_1,t**__pyt_**~:J2_~!**__ _ Risk Manager Reviewer: Bonaventure Akinlosotu BAKINlOS
Calculated Due Date: 19-Nov-201 t Type of Registration:**~~?_~_1l_c_~_Fl._~~i~~~_!i'?_I'!**__:

__**~~9!!'?!1**

### ___ 3_ Decision 

### #: 448350 DP 

### #: (390814) PRIA Parent DP 

### #: Submission 

### #: 896235

Edited Due Date:

Action Desc:**(~_~_1_g.L!"I_§~**__**~~Q~~gI;_f'j_~_f±_F~_~I_!_~g_I'(**

### __**(I~C::_ly[)~_~**

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### <?y

___**p_~q_[)_~~I_~_~_~_MIS_l** Ingredients: 109701, Permethrin(44.88%)

1

__**2_~_~~_!_.** __**~_ip'~9~~I(~:9.~.'J{,.)** 

### * * * Data Package Information 

### * * 

### *

Expedite: 

### 0 Yes. No Date Sent: 15-Jun-2011 Due Back:

DP Ingredient: 109701, Permethrin**.!?g.!?~.,** .F'ipro.n!1 _ . DP Title: I?:rod chem

CSF Included: • Yes 

### 0 No label Included: • Yes 

### 0 No Parent DP#:

Date In Date Out
Organizatfon: RD f TRB last Possible Science Due Date: 20-0ct-2011

## ~'-- Team Name: CHEM Science Due Date:

Reviewer Name: Sub Data Package Due Date:
Contractor Name: 

### * 

### * * Studies Sent for Review 

### * * *

Printed on Page 2 

### * * * Additional Data Package for this Decision 

### * * *

No Additional Data Packages 

### * * * Data Package Instructions 

### * 

### * *Df#: (390814)

48467102

48467103

48467104

48467101

48467101

48467107

48467101

48467101

48467102

48467104

48467t07

48467107

48467107

48467104

48467110

4846710t

48467107

48467105

4846710t

4848730t

48467108 Page 2 * * * Studies Sent for Review···

i C24732. 29 p. Decision#: (448350)

Zepperitz, Ch. (2010) Project : Quanlification of the Active 830. t800/Enforcement analytical Ingredients Fipronil and Permethrin in Five Balches by a Validated method Method: Final Report. Project Number: C96541. Unpublished study prepared by Harlan Labora10ries, Ud. 44 p. Zepperitz, Ch. (2010) Project 104.05: Enforcement Analytical Method: Final Report. Project Number: C96552. Unpublished study prepared by Harlan Labora"lories, Ltd. 34 p. Habeck, C. (2009) Project 104.05: Determination of Color, Physical State and Odor; Final Report. Project Number: C32753. Unpublished study prepared by Harlan Laboratories, Ud. 26 p. Villard, I. (2011) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/104/05/1. Unpublished Sludy prepared by Virbac. 36 p. Villard, 1. (2011) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/1 04/05/1. Unpublished study prepared by Virbac. 36 p. 830. t800/Enforcement analytical method

830.6304/0dor

830.1550/Product Jdentity and composition

830.1750/Certified limits

Habeck, C. (2010) Project 104.05: Determination ofthe Storage 830.6304/0dor Stability (Shelf-Life): Final Report. Project Number: C24697. Unpublished study prepared by Harlan Laboratories, Ud. 79 p. Villard, I. (2011) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/104/05/1. Unpublished Sludy prepared by Virbac. 36 p. Villard, 1. (2011) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/1 04/05/1. Unpublished study prepared by Virbac. 36 p. 830.1620/Description of production process 830.1600fDescription of materials used to produce the product
Zepperitz, Ch. (2010) Project 104.05: Quantification of the Active 830.1700/Preliminary analysis Ingredients Fipronil and Permethrin in Five Batches by a Validated Method: Final Report. Project Number: C96541. Unpublished study prepared by Harlan Laboratories, Ud. 44 p. Habeck, C. (2009) Project 104.05: Determination of Color. Physical State and Odor: Final Report. Project Number: C32753. Unpublished study prepared by Harlan Laboratories, Ud. 26 p. Habeck, C. (2010) Project 104.05: Determination of the Storage Stability (Shelf-Life): Final Report. Project Number: C24697. Unpublished study prepared by Harlan Laboratories, Ud. 79 p. Habeck, C. (2010) Project 104.05: Determination of the Storage Stability (Shelf-Life): Final Report. Project Number: C24697. Unpublished study prepared by Harlan Laboratories, Ltd. 79 p. Habeck, C. (2010) Project 104.05: Determination ofthe Storage S1ability (Shelf-Life): Final Report. Project Number: C24697. Unpublished study prepared by Harlan Laboratories, Ltd. 79 p. Habeck, C. (2009) Project 104.05: Determination of Color, Physical State and Odor: Final Report. Project Number: C32753. Unpublished study prepared by Harlan Laboratories, Ud. 26 p. Habeck, C. (2009) Project t04.05: Determination of the Relative Density: Final Report. Project Number. C24710. Unpublished study prepared by Harlan Laboratories, Ltd. 36 p. Villard, 1. (2011) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/104/05/1. Unpublished study prepared by Virbac. 36 p. 830.6303/Physical state

830.6320/Corrosion characteristics

830.63 t7/Storage stability

830.6303fPhysical state

830.6302/Color

830.7300/0ensity/relative density

830.1650/Description of formulation process Habeck, C. (2010) Project 104.05: Determination of the Storage 830.6302/Color Stability (Shelf-Life): Final Report. Project Number: C24697. Unpublished study prepared by Harlan Laboratories, Ud. 79 p. Habeck, C. (2009) Project 104.05: Oetermination of Oxidation/Reduction and Chemical Incompatibility with Certain Agents: Final Report. Project Number: C2472t. Unpublished study prepared by Harlan Labora10ries, Ltd. 28 p. Villard, I. (201 t) Product Specific Chemistry for Efftix Topical Solution for Dogs. Project Number: VIRBAC/t04/05/1. Unpublished study prepared by Virbac. 36 p. 830.63 t4/0xidizing or reducing action

830.1670/Discussion of formation of impurities
Habeck, C. (2009) Project 104.05: Determination of the Viscosity: 830.7 tOONiscosity Final Report. Project Number: C24708. Unpublished study prepared by Harlan Laboratories, Ud. 37 p. Habeck, C. (2009) Project 104.05: pH-De"1ermination: Final Report. Project Number: C24743. Unpublished study prepared by Harlan Laboratories, Ud. 28 p. 830.7000/pH- 

### , , ' 

# Rejected

Studies

# Memorandum

Date: S 1 J 

# I 1---'-1..11_



# To:
____ .LPl-M-"---"I-l.O'--

__ , 

# Regulatory Manager

From: Information Services Branch, ITRMD

Your receipt of this data submission is not an indication that MRIDs for the enclosed studies have been posted to OPPIN.



# We expect that it 

# will be approximately 5 days from the above date before the study-level data is available iu OPPIN.

If 

# you have any questions about this process, please contact Teresa Downs (305-5363).

This is a: I I 

# fully accepted submission l2'lpartially accepted submission LJ 

# rejected submissionTracking Create ReSubmiasion

Action ClXle History



# 15(n/VOI/

# 21-Day Screen Completed by Contractor

21-Day Expires on _----'S-:::..--.!-I 

# C,.:---.:./-!...i_



# Jacket 

# # 

# z. 3 

# g 

# 2.

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# T 

# MRID# l.f 

# S Lf " 

# 7 I


# Content Screen: Recommend to

# ~lFaii 86-5 Review: Pas ai A

Overall Status: Recommend to 

# PassE)


# Transfer This Jacket to:

# Memorandum \(, """-'120<, w.-;",t ",0 ,,", 

### 23'''2 -i«T



# Date: 01) /

## I~ / II



# To: 

# PM 10 

# ,Regulatory Manager

From: Information Services Branch, ITRMD

Your receipt of this data submission is not an indication that MRIDs for the enclosed studies have been posted to OPPIN.



# We expect that it will 

# be approximately 5 days from the above date before the study-level data is available in OPPIN.

If you have any questions about this process, please contact Teresa Downs (305-5363).

This is a: 

# o fully accepted submission

# ~artially accepted submission 

# o rejected submission

# NEW APPLICATIONS

DATE: APR 2 8 2011

",- 

# FILE NUMBER: j)3l?

## 5i.~ f< 

# I I**--""~'-------** 

# FEP (OPPIN ENTRY)' 

# Lv 4(/-9 ('Jot I 

# (Initial 

# & date) , 

# FILE ROOM:



# ------ (Initial 

# & date)

SIG: (Initial & 

# date)



# FILE ROOM:

_____ _ (Initial & date)
,/ ASSIGN 

# TO PM 

# Co

-- 

# (NO DATA)



# __ JACKET TO SHELF (DATA)

## PRIA 2 - 21 Day Content Screen Review Worksheet (EPNOPP Use Only) 

# Lf**~<:T** 

### 3123/09 -C7IP-1/ 

### 21 Day Screen Start Date:**--'-~<>--:o,-------=::-----;~** 

### Experts In-Processing Signature: 7S. 

# rz-- Date G -.L. -I / 

### Fee Paid: Yes

### ~ Division management contacted on issues No,

___ Yes

____ Date

______ _

EPA Reg. Number: 

# ;? 3; 

# 8;<

_ 

# /?J. T EPA Receipt Date: 

# c.j -,,;( [3 - / /

1

2



### 3

4



### 5

6 

### Items for Review Application Form (EPA Form 8570·1)(link to form) signed & 

### complete including package type

Confidential Statement ofFormula all boxes completed, form signed, and 

### dated Form to a) All inerts (link to http://www.epa.gov/opprdOOllinerts/), including fragrances, approved for the proposed uses (see Footnote Certification with Respect to Citation of Data (EPA Form 8570-34) (Link to form) completed and signed (N/A 

### if 100% repack)
Certificate and data matrix consistent

If applicant is relying on data that are compensable, is the offer to pay statement included. (see Footnote B) yes

and signed (N/A 

### if source is unregistered or applicant owns the no

Data Matrix (EPA Form**8570~35)** 

### (Link 

### to fonn) both internal and external copies (PR 98·5) (Link to PR 98·5) completed and signed (N/A 

### if 100%

Selective Method b)**Cite~All** 

### (Fee category experts use)
c) Applicant owns all data (Fee category experts use)

5 Copies of Label (link to http://www.epa.gov/oppfeadlflabeling!lrm!) 

### Yes No 

### N/A*

)I



### ,

(Electronic labels on CD are encouraged and guidance is available)( link to http://www.epa. govJpesticidesJregulating/registering/subm issi ons/index.h bn#labels 

# K

1

### 7 

### Is the data package consistent with PR Notice**86~5** 

### (link to PRN 86-5) 

# X

Notice of Filing (link to 8 

### httl2:lIwww.el!a.gov/l2esticides/regulatinllftolerance (!etitions.htm) included with petitions (link to http://www.epa.20v/pesticides/regulatinl'ltolerances.htm) 

### ""- 9 

### Ifapplicable for conventional applications, reduced risk rationale (link to http://www.epa.gov/opprdOOl/workplan/reducedrisk.html) 

# ""- Required Data (link to htt(!:lIwww.e)2a.gov/l!esticides/regulatin2fdata reguirements.htm) and/or data waivers. See Footnote C.

a) List study (or studies) not included with application



### 10

2

### Comments:



### 2.S**I~** rilt"sSUIl\**f"c~je** 

### bt..t-\- flu rc.spC'U1!;c.C**L~** 

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## * N/A

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### Not Applicable

Footnotes**~**
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## J**CJ?l~ r'(~Ce1v<:J**  

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### A. During the 21 day initial content review, all CSFs will be reviewed to detenuine whether all inerts listed, including fragrances, are approved for the proposed uses. If an unapproved inert is identified, the applicant must either 1) resolve the inert issue by, for example, removing the inert, substituting it with an approved inert, submitting documentation that EPA approved the inert for the proposed pesticidal uses, correcting mistakes on the CSF, etc. or 2) provide the data to support OPP approval of the inert or 3) withdraw the application. Removing or substituting an inert ingredient will require a new CSF and may require submission of data. All infonuation, fonus, data and documentation resolving the inert issue must have been received by the Agency or the application withdrawn within the 21 day period, otherwise, the Agency will 

### reject the application as described below.

To successfully complete this aspect of the 21 day initial content screen, applicants are strongly encouraged to verify that all inert ingredients have been approved for the application's uses even if 

### a product is currently registered by consulting the inert Web 3

### site [link to http://www.epa.gov/opprdOOllinerts/lists.html] and if the inert is not approved, to obtain the necessary inert approval prior to submitting an application to register a pesticide product containing that inert ingredient. Some inert ingredients are no longer approved for food uses or certain types of uses. The name andlor CAS number on a CSF must match the name and CAS 

### number on this web site. Simple typographical errors in the name or CAS 

### number have resulted in processing delays.

If an inert is not listed on the inert ingredient web site and the applicant believes that the inert has been approved, the applicant should contact the fuert Ingredient Assessment Branch (IIAB) at inertsbranch@epa.gov and resolve the issue. Copies of the correspondence with nAB resolving the issue should accompany the application. All
new inerts except PIP inerts are reviewed by IIAB. The IIAB should also be contacted for any questions on what supporting data needs to be submitted for and the Agency's inert review process. Questions on PIP inerts should be directed to the Chief of Microbial Pesticides Branch [Link to hUp:/ /www.epa.gov/oppbppdllbiopesticides/contactsbppd.htm].

When a brand, trade, or proprietary name of an inert ingredient is listed on a CSF, additional information such as an alternate name of the inert, CAS number or other infonnation [link to http://www.epa.gov/opprdOOllinerts/tips.pdfl must also be included to enable the Agency to determine if it has been approved. Each component of an inert mixture (including a fragrance) must be identified. In 

### some cases, the supplier of the mixture or fragrance may need to provide this information to the Agency. Prior to the Agency's receipt of an application, applicants must arrange with a proprietary mixture or fragrance supplier to provide the component information to the Agency or promptly upon EPA's request. If the inert ingredients in a proprietary blend (including fragrances) carulOt or are not identified or provided within the 21-day content review period, the Agency will reject the application.
During the 21 day content review, applicants should submit information to the individual identified by the Agency when the applicant is infonned of an unapproved inert.
Unapproved Inerts Identified on CSFs

All applications except conventional new products and PIPs

Once an unapproved inert is identified on a CSF, the Agency will contact the applicant with the following options:

1. Correct the application by, for instance, correcting the inert's identity or CAS number, providing documentation that the inert has been approved, or removing the unapproved inert from the CSF or replacing it with one that is approved for the application's uses; or

2. Submit the information and data needed for the Agency to approve the unapproved inert If 

### this option is selected and implemented, the Agency may request an extension in the PRIA decision review timeframe to accommodate the inert review/approval process;



### 43. Withdraw the application (the Agency retains 25% of the fun fee for the fee category estimated); or


### If none of these options is selected and implemented by the applicant within the 21 day content review period, the Agency will reject the application and retain 25% of the full fee of the category identified.

Conventional New Product Applications

When the Registration Division identifies an unapproved inert on a CSF with an application for a new product that the applicant has not identified as requiring an inert approval (R311, R312 or R313), it will contact the applicant with the fonowing options:

1. Correct the application by, for instance, correcting the inert's identity or CAS number, providing documentation that the inert has been approved, or removing the unapproved inert from the CSF or replacing it with one that is approved for the application's uses; or

2. Submit the information and data needed for the Agency to approve the unapproved inert, including any required petition to establish or amend a tolerance or exemption from a tolerance. (This option may change the PRIA category for the application, which could require a longer decision review time and a larger fee. 

### If additional fees are due, they must be received by the Agency within the 21 day content review period.)

3. Withdraw the application (the Agency retains 25% of the fun fee for the fee category**estimated)~** or

If none of the above options is selected and implemented during the 21-day content-review period, the Agency wi11 reject the application and retain 25% of the appropriate fee for the new product-inert approval category.

PIP Applications

When the Biopesticide and Pollution Prevention Division identifIes an unapproved inert on a PIP CSF and a request to approve the inert does not accompany the application, it will contact the applicant with the fonowing options:

1. Correct the application by, for instance, correcting the spe11ing or name of the inert to that in 40 CFR 174, or providing documentation that the inert has been approved; or

2. Submit the information and data needed for the Agency to approve the unapproved inert. If an inert ingredient tolerance exemption petition is required, the petition must be received by the Agency and the B903 fee paid within the 21 day period. If this option is selected and implemented, the Agency will discuss harmonizing the timeframe for both actions. 5

### 3. Withdraw the application (the Agency retains 25% of the full fee for the fee category estimated); or

If none of the above options is selected and implemented during the 21 day content review period, the Agency will reject the application and retain 25% of the fee.

B. A policy on documentation of offers to pay is still being developed, however, for a me-too or fast track (similar/identical) new product, R300 or A530, an application without the necessary authorizations of offers to pay will be placed into either R301 or A531. The Agency recommends that authorizations of offers to pay be submitted with other PRIA applications to avoid delays in the Agency's decision.

C. 

### Biopesticide applicants are advised to contact the Agency and discuss study waivers prior to submitting their application to the Agency. Documentation of such discussions should be submitted with the study waiver.



### 6

# j
IFee for Servicel 

# {894831/-

,-------**'~------l** 

### This package includes the following

@ 

# New Registration 

# °Amendment

S?J 

# Studies? , I 

# Fee Waiver?

[J 

# volpay 

# % Reduction:

__ for Division 

# OAD OBPPD @RD

Risk Mgr. 

# [J]J**===----=~i===-=~------------------** 

# Receipt No. 

# s-I 894831**i=====~** 

# EPA File Symbol/Reg. No.

:=1

# =2=3=8=2-=R=IT~ Pin-Punch Date: 1 

# 4/28/2011

"-----



### -------

-- -- ----_.- --- --------_._--- ------_.----- ---



# C This item is NOT subject to FFS action.

-- -- Actiorreo-de:-l i 

# Parent/Child Decisions: i: 

## Requested:

# I\\~**~G** 

# I

Granted:

# I~~ \,0 

# I**c~** 

## Amount Due: 

# $ 

# 4,

# yo'" - ,

,!

# -----------~----.!
ill1l 

## Inert**Cle~y?d** 

## for Intended Use [J 

## Uncleared Inert in Product
Reviewer: 

# If ( 

# L:JS**~..** 

# d-r-:=::>- Date: L(

# ~ '2. '\

- (I**j>~** 

### Remarks:

### -- 

## ISB'S Front-end PRlA 

## Completeness Screen Draft 3; /0/25107



### eccipl Date: 

## APR 2 8 2011 EPA Reg. Number: 

## )3i?:2

- '/:;" II

Cheek List Item

. [us the PRIA Fce been Paid; is a copy ofthe check or p

### ily.gnv n.:ccipt included in the Submission Package?

---- 

### Is

· "" /I

### pplication Form (EP A Forn1 8570- I) Included in the ') S 'llhmiss"ioll 

### Package, is 

### it completely tilled oul 

### and signed



### 3

,

# , II lcludil1g package type?

...**~.-'~** 

### · a Confidential Statement of Formula (EPA Fonn**8570~** 

### Is 2 

## r9) Included in the Submission Package, is 

### it completely 

### IIkd uul and signed (boxes 1-2i)?

- · a Formulator's Exemption Statement (EPA Fonn SS70- 

### Is 27) Induded in the Submission Package?**.-~---------**

, it 

### Certification wlth Respect to Citation of Data (EPA 

### Is I ,'(,ml**H570~34)** Included in the Submission Package'?



## -_

..'.,-----


### s u n"tn Matrix (EPA Form 8570-35) Included in the I. S

'Uhlllissiul1 Package?

,.,,"- 

### Is

, 11 

### Lnhcl Included in the Submission Package? 

### -._- X /I 

### rc Datl1 Included in the Submission Package? ,._- 

## 1_<> I 

### s the Snhmission an Amendment?

-. 

### Yes No NIA 

# x:
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# K

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# y:.

### NOTICE OF PESTICIDE: 

### L Registration Reregistration (under**FI~,** as amenoed) U.S. ENVIRONMENTAL pROTECTION AGENCY Office of Pesticide Programs Registration Division (7505C) 1200 Pennsylvania Avenue NW Washington, D.C. 20460

Name and,Address of Registrant (include ZIP Code): Virbac Animal Health, Inc. P.O. Box 162059 Fort Worth, TX 76161 EPA Reg. Number: 2382-187

Term of Issuance: Conditional Dale of Issuance: 11118/2011

Name of Pesticide Product:
EffitixTM Tropical Solution for Dogs

Note: Cha'ngesjn JabeJing differing in substance from that accepted in connection with this registratfon must be submitted to and accepted by th,e Registratlon Division prior to use of the label in commerce. Jn any corresporoence on th'ls product always refer to the 'above'EPA registration number.

On the basis of information furnished by the registrant, the above named pesticide is hereby registered under the Federal Insecticide, Fungicide and Rodenticide Act.

Registration is in no way to be construed as an endorsement or recommendation of this product by the Agency. In order to protect health and the environment, the Administrator, on his motion, may at any time suspend or cancel the registration of a pesticide in accordance with the Act. The acceptance of any name in connection with the registration of a product under this Act is not to be construed as giving the registrant a right to exclusive use of the name or to its use if it has been covered by others.

This product is registered in accordance -with FIFRA sec 3(c)(7)(A), contingent on the following:
1, Make the following labeling changes before releasing the product for shipment: a, Revise the EPA Registration Number to read: "EPA Registration No. 2382-187",

Signature of Approving Official:



### See page 4

Richard Gebken, Product Manager (RM 10) Insecticide Branch Registration Division (MC 7505P)

PA Form 8570-6 Date:

November 18, 20112



### 2. This registration is time-limited and expires two years from the date this product is first released for shipment.

You must provide the Agency with a projected "release for shipment date", in writing within 30 days ofthe date ofthis Notice ofRegistration. The Agency will calculate the expiration date based on the projected "release for shipment date" until an actual release for shipment date is provided in writing.

3. Only one basic confidential statement offormula (CSF) will be on file for this product at any time (i.e.,
no alternate formulations or minor formulation amendments will be submitted and/or approved for this product, except to allow for alternate sources of any individual inert ingredient).

4. Ifapplicable, you must submit the following data vvithin the timeframe described below: 

### Within sixteen (16) 

### months of the date on this Notice of Registration,provide to theAgency acceptable data packages for Guideline Studies: OPPTS 830.6320 (Corrosion Characteristics) and OPPTS 830.6317 (Storage Stability).

Acute Dermal Sensitization Study: Within 60 days of this NOR, acceptablepositive control data (See copy of DER).

5. You must submit quarterly enhanced incident reports and quarterly sales infonnation in doses sold for this product for the quarter that begins on April I, 2012.

The quarterly reports are due two months after the end ofeach quarter. Please flag any Confidential Business Infonnation CBI) as such. Enhanced incident reporting should be submitted to the Product Manager. Quarterly sales information should be submitted to the Registration Division, Immediate Officc (attn: Kimberly Nesci).

The following is a list of information that must be included in the quarterly repOlts for each incident: EPA Registration Number Product name (brand name) Lot # Where purchased: internet, store, Veterinarian Active Ingredient(s) Weight range for product

Date on which incident occurred. (mm/dd/yyyy) 

### State in which the incident occurred. (standard 2 letter abbreviation) Registrant case #
Species: dog, cat, other (specify) Breed: (as reported by pet owner) Age: months or years Sex: M, F, or neutered Weight: pounds3

Primary Route ofExposure: dermal, oral, other animal, inhalation, other Body System: neurological, dermatological, GI, respiratory, ocular, other Major signs noted with 

### separate column for each sign, using standard terminology Time to Onset: (hours, days) Treated by veterinarian: yes or no First time product used: yes or no Misuse: use on incorrect species, overdose, too frequent dosing, other (describe) Any known precondition EPA Severity Code: death, major, moderate, minor Outcome: died, recovered, still treated, unknown

6. Along with the enhanced incident reporting, you must submit an analysis of all incidents seen, to include the following details:

a. 

### All minor dermal and ocular irritation reports. b. Summary table for dogs showing number of incidents of each severity code for each route of exposure. Each incident should only be reported once. If one incident has several routes of exposure, the order should be ocular> oral> dermal. In other words, an incident with both oral and dermal exposure would be reported as oral exposure, and an incident with both ocular and oral exposure would be reported as ocular exposure.
c. A similar summary table for cats (misuse or secondary exposure) showing number ofincidents of each severity code for each route of exposure. d. Summary table for dogs and table for cats showing number of incidents that are believed due to secondary exposure (e.g.,**multi~pet** households).

e. A swnmary table for dogs showing number of incidents for each severity code for these age ranges: <3 months, 3-6 months,**6~9** months,**9~12** months, 1 yr, 2 yr, 3 yr, 4 yr, 5 yr, 6 yr, 7 yr, 

### 8yr,9yr, lOyr, II yr, 12yr, 13yr, 14yr, ISyr,>ISyr. f. A sununary table showing the number of dog incidents for each severity code for each pet weight range on the product label. g. A sununary table for dog weight showing nwnber of incidents for each product weight range. This table should show number ofincidents in dogs weighing less than that product weight range, nwnber ofincidents in dogs in lower half of weight range, number ofincidents in dogs in upper half of weight range, and dogs weighing more than the product weight range. h. Table showing nwnber ofincidents for each dog breed.
1. Table showing number ofincidents in dogs for each clinical sign. J. Table showing number of incidents in dogs for each organ system. k. Report aggregate incidents, but do not combine moderate and minor incidents.

7. You must submit 

### andlor cite all data required for registration of your product under FIFRA Section 3(c)(5) when the Agency requires all registrants of similar products to submit such data, and submit acceptable responses required for re-registration (registration review) ofyour product under FIFRA

. section 4.4



### IfEPA determines that future mitigation measures are necessary for all pet spot-on products, the Agency will inform all registrants concerned. If mitigation measures are necessary, EPA may take regulatory action.

Two copies of the finished labeling must be submitted prior to releasing the product for shipment. Ifyou fail to comply with the above stated conditions, the registration will be subject to cancellation in accordance with FIFRA sec. 6(e) and/or automatically expire. Your release for shipment of the product constitutes your acceptance ofthese conditions.

A copy ofyour label stamped "Accepted with Comments" is enclosed for your records. If you have any questions concerning this action, please contact me or Dr. 

### B. A. Akinlosotu via (703) 605-0653
or akinlosotu.bonaventure@epa.gov.

lchard Gebken, Product Manager (RM 10) Insecticide Branch Registration Division 

### (Me 7505P)

Enclasures Stamped Label

# Virbac's Master Label
Oate 16NOV11 Version U8·9 EPA Reg. No. 2382·RtT Fipronil+Pennethrin Topical Solution for Dogs Optional text appears in brackets. 

# E F FIT IX

# TMTOPICAL SOLUTION FOR DOGS Alternate brand names: 

# (E F FIX

# TM TOPICAL SOLUTION FOR DOGS) 

# (EFFICANIXTM TOPICAL SOLUTION FOR DOGS) 

# (EFFIPROTIXTM TOPICAL SOLUTION FOR DOGS)
FOR USE ONLY ON DOGS 12 WEEKS OLD OR OLDER (WEIGHING UP TO 22.9 LBS, WEIGHING 23 TO 44.9 LBS r WEIGHING 45 TO 88.9 LBS, WEIGHING 89 TO 132 LBS) ACTIVE INGREDIENTS: FiproniL

.. Permethrin'

.. OTHER INGREDIENTS:

. TOTAL:

. • cis/trans ratio: maximum 55% (f) cis and minimum 45% {±} trans
KEEP OUT OF REACH OF CHILDREN 

### CAUTION READ ENTIRE LABEL BEFORE EACH USE ., ,.. 6.01%

__ 44,88%

.. 49.11%

100.00% ACCEPTED With COMMENTS tn EPA Letter Dated: 

## NOV 18 1011 Under the Federallnseclicide, Fungicide PRECAUTIONARY STATEMENTS and

### ~?dentici~e Act, As amended, for 

### the pesticide Registered under EPA Reg No' HAZARDS TO HUMANS AND DOMESTIC ANIMALS .., 

# '2"'" 

# -1<71 "
HAZARDS TO HUMANS """ J 0 '- [;)

_ Harmful if swallowed. Causes eye irritafton. Avoid ccntact with skin, eyes, or cloth-Ing_ Wash hands thoroughly with soap and water after handling and before eating, drinking, chewing gum, using tobacco, or using the toilet. HAZAROS TO DOMESTIC ANIMALS For external use on dogs ONLY.

DO NOT USE ON CATS -IF INGESTED BY CAT THAT ACTIVELY GROOMS A RECENTLY TREATED DOG, THIS PRODUCT MAY HAVE SERIOUS HARMFUL EFFECTS. IF THIS OCCURS, CONTACT YOUR VETERINARIAN IMMEDIATELY,

00 not use on dogs under 12 weeks of age. Individual sensitivities, wl1ile rare, may occur after USing ANY pesticide product. Dogs may experience some temporary irritation at the site of product application. If signs of sensitivity occur, bathe your pet with mild soap or shampoc and rinse with large amounts of water. If signs of sensitivity occur and persist, contact a veterinarian immediately. If your dog has an unusual reaction to the initial application, consult a veterinarian before repeating application. Certain medications can interact witl1 pesticides. Consult a veterinarian before using on medicated, debilitated, aged, pregnant or nursing dogs, or animals known to be sensitive to pesticide products.

EPA Reg. No. 2382-R1T page t of 6 - Master tabet**ve.~i()n** 16 November, 20 t IIF SWALLOWED:

IFIN EYES:

IF ON SKIN OR CLOTHING: • Call a poison control center or doctor immediately fortrealment advice, Have person sip a glass of water if able to swallow, Do not induce**vom~ing** unless told to do so by a poison control center or doctor.

Hold eye open and rinse slowly and gently with water for 15-20 minutes, Remove contact lenses, if presenl, after the first 5 minutes, then continue rinsing eye,

Take off contaminated dothing, Rinse skin immediately with plenly of water for 15-20 minutes.

You may also contact the Hotline number 1-800-338-3659 for human or veterinary health concerns, emergency medical treatment information or pesticide incidents.

DIRECTIONS FOR USE It is a violation of Federal law to use this product in any manner inconsistent with ils labelling. Do not allow children to apply product. TO PREVENT HARM TO YOU AND YOUR DOG, READ ENTIRE LABEL AND DIRECTIONS BEFORE EACH USE. FOLLOW ALL DIRECTIONS AND PRECAUTIONARY STATEMENTS CAREFULLY. FOR EXTERNAL USE ON DOGS ONLY, DO NOT USE ON CATS OR RABBITS. DO NOT USE ON OTHER ANIMALS. DO NOT USE ON CATS. FOR EXTERNAL USE ON DOGS ONLY. Do not use on dogs under 12 weeks of age, Do not Split tubes between dogs. Do not use**mul~ple** tubes on one dog. Weigh your dog to be sure you are applying the right dose formulated for the weight of your dog. Overdosing your dog can result in serious illness. Do not bathe your dog wilhin the first 24 hours after the product has been applied. If your dog is exhibiting signs of and/or is being treated for skin problems, talk to your veterinarian before applying any10pical fiea and tick conlrol product Do not apply more often than once a (per) month (every 30 days).

For use in DOGS (12 weeks old or older). To repel and kill fieas,**~cks,** and mosquitoes; to kill lice and to aid in conlrol of mites; 10 repel and prevent blood feeding by biting fiies. Apply monthly according to directions.
APPLICATION DIRECTIONS

1. Remove one applicator from packaging. Hold applicator upright and remove cap, 2. Invert cap and place other end back onto applicator tip. Push cap down to break seal. Remove cap prior to treatment application. 3. Part dog's hair until skin is visible, Place applicator**~p** direcfly against exposed skin. 3a. For smalt dogs (12 weeks old or older) and weighing up to 22.9 Ibs- Deposit entire contents by squeezing the entire applicator contents onto dog's skin, at a single site, between the shoulder blades as shown in diagram 3a. 3b. For medium dogs 23-4-4.9 Ibs or large dogs 45-88.9 Ibs- Apply the producl evenly to three spots on the dog's tack, starting between the shoulder blades and contiroing on to the second and third spots as shown in diagram 3b, squeezing the applicator until empty. 3c, For extra targe dogs 89-132 Ibs- Apply the product evenly to four spots on the dog's back, starting between the shoulder blades and continuing on to the second, third and fourth spots as shown in diagram 3c, squeezing the applicator until empt¥: Ensure that EFFITIX ," Topical Solution for Dogs is not applied superficially on dog's hair,

## .~

# ~

EPA Reg. No, 2382_RIT page 2 of 6 - Master label vers;on 16 November. 20 IIFREQUENCY OF APPLICATION Fleas, ticks, {Mlng and chewing} lice infestations can be controlled with monthly applications of EFfITlXm Topical Solution for Dogs, Biting fiies and mosquitoes are (also) repelled by EFFITIXTM Topical Solution for Dogs.
Fteas: EFFITIXTM Topical Solution for Dogs can start**~lIing** adult fleas within 6 hours and lasts for (up to) a month. Apply monthly if your dog has fleas tllat may cause flea allergy dermatitis (FAD), or if re-infestation is likely. Ticks: EFFITlXTM Topical Solution for Dogs can kill ticks for (up to) a month, Apply monthly where tick control is consistently needed, Lice: EFFITIX'M Topical Solution for Dogs can kill biting and chewing lice for {up to} a month, Apply monthly where lice control is consistently needed. Mites: EFFITIXTM Topical Solution for Dogs aids in {the} control of (sarcoptic mange}!{mite infestaMns that may cause sarcoptic mange). Biting flies imd Mosquitoes: When applied monthly, EFFITIX'" Topical Solution for Dogs (prevents blood feeding by) (and) {repels} biting flies and mosquitoes for up to 4 weeks {a loner month}. Kms mosqurtoes for up to four weeks (a [one) month).

Notes: Wait at least 30 days before re-application of EFFITIX"" Topical Solution for Dogs, Avoid contact with treated area until dry.

STORAGE AND DISPOSAL Do not contaminate water, food, or feed by storage and disposal. STORAGE: Store unused product in original container only, out of reach of children and animals, PESTICIDE fCONTAINER DISPOSAL: If empty: Nonrefillable. 00 not reuse or refill this container. Offer for recycling, if available. If partialty filled: Call your local solid waste agency for disposal instructions, Never place unused product down any indoor or outdoor drain, LIMITED WARRANTY AND DISCLAIMER VIRBAC warrants this product only if rt is used, stored and handled in accordance with the label instructions. The buyers and users are solely responsible for all risks of use and handling of this product when such use and handling are contrary to or differ from the label instructions. To tlle extent permitted by applicable law, any damages arising from a breach of this warranty shall be limited to direct damages only and shall not include any type of consequential damages.

How supptied: For easy and convenient application, EFFITIXTM Topical Solution for Dogs is available in sizes for small dogs 12 weeks old or older up to 22,9 Ibs {0.034 fl oz}/(t.O mL}, medium dogs 23-44.9Ibs {0.068 fl oz}/(2,0 mL}. large dogs 45-88.9 Ibs (0. t35 fl oz)/{4.0 mL), and extra large dogs 89-1321bs (0.203 fl oz}/(6,0 mL). Net Contents: t {3, 6 or 36} single-dose applicator{s} per package containing tmL (2mL, 4mL or 6mL)! 0.034 fi oz {0,06S fl oz, O. f35 fl oz, 0.203 fl oz} {of solution},
{Detachable} calendar (monthly application) reminder stickers (with illustration of dog or puppy)

EPA Reg. No. 2382-RtT EPA Est No. 2382-FRA·1

VIRBAC AH, tNC. PO BOX 162059 FORT WORTH TX 76161 1·800·338-3659

Made in France EFFITIX'M is a trademark of Virbac S.A Questions or comments? Calt: 1·800-338·3659 

### {Text for Front Panel, Back Panel, Inside Flap and Side Panel}

See package insert{s} for directions for use and frequency of application See package insert for directions for use and storage and disposal See package insert for frequency of application and storage and disposal Open resealable label for directions for use Open resealable label for directions for use and storage and disposal See back panel for additional precautionary statements See package insert{s} for frequency of application See enclosed insert{s} for directions for use and storage and disposal See enclosed insert{s} for directions for use lift here to open (LIFT HERE TO OPEN) For Use on Dogs ONLY Use ONLY on dogs See inside flap for directions for use

EPA Reg. No, 2382_Rrr page 3 of 6 - Master label version t6 Novcmlx!r, 20t t

### {Text for Foil of Blister package} Virbac**EFFITIXr>~Topical** Solution For Dogs Only for use on dogs up to 22.91bs (23-44.9 lbs, 45·88.9Ibs, 89·132Ibs)/O.034 fl 02 (0.068 fl oz, 0.135 fl OZ, 0.203 fi 02) (1.0 mL, 2.0 ml, 4.0 mL, 6.0rnl) Contains fipronil (6.01%) and permethrin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUTION See full label for additional directions EPA Reg. No, 2382-XXX 00 NOT USE ON CATS CAT PROH1B1110N ICON 

### {Text for Applicator Tube} Virbac EFFIT1XTM Topical Solution For Dogs Only for use on dogs up to 22.91bs (23-44.9Ibs. 45-88.9Ibs, 89-132Ibs) 0.034 fl 01: (0.068 fl OZ, 0.135 fl OZ, 0.203 II 0:;::) [I 1.0 mL (2.0 mL, 4.0 mL, 6.0mll) Contains fipronil (6.01%) and permetl1rin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUnON See full labe! for additional directions DO NOT USE ON CATS EPA Reg. No. 2382-XXX CAT PROHIBITION ICON

MARKETING CLAIMS

IMultiple infestationsl
• For convenient, quick-acting, long-lasting control of fleas, ticks, mosquitoes and lice. (When) Applied topically on a monthly basis, EFFITIX"" Topical Solution for Dogs repels and kills fleas, ticks and**mosqu~oes,** kills (biting, chewing) lice, aids in control of mites and repels (and inhibits blood feeding) by biting flies and mosquitoes.
• For easy and convenient application, EFFlnX'" Topical Solution for Dogs is available in sizes for small dogs (12 weeks old or older) and up to 22.9 100 (0.034 fI oz)(1.0 mL), medium dogs 23-44.9Ibs (0.068 fl oz) (2.0ml), large dogs 45-88.9 100 (0.135 fI 02:) (4.0 mL), and extra large dogs 89-132 lbs (0.20311 02) (6.0 ml).**EFFITIX~M** Topical Solution for Dogs contains the ac1ive ingredients fipronil and permethrin, whiCh control in1estations caused by fleas,1icks and lice; repel (against) biting flies, and repel and kin mosquitoes.

• Kills fleas,1icks, lice, and mosquitoes, repels biting flies and mosquitoes Repels and kills fleas and ticks Repels fleas, ticks, biting flies and mosquitoes KiITs, repels and detaches ticks

• For the control and prevention 01 flea [and lice] in1estations Flea, tick, (biting and chewing) lice in1estations can be controlled with monthly applications of EFFITIXTM Topical Solution for Oogs. Biting files and mosquitoes are (also) repelled by EFF1T1XTM Topical Solution for Dogs. Monthly application against fleas, ticks and mosquitoes Kills fleas, ticks and mosquitoes for (up to) one month

• Monthly application is recommended for control and prevention of fleas, ticks and mosquitoes
• Long lasting flea, tick and mosquito control for your pet EFFITIXTM Topical Solution for Dogs is indicated for the prevention and control of fleas, ticks, mosquitoes, and lice on dogs 12 weeks of age am older Helps to relieve your dog's pain (discomfort) by controlling flea, tick and lice infestations

• Kills the vectors thal may transmit Lyme disease, Rocky Mountain spotted fever, ehr1ichiosis, hepetozoonosis and heartworm disease.
• Kills fleas, ticks, mosquitoes. lice, and aids in control of mites Kills and repels fleas, ticks, and mosquitoes.

[Fleas} Fleas: EFF1T1XTM Topical Solution for Dogs can kill adult fleas in 6 hours (and lasts) for (up to) one [a) month. Apply monthly if your dog has fleas that may cause flea allergy dermatitis (FAD), or if reinfestation is likely. Kills newly emerged adult fleas prior to egg laying

• Kills fleas (within 6 hours) that may transmit bartonellosis, (tularemia) (and tapeworm)
• Kills fleas (within 6 hours) that may transmit diseases, including bartonellosis, (tularemia) (and tapeworm infestations)

• Kills fleas (within 6 hours) that may transmit diseases, including bartonellosis and tularemia Rapid kill of fleas is important in the prevention of disease transmission by (these) parasites

• Acts to kill fleas that may transmit disease, such as bartoneITosis and tularemia

EPA Reg. No 2382-RIT page 4 of 6 - Master label version 16**Novernb~'T.** 2011Kills fleas that may serve as an intermediate host for tapeworms (Dipylidrum caninum)

• Kills fleas that may serve as an intermediate host for cysticercoids of tapeworms Kills fleas that may serve as hosts for life cycle intermediates of tapeworms
• Kills (adult) fleas (within 6 hours) that may cause Flea Allergy Dermatitis (FAD) (or) (Ilea-bite anemia) Fleas do not have to bite to die Controls highly [irritating] [annoying] [flea] bites
• EFFITIXTM Topical Solution for Dogs rapidly kills fleas that may cause FAD (Flea Allergy Dermatitis) The successive feeding activity of fleas on dogs may elicit a hypersensitivity skin disorder known as Flea Allergy Dermatitis (FAD) EFFITIX'" Topical Solution for Dogs kills fleas and may reduce the incidence of Flea Allergy Dermatitis (FAD)

• Kills adult fleas for up to one month (4 weeks) Kills fleas
• Easy to apply, control of (for) fleas that lasts up to 1 month (4 weeks) EFFITIXTM Topical Solution for Dogs kills fleas on your dog

• Once a month topical flea control for dogs 12 weeks of age or older EFFITIXTM Topical Solution for Dogs is indicated for the prevention and control 01 fleas on dogs 12 weeks of age and older

• One application prevents further flea infestations for up to (4 weeks) (a (one) month) Monthly treatment (all year] is recommended for control and prevention of fleas

• Provides ongoing protection against fleas and the diseases they may transmit for one month Stops existing flea infestations by rapidly killing Mutt fleas

[Ticks] Kills fleas before they lay eggs Stops existing flea infestations by killing adult fleas Prevents (Stops] re-infestations by killing adult fleas (before they lay eggs) Treatment with EFFiTlXTM rapidly kills fleas which may cause flea allergic dermatitis [FAD] or Ilea bite hypersensitivity Controls flea problems Provides flea protection Use flea )prevention) [protection) year-round EFFITIX MTopical Solution for Dogs controls flea infestation that may lead to painful skin irritation and bacterial infection

Ticks: EFFITIXTM Topical Solution for Dogs can kill ticks for (up to) a (one) month, Apply monthly where tick control is consistently needed. Kills and repels all stages of Brown dog ticks, American dog ticks, Lone Star ticks, and Deer ticks (that may transmit Lyme disease, Rocky Mountain Spotted Fever, babesiosis, ehrlichiosis and anaplasmosis) Kills ticks including Deer ticks (that may transmit Lyme disease), American dog ticks (that may transmit Rocky Mountain Spotted Fever), Brown dog ticks (that may transmit ehrlichiosis), and Lone Star ticks (that may transmit hepatozoonosis) for up to one month (4 weeks] Kills ticks including Deer ticks (that may transmit Lyme disease]. American dog ticks (that may transmit Rocky Mountain Spotted Fever), and BrO'Wll dog ticks (that may transmit ehrllchiosis) for up to one month (4 weeks). Kills Brown dog ticks (Rhipicephalus spp). American dog ticks (Dermacentorvariabllis), Deer ticks (Ixodes spp) and Lone Star ticks (Amblyomma americanum) for up to one month (4 weeks). Kills Amblyomma amen'canum (Lone Star ticks) for 4 weekS (for up to one month). Monthly application against ticks [Mosquitoes ilnd biting flies) Kills mosquitoes Kills mosquitoes for up to 28 days (four weeks) (a [one] month) Repels and inhibits blood feeding by biting flies and mosquitoes Biting flies and mosquitoes: When applied monthly, EFFITIXTM Topical Solution for Dogs (prevents blood feeding by) (and) (repels) biting flies and mosquitoes for (up to) 4 weeks (a (one] month) Repels and kills mosquitoes for up to four (4) weeks Prevents blood feeding by mosquitoes Repels and prevents (inhibits) blood-feeding by biting fiies Repels and kills mosquitoes often before they have a chance to take a blood meal [(Prevents blood-feeding by) (Kills and repels)] mosquitoes Repels biting flies Repels [(annoying)(bothersome)(nuisance)] biting flies tnhibits [(annoying)(bothersome )(nuisance)) biting flies «Prevents)(inhibits)[ blood-feeding by biting files Kills mosquitoes that may carry heartlNorm disease Repels and kills mosquitos (Culex spp, Ochlerolalus spp, Aedes spp) which may vector hearnvorm (Dirofilaria immilis] for
one month [Lice and Mites] Lice: EFFITlX TPJ Topical Solution for Dogs can kill biting and chewing lice for (up to) a [one] month, Apply monthly where lice control is consistently needed Mites: (EFFITlXTM Topical Solution for Dogs) aids in (the) control of mites (that may cause sarcoptic mange) EFFITIXTM Topical Solution for Dogs aids in (the) control of mite infestattons (that may cause sarcoptic mange),
• (When applied monthly,) EFFiTlXTM Topical Solution for Dogs aids in (the) control of sarcoptic mange, Aids in (the) control of sarcoptic mange mite infestation Kills chewing and biting lice

• (Also) Kills lice and aids in control 01 mites

EPA Reg, No. 2382_RIT page 5 of 6 - Master label version t6 Noveml>cr, 20 t I[Others] Controls existing cI1ewing/biting lice infestations Kills [(biting) (chewing)] lice For control and prevention of [(biting) (chewing)llice (imestations) Stops existing [(biting) (chewing)[ lice infestations Prevents and controls [(biting) (chewing)llice (infestations) Provides control of I(biting) (cI1ewing) J lice (infestations) Kills [(biting) (cI1ewing)] lice and prevents further infestations For control and prevention of (infestations with) [(biting) (chewing)[ lice

t (3, 6, 36) applicator(s) (tube[s)) 1.0 mL (2.0 mL, 4.0 mL, 6,0 mL) f (3, 6, 36) applicator(s) (tubeJs]) 0.034 fI oz (0,068 fi OZ, 0, t35 fI oz, 0.203 fI oz) t (3, 6, 36) applicator(s) (tube[s)) 0.034 fI oz [1,0 mL) (0.068 fl oz J2.0 mL), 0, f35ft oz [4.0 mLJ, 0.203 ft oz J6.0 mL]) t (3, 6, 36) applicator(s) (tubeJs]) (each) containing 0,034 fi oz [t.O mL) (0.068 fl oz [2.0 mL), 0, t35 fI oz [4.0**mL~** 0,203 fI oz [6.0 mLJ) t (3, 6, 36) applicator(s) (tube[s)) t (3, 6, 36) monthly dose(s)**(app~cation[sD** t (3, 6, 36) applicator(s) (tube[s)) f (3, 6, 36) month(ly) dose(s) (application(s) DO NOT USE ON CATS This product is only for use on dogs 12 weeks of age or older up to 22.9 Ibs (weighing 23 to 44.91bs, weighing 45 to 88.9 Ibs, weighing 89 to 1321bs) Up to 22.91bs (weighing 23 to 44.9 Ibs, weighing 45 to 88.9 Ibs, weighing 89 to 1321bs) Easy and convenient application (applications) Remains effective for a (one) month (4 weeksJ Stops existing infestations and prevents establishment of new infestations Reinfestation of fleas, ticks and mosquitoes, (biting, cI1ewingJ Uce and biting flies is prevented for a (one) month or longer Convenient topical treatment for dogs Quick onset of activity Persistent efficacy through 30 days Prevents (re-)infestation for one month Once monthly appNcation Quick drying, non-greasy (Convenient) (to use) Easy (to apply) spot-on (topical) application Fragrance (odor) free No noticeable odors Single application lasts 4 weeks (one month) (30 days) Easy to use applicator makes treatment simple (trouble free, smooth) and comfortable for your pet Convenient, easy to appty topical solution Convenient, easy to apply and fragrance free topical solution Starts working by (on) contact (In) Child-resistant packaging Convenient (to use). easy to apply (topical solution) EFFITIX'''' Topical Solution for Dogs remains effective after bathing, shampooing, water immersion, or sunlight exposure, Waterproof (remains effective after bathing and swimming) for up to four weeks (a month) (one month) Remains effective after exposure to sunlight Remains effective even after bathing, water immersion, or exposure to rain or sunlight Remains effective even after bathing (and swimming) Remains effective after exposure to rain and/or sunlight Still works after bathing, swimming or exposure to sunlight Maintains residual efficacy after bathing and swimming Remains effective after bathing (and swimming) [(for a month) (for one month) (for up to four weeks)) For dogs that enjoy the outdoors For indoor and outdoor dogs Convenient topical treatment for dogs who enjoy the outdoors

• Formulated for dogs that love the outdoors For dogs that enjoy the outdoors

• Available from licensed veterinarians Illustration of flea life cycle

• Illustration of tick life cycle
• Illustration of mosquito life cycle Illustration of mite life cycle

• Illustration of louse life cycle

• Illustration of flea Illustration of tick

• Illustration of mosquito Illustration of mite

• Illustration of louse Picture or illustration of a dog (or puppy)
• Picture or illustration of the Virbac logo Picture or illustration of the primary package (applicator rubes)

EPA Reg, No, 2382-RtT page 6 of 6 - Master**la~t** version t6 November, 20t tEffitix PDP with no strikeouts Jim Barron to: Bonaventure Akinlosotu 11117/201101:11 PM Hide Details From: "Jim Barron" <jbarron@exponent.com>

To: Bonaventure AkinlosotuJDC/uSEPAlUS@EPA

2 Attachments

image003.jpg Effitix Master label resubmitted to EPA Nov 162011 ver 2.pdf
Bonaventure, Page 1 of2

Per our telephone conversation, attached is a copy of the pdf version of the Effitix label with no strikeouts. It is derived from the same exact pdf file that you received from me yesterday.
Let me know if you need anything else or have any questions.
Thank you,

Jim Barron, Ph. D. Managing Regulatory Consultant 

### E

X

ponel1t@, 

### Inc. 1000 Centre Green Way Suite 200 Cary, NC 27513

Office Telephone (919)**228~6479** Mobile Telephone (919) 534-6018

file:IIC:\Documents and SettingslBAkinloslLocal SettingsITemplnotes87944B1-web8272... 11117/2011

### Page 20f2

Facsimile (919) 228-6501 Email Addressjbarron@exponent.com
CONFIDENTIALITY NOTICE: This electronic transmission (including any files attached hereto) may contain information that is privileged, confidential and protected from disclosure. The information is intended only for the use of the individual or entity named above and is subject to any confidentiality agreements with such party. If the reader of this message is not the intended recipient or any employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any disclosure, dissemination, copying, distribution, or the taking of any action in reliance on the contents of this confidential information is strictly prohibited. If you have received this communication in error, please destroy it immediately and notify the sender by telephone. Thank you

file:IIC:IDocuments 

### and SettingslBAkinloslLocal SettingsITemplnotes87944BI-wcb8272.

.. 11117/2011

# ,.

Corrected Effitix Label-2382-RIT Jim Barron 

### to: Richard Gebken 11116/201111:48 AM Cc: Bonaventure Akinlosotu, "Brenton Smith" Hide Details 

### From: "Jim Barron" 1barron@exponentcom>



### To: Richard GebkenJDCIUSEPAlUS@EPA

Cc: Bonaventure AkinlosotnJDC/USEPAlUS@EPA, "Brenton Smith" <brenton.smith@virbacus.com>

2 Attachments 

# i1
image003jpg Effitix Master label resubmitted to EPA Nov 16 201l.pdf

Richard and Bonaventure,
Please find attached the Effitix label with the following changes: Page 1 of2

(1) All corrections and deletions requested in the efficacy review of Clayton Myers dated November 8, 2011. (2) According to PR 96
R 6, and confirmation from Richard, we have deleted the puppy claim and proposed a minimum age of 12 weeks for treatment with this product. (3) Bullets describing illustrations have been moved from page 4 to the end of MARKETING CLAIMS at request of R. Gross.
Thank you for your help in registering this product.
Please let me know immediately if there are any other questions.

Jim Barron, Ph. D.

fiie:IIC:\Documents 

### and Settings\BAkinios\Local**Settings\Temp\notes87944B\~web0638...** 

### 1III 7/201 

### 1

# Virbac's Master Label
Date 16NOV11 Version US-g EPA Reg. No. 2382-Rlr Fipronil+Pennethrin Topical Solution for Dogs Optional text appears in brackets.


## EFFITIXTM TOPICAL SOLUTION FOR DOGS Alternate brand names: 

## (EFFIXTM TOPICAL SOLUTION FOR DOGS) (EFFICANIXTM TOPICAL SOLUTION FOR DOGS) (EFFIPROTIXTM TOPICAL SOLUTION FOR DOGS)
FOR USE ONLY ON DOGS 12 WEEKS OLD OR OLDER (WEIGHING UP TO 22.9 LBS, WEIGHING 23 TO 44.9 LBS, WEIGHING 45 TO 88.9 LBS, WEIGHING 89 TO 132 LBS) ACTIVE INGREDIENTS: FiproniL

.. Permethrin*

. OTHER INGREDIENTS:

. TOTAL:

. * cis/trans ratio: maximum 55% (±) cis and minimum 45% (±) trans

HAZARDS TO HUMANS KEEP OUT OF REACH OF CHILDREN 

### CAUTION READ ENTIRE LABEL BEFORE EACH USE

PRECAUTIONARY STATEMENTS HAZARDS TO HUMANS AND DOMESTIC ANIMALS 6.01% 44_88% 49.11% 100.00%

Harmful if swallowed. Causes eye irritation. Avoid contact witll skin, eyes, or clothing. Wash hands thoroughly with soap and water after handling and before eating, drinking, chewing gum, using tobacco, or using the toilet. HAZARDS TO DOMESnC ANIMALS For external use on dogs ONLY.

DO NOT USE ON CATS-IF INGESTED BY CAT THAT ACTIVELY GROOMS A RECENTLY TREATED DOG, THIS PROOUCT MAY HAVE SERIOUS HARMFUL EFFECTS. IF THIS OCCURS, CONTACT YOUR VETERINARIAN IMMEDIATELY.

00 not use on dogs under 12 weeks of age. Individual sensitivities, while rare, may occur after using ANY pesticide product. Dogs may experience some temporary irritation at the Site of product application. If signs of**sensitiv~y** occur, bathe your pet with mild soap or shampoo and rinse with large amounts 01 water, If signs of sensitivity occur and persist, contact a veterinarian immediately. If your dog has an unusual reaction to the initial application, consult a veterinarian before repeating application. Certain medications can interact with pesticides. Consult a veterinarian before using on medicated, debilitated, aged, pregnanl or nursing dogs, or animals known to be sensitive to pesticide producls.

EPA Reg No. 23S2·RIT page I of 7 - Masterlal:d version 16 November, 1011I IF SWALLOWED: 

### • Call a poison control center or doctor immediately for treatment advice. 

# · Have person sip a glass ofwater if able to swalk)w, 

# · Do not induce vomiting unless told to do so by a poison conlrol center or doctor. Do Mtol, IF IN EYES: 

### • Hold eye open and rinse slowly and gently with water for 15-20 minutes.


### • Remove contact lenses, if present, after the first 5 minutes, then continue rinsing eye. Call a DOi 1 IF ON SKIN OR 

### • Take off contaminated clothing. CLOTHING: Rinse skin immediately With plenty afwater for \5-20 minutes_ 

### •
1 

## ,"'''m, 

# ,,,

,H." 1 '01 I Y" 1 

## ,co,." "m" 01
,**~,j** ..", You may also contact the Hotline number 1-800·338·3659 for human or veterinary health concerns, emergency medical treatment infonnation or pesticide inCidents.

DIRECTIONS FOR USE It is a violation of Federal law to use this product in any manner inconsistent with its labelling. Do not alk)w children to apply product. TO PREVENT HARM TO YOU AND YOUR DOG, READ ENTIRE LABEL AND DIRECTIONS BEFORE EACH USE. FOLLOW ALL DIRECTIONS AND PRECAUTIONARY STATEMENTS CAREFULLY. FOR EXTERNAL USE ON DOGS ONLY. DO NOT USE ON CATS OR RABBITS. DO NOT USE ON OTHER ANIMALS. DO NOT USE DN CATS. FOR EXTERNAL USE ON DOGS ONLY. Do not use on dogs under 12 weeks of age.**~Do** not splft tubes between dogs. Do not use multiple tubes on one dog. Weigh your dog to be sure you are applying the right dose fOffilulated for the weight of your dog. OverdOsing your dog can result in serious illness. Do not bathe your dog within the first 24 hours after the product has been applied. If your dog is exhibiting signs of and/or is being treated for skin problems. talk to your veterinarian before applying any topical flea and tick control product. Do not apply more often than once a (per) month (every 30 days).

For use in DOGS (t2 weeks old or older). To repel and kill fleas. ticks, and mosquitoes; to kill lice and to aids in control of mites; to repel and prevent blood feeding by biting flies. Apply monthly according to directions.
APPliCATION DIRECTIONS

t. Remove one applicator from packaging. Hold applicator upright and remove cap. 2. Invert cap and place other end back onto applicator tip. Push cap down to break seal. Remove cap prior to treatment application. 3 Part dog's hair until skin is visible. Place applicator tip directly against exposed skin. 3a. For small dogs (12 weeks old or older) and weighing up to 22.9 tbs- Deposit entire contents by squeezing the entire applicator contents onto dog's skin, at a single site, between the shOulder blades as shown in diagram 3a. 3b. For medium dogs 23-44.9 Ibs or large dogs 45-88.9 Ibs- Apply the product evenly to three spots on the dog's back, starting between the shOUlder blades and continuing on to the second and third spots as shown in diagram 3b, squeezing the applicator until empty. 3c. For extra large dogs 89-132 Ibs_ Apply the product evenly to four spots on the dog's back, starting between the shoulder blades and continuing on to the second, third and fourth spots as shown in diagram 3c. squeezing the applicator until empt¥. Ensure that EFFITIX " Topical Solution for Dogs is not appied superfiCially on dog's hair.

# ~

# ~

EPA Rcg. No. 23S2_RIT page 2 of 7 - Master tabet version t6 Novclnbcr. 20t IFREQUENCY OF APPLICATION Fleas, ticks, (biting and chewing) lice Infestations**aAQ..mite-iflfe~can** be controlled with monthly applications of EFFITIXTrt Topical Solution for Dogs. Biting fiies and mosquitoes are (also) repelled by EFFITIX T " Topical Solulion for Dogs.
Fleas: EFRTIXTM Topical Solution for OOgs can start killilli;! adult fleas within 6 hours and lasts for (up to) a month. Apply monthly if your dog has fleas that may cause flea allergy dermatitis (FAD), or if re-infestation is likely. Ticks: EFFITIX T " Topical Solution for Dogs can kill ticks for (up to) a month. Apply monthly where tick control is consistently needed. Lice: EFFITIXTM Topical Solution for Dogs can kill biting and chewing lice for (up to) a month. Apply monthly where lice control is consistently needed. Mites: EFFITIXTr; Topical Solution for Dogs aids in (lhe) conlrol of (sarcoplic mange)/(mite mfestat,ons that may cause sarcoplic mange). Biting flies and Mosquitoes, When applied monthly, EFFITIXTrx Topical Solution for Dogs (prevents blood feeding by) (and) (repels) biting flies and mosquitoes for up to 4 weeks (a lone] month). Kills mosquitoes for up to four weeks (a [one] month),
Notes: Wait at least 30 days before re-application of EFFITlXTM Topical Solution for Dogs. Avoid contact with treated area until dry.

STORAGE AND DISPOSAL Do not contaminate water, food, or feed by storage and disposal STORAGE: Store unused product in original container only, out of reacl1 of chidren and animals, PESTICIDE ICDNTAINER DISPOSAL: If empty: Nonrefillable. Do not reuse or refililhis container. Offer for recycling, if available, If partially filled: Call your local solid waste agency for disposal instructions. Never place unused product down any indoor or outdoor drain. LIMITED WARRANTY AND DISCLAIMER VIRBAC warrants this product only if it is used, stored and handled in accordance with the label instructions. The buyers and users are solely responsible for all risks of use and handling of this product when such use and handling are contrary to or differ from the label instructions. To the extent permitted by applicable law, any damages arising from a breach of this warranty shall be limited to direct damages only and shall not include any type of consequential damages.

How supplied: For easy and convenient application, EFFITIXTM Topical Solution for Dogs is available in sizes for small dogs 12 weeks old or older up to 22,9 Ibs (0.034 fI oz}/(t.O mL), medium dogs 23-44,9 Ibs (0.068 fl oz)/(2,0 mL), large dogs 45-88.9Ibs (0,135 fl oz}/(4,0 mL), and extra large dogs 89-132 Ibs (0.203 fI oz)/(6.0 mL). Net Contents: t (3, 6 or 36) single-dose applicator(s} per package containing 1mL (2mL, 4mL or 6mL)/ 0.034 fi oz (0.068 fI 02, 0,135 fl oz, 0.203 fi oz) (of solution).
(Detachable) calendar (monthly application) reminder stickers (with illustration of dog or puppy)

EPA Reg. No. 2382-RIT EPA Est. No. 2382-FRA-1

VIRBAC AH, INC. PO BOX 162059 FORT WORTH TX 76161 1-800-338-3659
Made in France EFFITIXTM is a trademark of Virbac SA Questions or comments? Call: 1-800-338-3659 

### {Text for Front Panel, Back Panel, Inside Flap and Side Panel}

See package insert(s) for directions for use and frequency of application See package insert for directions for use and storage and disposal See package insert for frequency of application and storage and disposal Open resealable label for directions for use Open reseal able label for directions for use and storage and disposal See back panel for additional precautionary statements See package insert(s) for frequency of application See enclosed insert(s) for directions br use and storage and dsposal See enclosed insert(s) for directions for use Lift here to open (LIFT HERE TO OPEN) For Use on Dogs ONLY Use ONLY on dogs See inside flap for directions for use

EPA Reg, No. 2382-RIT page 3 of 7 - MasteT label version 16 November, 2011

### {Text for Foil of Blister package}
Virbac EFFITIX"" Topical Solution For Dogs Only for use on dogs up to 22.91bs (2344.9Ibs, 45-88.9Ibs, 89-f32Ibs)/O.034 II oz (O.OSS fI oz, O. 135 II OZ, 0.203 II 02) (1.0 mL, 2.0 mL, 4.0 mL, 6.0mL) Contains fipronil (6.01%) and permethrin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUTION See full label for additional directions EPA Reg. No. 2382-XXX DO NOT USE ON CATS CAT PROHIBITION ICON 

### {Text for Applicator Tube} Virbac EFFITlxTM Topical Solution For Dogs Only for use on dogs up to 22.9 Ibs (23-44.9Ib$, 45-88.9 Ibs, 89-132 Ibs) 0,034 fI oz (0.06811 oz, O. 135 fI oz, 0.203 fI OZ) [/ 1.0 mL (2,0 mL, 4.0 mL, 6.0mL)] Contains fipronil (6.01%) and permefhrin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUTION See fuiliahel for additional directions 00 NOT USE ON CATS EPA Reg. No. 2382-XXX CAT PROHIBITION ICON

MARKETING CLAIMS

[Multiple infestations] For convenient, quick-acting, long-Iasfing,effootive- control of fleas, ticks, mosquitoes and ,lice-aflG-mites. (When) Applied topically on a monthly basis, EFFITIXTM Topical Solution for Dogs repels and kills fleas, ticks and mosquitoes. kills (biting, chewing) llee. aids in control of mites,- ,and repels (and inhibits blood feeding) by biting flies and mosquitoes. "(VLJheF!) /'pplied tS>Jioolly on a menlhly basis, EfflTIX w**~l-Selution** for**Do~s** fOpels aA4!\ills tleas. tiells and**mo~oos,** kills (eitinQ. shewing) lice, aids iF! senlml el mites. ane FOpe!s-aruHAhibits aleee lee ding aj' biling fiies aAC'! mesl:111ilees. For easy and convenient application, EFFI1lXfll. Topical Solution for Dogs is available in sizes for small dogs (12 weeks old or older) and up to 22.91bs (0.034 fI oz){ 1.0 mL), medium dogs 23-44.9Ibs (0.068 fI oz) (2.0mL), large dogs 45-88.9 100 (0.135 fi oz) (4.0 mL), and extra large dogs 89-1321bs (0.203 fl oz) (6.0 mL). EFFITIXTM Topical Solution for Dogs contains the active ingredients fipronil and pennethrin, which control infestations caused by fleas, ticks and ,lice one mites; repel (against) biting flies, and repel and kill mosquitoes. Kills fieas, ticks, lice, and mosquitoes, repels biting flies and mosquifoes Repels and kills fleas and ficks Repels fleas, ticks, biting fHes and mosquitoes Kills, repels and detaches ficks "Kills li08 one aies in eontrGl I'll mites For the control and prevenfion of flea land lice] infestations Flea, tick, (biting and chewing) 008 and mite lice infestations, can be controlled with monthly applicafions of EFFITIX'" Topical Solution for Dogs. Biting flies and mosquifoes are (also) repelled by EFFtTIXTM Topical Solution for Dogs

. .o.GootrGls highly [irritatinllJ [onneying] Eflea] bito&
• ElfeWve-Mmonthly application against fleas, ticks and mosquitoes Ki!s fleas, ticks and mosquitoes for (up to) one month
• Monthly application is recommended for control and prevention of fleas, ticks and mosquitoes Long lasting flea, tick and mosquito control for your pet
• EFFITIXTM Topical Solution for Dogs is indicated for the prevention and control of fleas, ticks, mosquitoes. and lice on dog s 8-12 weekS of ag e and older Helps to relieve your dog's pain (discomfort) by controlling flea. tlck;--mite- and lice infestations Kills the vectors that may transmit Lyme disease, Rocky Mountain spotted fever, ehrlichiosis. hepatozoonosis and heartworm disease. Kills fleas, ticks, mosquitoes, lice, and aids in control of mites

.. Kills and repels fieas, ticks. and mosquitoes. fAlso) kil's lice. and aids in the sentrsl ef mileS,

[Fleas]

EPA Reg. No. 2382_RtT page 4 of 7 -**Mast~.,.label** version 16 November. 20t tFleas: EFFITIXTM Topical Solution for Dogs can kiIT adurt fleas in 6 hours (and lasts) for (up to) one (aj month. Apply monthly if your dog has fleas that may cause flea allergy dermatitis (FAD), or if reinfestation is likely. Kills newly emerged adult fleas prior to egg laying Kills fleas (within 6 hours) that may transmit bartonellosis, (tularemia) (and tapeworm) Kills fleas (within 6 hours) that may transmit diseases, including bartonellosis, (tularemia) (and tapeworm infestations)
• Kills fleas (within 6 hours) that may transmit diseases, including bartoneITosis and tularemia Rapid kill of fleas is important in the prevention of disease transmission by (these) parasites
• Acts to kill fleas that may transmit disease, such as bartonellosis and tularemia Kills fleas fuat may serve as an intermediate host for tapeworms (Dipylidium canlnum)
• Kills fleas that may serve as an inlermediate host for cysticercoids of tapeworms Kills fleas fuat may serve as hosts for life cycle intermediates of tapeworms
• Kills (adult) fleas (within 6 hours) that may cause Flea Allergy Dermatitis (FAD) (or) (flea-bite anemia) Fleas do not have to bite to die Controls highly jinitatingj [annoying] (flea] bites EFFITtXnJ Topical Solution for Dogs rapidly kills fleas that may cause FAD (Flea Allergy Dermatitis) The successive feeding activity of fleas on dogs may elicit a hypersensitivity skin disorder known as Flea Allergy Dermatitis (FAD) EFFITlXTM Topical Solution for Dogs kills fleas and may reduce the incidence of Flea Allergy Dermatitis (FAD)
• Kills adult fieas for up to one month (4 weeks) Kills fleas Easy to apply, control of (for) fleas that lasts up to 1 month (4 weeks) EFFITIXTP " Topical Solution for Dogs kills fleas on your dog Once a month topical flea control for dogs t28 weeks of age or older EFFITIX T " Topical Solution for Dogs is indicated for the prevention and control of fleas on dogs 12 weeks of age and older One application prevents further flea infestations for up to (4 weeks) (a [one] month] Monthly treatment (all year) is recommended for control and prevention of fleas**~~thly) ~se**  areai'!, the**~ea** life GYGlo Provides ongoing protection against fleas and the diseases they may transmit for one month Stops existing flea infestations by rapidly killing adult fleas Kills fleas before they lay eggs Stops existing flea infestations by killing adult fieas
• Prevents ]Stopsj re-infestations by killing adult fleas (before they lay eggs) Treatment with EFF!T!XTM rapidly kills fleas which may cause flea allergic dermatitis jFADj or flea bite hypersensitivity
• Controls flea problems
• Provides flea protection Use flea [prevention]]prolection] year-round
• EFFITlX nJ Topical Solution for Dogs controls flea infestation that may lead to painful skin irritation and bacterial infection [Ticks] Ticks: EFFITIXTM Topical Solution for Dogs can kill ticks for at-Iea&--a(up to) a jone] month. Apply monthly where tick control is consistently needed. Kills and repels all stages of Brown dog ticks, American dog ticks, Lone Star tleks, and Deer ticks (that may transmit Lyme disease, Rocky Mountain Spotted Fever, babesiosis, ehrlichiosis and anaplasmosis) Kills ticks including Deer ticks (that may transmit Lyme disease), American dog ticks (that may transmit Rocky Mountain Spotted Fever), Brown dog ticks (that may transmit ehrlichiosis), and Lone Star ticks (that may transmit hepatozoonosis) for up to one month (4 weeks)
• Kills ticks including Deer ticks (that may transmit Lyme disease), American dog ticks (that may transmit Rocky Mountain Spotted Fever], and Brown dog ticks (that may transmit ehrlichiosis) for up to one month (4 weeks).
• Kills Brown dog ticks (Rhipicephalus spp), American dog ticks (Dermacenfor variabi/is), Deer ticks (Ixodes spp) and lone Star ticks (Amblyomma americanum) for up to one month (4 weeks).
• Kins Amblyomma americanum (Lone Star ticks) for 4 weeks (for up to one month).**ME#eG~Wl** monthly application against ticks [Mosquitoes and biting flies] Kills mosquitoes Kills mosquitoes for up to 28 days (four weeks) (a jone) month) Repels and inhibits blood feeding by biting fiies and mosquitoes Biting flies and mosquitoes: When applied monthly, EFF!T!XTM Topical Solution for Dogs (prevents blood feeding by) (and) (repels] biting flies and mosquitoes for (up to) 4 weeks (a (one] month) Repels and kills mosquitoes for up to four (4) weeks Prevents blood feeding by mosquitoes Repels and prevents (inhibits) blcod-feeding by biting flies Repels and I\ills mosquitoes often before they have a chance to take a blood meal ((Prevents blood-feeding by) (Kills and repels)] mosquitoes Repels biting flies**~Is** ans inAlailG blmlH**foesln~** a)' biling flios Repels [(annoying)(bothersome)(nuisance)] biting flies
• Inhibits (annoying)(bothersome )(nuisanca)) biting fiies «Preventsj(inhibits)] blood-feeding by biting flies Kills mosquitoes that may carry heartworm disease Repels and kills mosquitos (Culex spp, Ochlerofatus spp, Aedes spp) which may vector heartworm (Diroftfaria immitis) for one month

EPA Reg. No. 2382-RtT page 5 of 7 - Mm>tCT tabel version 16 November, 20t 1[Lice and Mites] Lice: EFFITIX!M Topical Solution for Dogs can kill biting and chewing lice for -{up to) a lonel month O'ionger. Apply monthly where lice control is consistently needed.

. Mites:**(~f.>IieG!** FR(lntf1ly, EFFITIX'M Topical Solution for Dogs) aids in (the) control of mites (that may cause sarcoptic mange)
EFFITIX"" Topical Solullon for Dogs aids In (the) control of mEte infestations (that may cause sarcoptic mange). (When applied monthly,) EFFITIX"'" Topical Solution for Dogs aids in (the) control of sarcoptlC mange .VVllen applied msnthl", EF"ITIX'"'' TOllisal 8alu\ion for DO!l5 aid5 in t11e sORtml el sal'GeptiG maRQe (mile), .oAi€js---if1.--#1o Ganlml 01 mites (thal·ffiay

..**G~l\Jse** sarGoplic mange) Aids in (the) control of sarcoptic mange mite infestation
• Kills chewing and ,biUng ---arul---lice (Also) Kills lice and aids En control of mites
Controls existing el1ewinglbiting lice infestations
• Kills IIbiting) (chewing)) lice

[Others] For control and prevention of I(biting) (chewing)llice (infestations) Stops existing [(biting) Ichewing)) lice infestations Prevents and controls [(biting) (chewing)] lice (infestations) Provides effectiv€E-control of [(biting) (chewing) I lice (infestations) Kills I(biting) (chewing)) lice and prevents further infestations For control and prevention of (infestations with) I(biting) (chewing)llice

1 (3, 6, 36) applicator(sl (tubelsl) 1.0 mL (2,0 mL, 4.0 mL, 6.0 mL) 1 (3, 6, 36) applicator(s) (tube[s]) 0.034 fi 02 (0.068 fl oz, 0,135 fi 02, 0.203 fl 02) 1 (3,6,36) applicator(sl (tubels)) 0.034 fi 02 [1.0 mll (0,068 fi oz 12,0 mL), 0.135fl 02 14.0 mLI, 0.203fl 02 (6.0 mLD 1 (3,6,36) applicator(s) (tube[s)) (each) containing 0.034 fl 02 [1.0 mL[ (0,068 fi 02 12,0 mL), 0,135 ft 02 14,0 mLI, 0.203 fi 0216.0 mLI) • 1 (3, 6, 36) applicator(s) (tube[s)) 1 (3, 6, 36) monthly dose(s) (applicationlsl) • f (3, 6, 36) applicator(s) (tube[s)) 1 (3,6.36) month(ly) dose(s) (application(s) DO NOT USE ON CATS This product is only for use on dogs 12 weeks of age or older up to 22.91bs (weighing 23 to 44.9 Ibs, weighing 45 to 88,9 Ibs. weighing 89 to 1321bs)
• Up to 22,91bs (weighing 23 to 44.9 Ibs, weighing 45 to 88.9 Ibs. weighing 89 to 132 Ibs)
• Easy and convenient application (applications) Remains effective for a (one) month (4 weeks) Stops existing infestations and prevents establishment of new infestations
• Reinfestation of fleas, ticks and mosquitoes, -(biting, chewing) lice amI miteE>;- and biting flies is prevented for a (one) month or longer Convenient topical treatment for dogs Quick onset of activity Persistent efficacy through 30 days Prevents (re-)infestation for one month Once monthly application Quick drying, non

..greasy (Convenient) (to use) Easy (to apply) spot.-on (topical) application Fragrance (odor) free No noticeable odors Single applicaUon lasts 4 weeks (one month) (30 days) Easy to use applicator makes treatment simple (trouble free, smooth) and comfortable for your pet Convenient, easy to apply topical solution Convenient, easy to apply and fragrance free topical solution Starts working by (on) contact (In) chHd-resistant packaging Convenient (to use), easy to apply (topical solution) EFFITIXrM Topical Solution for Oogs remains effective after bathing, shampooing, water immersion, or sunlight exposure. Waterproof (remains effective after bathing and swimming) for up to four weeks (a month) (one month)
• Remains effective after exposure to sunlight Remains effective even after bathing, water immersion, or exposure to rain or sunlight Remains effective even after bathing (and swimming) Remains effective after exposure to rain and/or sunlight Still works after bathing, swimming or exposure to sunlight Maintains residual efficacy after bathing and swimming Remains effective after bathing (and swimming) [(for a month) (for one month) (for up to four weeks)! For dogs that enioy the outdoors For indoor and outdoor dogs Convenient topical treatment for dogs who enjoy the outdoors Formulated for dogs that love the outdoors For dogs that enjoy the outdoors

EPA Reg. No. 2382·RtT page 6 of 7 - Mastertabd version t6 November, 20t tAvailable from licensed veterinarians .80'a ay ve\srinarioru;**~VeteriAariaA** reGommenaog

• Illustration of fiea life cycle Illustration of tick life cycle
• Illustration of mosquito life cycle

• Illustration of mite life cycle
• Illustration of louse life cycle Illustration of fiea

• Illustration of tick
• Illustration of mosquito

• Illustration of mite

• Illustration of louse
• Picture or illustration of a dog (or puppy) Picture or illustration of the Virbac logo .Picture or illustration of the primary package (applicator tubes)

EPA Reg. No_ 23112·RIT page 7 of 7**~** Master lal:><:l version 16 November, 2011tiNITED S"IATES**ENVIRON;vlI~1\q'Al~** PROTECTION AGENCY \\'ASIlINGTON. D.C 20460

MEMORANDUM:

To: Bonaventure Akinlosotu

From: Clayton Myers, Entomologist Date: November 8, 2011**'---~** Subject: PRODUCT PERFORMANCE DATA EVALUATION RECORD

DP barcode: Decision no.: Submission no: Action code: 391921 448350 897940 R310 Product Name: Effitix Topical Solution for Dogs EPA Reg. No or File Symbol: 2382-RlT Formulation Type: Pet Spot-On OFfiCi, OF CllEMICAL SAFUS I'lND POLLUTION 1'1<\,VENTION

Ingredients statement from the label with PC codes included: Pennethrin, 44.88% PC: 10970 I; Fipronil, 6.01% PC: 129121 Application rate(s) of product and each active ingredient (ibs. or gallons/1000 square feet or per acre as appropriate; and g/m 2 or mg/cm 2 as appropriate): Rate not provided on label. States one bottle (sizes not listed in net contents) will treat a surface up to [360][500] square feet.

I. Action Requested: Data was submitted to support pest claims for a pet spot-on product.

II. Background: The registrant seeks to register a fipronillpermethrin combo spot-on product for control of fleas, ticks, and other pests on dogs. The registrant has submitted 9 studies to support efficacy claims, in addition to selective citations.

III. MRID Summaries: (Primary Review attached)

a. MRID 4851070 I: Efficacy Study Against Fleas (Ctenocephalides) on Dogs: Onset of Action.

!. GLP Study 2. A laboratory study was conducted to test the speed of effectiveness of a fipronil/permethrin combination product with equivalent concentrations as the submitted product (on a w/w % basis). Dogs were qualified for flea retention and allocated into 2 groups, a treatment and a control group (10 dogs each in the treated groups and 6 in the control group). Dogs were infested with fleas on day -6 and day -I. Aftertreatment on day 0, dogs were kept in individual pens. Flea comb counts were conducted on day -5 and on day 0 at 2, 6, and 12 hours after treatment. Efficacy calculations were based on geometric means and percent efficacy
was calculated using Abbott's Formula. 3. Mean flea reduction efficacy at 6 hours after treatment was 94.4% (88.6% ifthe regular arithmetic mean was used). Flea efficacy exceeded 99% by 12 hours after treatment. 4. The primary reviewer agrees that the study is adequate to support killing claims against fleas within 6 hours of treatment. The reviewer comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the Page 1 of6concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. This study is acceptable and claims ofkil1ing fleas within 6 hours oftreatment are adequately supported.

b. MRlD 48467122: Efficacy Study Against Rhipicephalus sanguineus in Dogs: Duration of Action.

I. GLP Study 2. A laboratory study was conducted to test the efficacy and duration ofcontrol of Brown Dog Ticks on dogs for a fipronil/pennethrin combination product with equivalent concentrations as the submitted product
on a wlw % basis). Dogs were infested with adult ticks for the study. 6 dogs were placed in a treatment group and 6 others in a control group. Each dog received 50 ticks on day**~6,** and days 0, 7, 14,21,28,35, 42,29,56, and 63. Tick counts and mortality assessment was conducted on day -4, 1,2,9, 16,23,30,37, 44, 51,58, and 65. The ticks were categorized as being alive or dead, and also in 3 subgroups: free, attached and unengorged, or attached and engorged. Ticks were counted and removed during the 48 h assessment. Efficacy calculations were based on geometric means and percent efficacy was calculated using Abbott's Formula. 3. Efficacy at 2 days after treatment was 86.6%, but efficacy then exceeded 90% after each subsequent reinfestation through day 51. The study author states that efficacy should be adequately supported for 7 weeks after treatment. 4. The primary reviewer agrees that the study is adequate to support claims against BOT through 7 weeks after treatment. The reviewer comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the concentrations, when converted to a weight/weight ratio to calcUlate the active ingredient concentrations. This study is acceptable and claims of killing BOT are supported for 7 weeks after treatment.

c. MRlO 48467123: Efficacy Study Against Dennacentor variabilis on Dogs: Duration ofAction.

I. GLP Study 2. A laboratory study was conducted to test the efficacy and duration ofcontrol of American Dog Ticks on dogs for a ftpronillpermethrin combination product with equivalent concentrations as the submitted product
on a wlw % basis). Dogs were infested with adult ticks for the study. 6 dogs were placed in a treatment group and 6 others in a control group. Each dog received 50 ticks on day -6, and days 0, 7, 14, 21, 28, 35, 42,29, 56, and 63. Tick counts and mortality assessment was conducted on day -4, 1,2,9, 16,23,30, 37, 44, 51, 58, and 65. The ticks were categorized as being alive or dead, and also in 3 subgroups: free, attached and unengorged, or attached and engorged. Ticks were counted and removed during the 48 h assessment. Efficacy calculations were based on geometric means and percent efficacy was calculated using Abbott's Formula. 3. Efficacy at 2 days after treatment was 49.4%, but efficacy then exceeded 90% after each subsequent reinfestation through day 44. The study author states that efficacy should be adequately supported for 6 weeks after treatment. 4. The primary reviewer agrees that the study is adequate to support claims against ADT through 6 weeks after treatment. The reviewer comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. This study is acceptable and claims ofkilling ADT are supported for 6 weeks after treatment.

d. MRJD 48467124: Efficacy Study Against the Brown Dog Tick (Rhipicephalus sanguineus) and the Cat Flea (Ctenocehpalides felis) on Dogs: Effects ofShampooing and Periodic Water Immersions.

1. GLP Study 2. A laboratory study was conducted to to evaluate the efficacy and duration ofcontrol ofa fipronil/permethrin combination product against fleas and ticks after shampooing and water immersion, in support of waterproof claims. 24 dogs were blocked within gender and weight groups in 6 blocks of4 dogs in descending order ofpre-treatment flea counts, and assigned to 3 treatment groups: Group I Was a control group that was shampooed and water immersed, 6 dogs. Group 2 was treated with the test Page 2 of6substance, 6 dogs. Group 3 was treated with the test substance and shampooed, 6 dogs. Group 4 was treated with the test substance and water immersed, 6 dogs. Dogs were infested with fleas (100) on days4,0,7, 14,21, and 28. Dogs were also infested with ticks (50) on days -5, -I, 6, 13,20, and 27. Shampooing occurred on day 12. Water immersion on days 12 and 26. Flea and Tick counts were conducted on days -2, 2, 9, 16,23, and 30. For water immersion and shampooing, animals were rinsed using a shower head for 5 minutes at a flow rate of2 gallons/minute. Efficacy calculations were based on geometric means and percent efficacy was calculated using Abbott's Formula. 3. Tick efficacy at 2 days was variable, but at days 9-30, tick efficacy exceeded 99% for all treatment groups, including dogs that were shampooed or water immersed. Flea efficacy exceeded 90% at 2 days, and was at 100% at days 9-10, for all treatment groups, including dogs that were shampooed or water immersed. The study author states that efficacy is adequately supported for fleas and ticks after water immersion and shampooing. 4. The primary reviewer agrees that the study is adequate to support claims against ticks and fleas through I month after treatment, with shampooing and water immersion. The reviewer comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. This study is acceptable and claims of fleas and ticks for I month after treatment, with water immersion and shampooing, Le., 'waterproof claims.

e. MRID 48467125: The Duration of Efficacy ofa Single Application of 104.05 (Fipronil 6.7%, Pennethrin 50%) Compared to a No Treatment Control Against Artificially Induced Infestations of Ticks (Amblyoma americanum) on Dogs.

I. GLP Study 2. A laboratory study was conducted to test the efficacy and duration of control ofAmblyoma americanum
on dogs for a fipronil/permethrin combination product with equivalent concentrations as the submitted product on a w/w % basis). Dogs were infested with adult ticks for the study. 6 dogs were placed in a treatment group and 6 others in a control group. Each dog received 50 ticks on day -7, and days 0, 7, 14, 21,28, 35, and 42. Tick counts and mortality assessment was conducted on day -4, 1,2,9, 16,23,30,37, and 44. The ticks were categorized as being alive or dead, and also in 3 subgroups: free, attached and unengorged, or attached and engorged. Ticks were counted and removed during the 48 h assessment. Efficacy calculations were based On geometric means and percent efficacy was calculated using Abbott's Formula. 3. Efficacy at 2 days after treatment was 70%, but efficacy then exceeded 90% after each subsequent reinfestation through day 23. Efficacy was 88% at day 37. The study author states that efficacy should be adequately supported for 23 days after treatment, with some residual control ofticks through 30 and 37 days. 4. The primary reviewer agrees that the study is adequate to support claims against BOT through 3 weeks after treatment, but that one month control claims were not adequately supported, as the 90% efficacy threshold was not met for day 30. The reviewer also comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. This study is unacceptable and claims of killing Amblyoma americana for one month, but is partially acceptable and is adequate to SUppOlt claims for 3 weeks after treatment.

f. MRID 48467126: Duration of Efficacy ofa Single Application of 104.05 (Fipronil 6.7% w/v, Pennethrin 50% w/v) Compared to a No Treatment Control Against Artificially Induced Infestations ofTicks (Ixodes scapularis) on Dogs.
I. GLP Study 2. A laboratory study was conducted to test the efficacy and duration of control of Black Legged Ticks on dogs for a fipronil/permethrin combination product with equivalent concentrations as the submitted product
on a w/w % basis). Dogs were infested with adult ticks for the study. 6 dogs were placed in a treatment group and 6 others in a control group. Each dog received 40 ticks on day -7, and with 50 ticks on days 0, 7, 14,21,28,35, and 42, and with 35 ticks on day 49. Tick counts and mortality assessment was conducted 3on day -5, 2, 9, 16,23,30,37,44 and 51, at 48 hours after infestation. The ticks were categorized as being alive or dead, and also in 3 subgroups: free, attached and un engorged, or attached and engorged. Ticks
were counted and removed during the 48 h assessment. Efficacy calculations were based on geometric
means and percent efficacy was calculated using Abbott's Fonnula. 3. Efficacy at 2 days after treatment was 94%, and efficacy then exceeded 90% after each subsequent reinfestation through day 37. The study author states that efficacy should be adequately suppOlted for 37 days after treatment, with some residual control of ticks through 44 and SI days. 4. The primary reviewer agrees that the study is adequate to support claims against BLT through 30 days after treatment. The reviewer also comments that the weight/volume 'concentrations' used in the study do not exactly match those on the submitted product CSF, but notes that another study validates the concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. This study is acceptable and one month claims against BLT are adequately supported.

g. MRJD 48467127: Detennination of a Combination of Fipronil and Permethrin in Topical Solution Against Mosquitoes (Aedes aegyptl) on Dogs.

I. GLP Study 2. A laboratory study was conducted to test the efficacy of a tJpronii/permethrin product against mosquitoes for repellence (preventing feeding) and killing ofA. aegypti. Dogs were qualitled as mosquito hosts, with dogs allowing a feeding rate of 40% were considered acceptable for the study. 12 dogs were randomly assigned into 2 groups, a treatment and control group. The product was applied on day O. Dogs
were exposed for 28-35 minutes to unfed female mosquitoes in exposure cages on days 1,7, 14,21/22,28, and 3S-37. Dogs were sedated during infestations. Afterwards, the mosquitoes were collected and dogs
were removed from the exposure cages and returned to normal housing. At SO-90 minutes after exposure, dead and alive mosquitoes were counted. The mosquitoes were frozen and crushed to determine if a blood meal had been taken. Mortality was calculated for both feeding efficacy (repellence) and killing efficacy. Efficacy calculations were made using Abbott's Formula. 3. Short-haired dogs were more susceptible to mosquitoes than long hair dogs. The test product has a more effective repellence efficacy than killing efficacy. Killing efficacy never exceeded 59.5%. Repellence efficacy was 91.7% efficacy at 7 days after treatment. 4. The primary reviewer concludes that the study is not acceptable to support claims against mosquitoes, as no killing efficacy was demonstrated and repellence was only adequate at 7 days after application. The study is not acceptable to support any claims against mosquitoes.

h. MRJD 48467128: Repellence Eftlcacy Study of 104.0S Against Ticks (Dermacentor variabilis and Rhipicephalus sanguineus) on Dogs Under Laboratory Conditions.

I. GLP Study 2. A laboratory study was conducted to evaluate the repellence ofticks for a fipronil/permethrin combination product. 12 dogs were used in the study, with 6 dogs given treatment and 6 dogs left as an untreated control group. Adult BOT and ADT were used in artificial infestations. Dogs were infested with 30 unfed ticks on day -6 (R. sanguineus only), and days 1,2,7, 14,21,22, and 28. Tick assessments were conducted on days 1,2,7, 14,21,22, and 28 at 3 hours after infestation/reinfestation. Tick counts with removal were conducted on days -5, 2, 4, 8, IS, 22, 23, and 29, 24 hours after the infestations. Ticks were categorized as being alive or killed and in 3 subgroups: free, attached and engorged, or attached and unengorged. Ticks found in the infestation chamber after removal of the dogs were categorized as live, moribund or dead. % mortality was calculated using Abbott's Formula. 3. BOT repellence efficacy was 90H9S% for the 3 hour assessments through 14 days. Efficacy was 99% or greater for the 24 hour assessment through 29 days. For ADT, repellence efficacy was 90-97% for the 3 hour assessments through 22 days. Efficacy was 97% or greater for the 24 hour assessment through 29 days. The author concludes that repellence efficacy for ticks is supported through up to 29 days after treatment. 4. The primary reviewer concurs that basic tick repellence claims are supported for up to one month after application. The study is acceptable to support claims oftick repellence for up to one month. Page40f6i. MRID 48467129: Summary of Efficacy Data for EffitixTM Topical Solution for Dogs End Use Product.

This MRID was a summary of selectively cited and submitted studies in support of label claims. The submission is supplemental. j. Selective Citations of60 MRlDs from the fipronil and permethrin efficacy database including the following: 43121114,43121115,43121116,43121119,43121120, 43121121, 43121122, 43444901, 43577701, 43577712,43577713,43951701,44088901,44942011,44942106,45618501,45620502,45620503, 45628104,45628105,45866901,435777 I 2,43121114,43121 I 15,43121 I 17,43121122,43121 I 18, 45620504,45620505,45620506,43444901,43444901,43577701,43951701,45612701,45620503, 45866901,45620501,45618101,45628102,45628103,45628201,45866902,46019202,46019201, 41038802,41038803,43137202,43137203, 43396409,43396410,46006002,41683903,43111607, 43396409,43396410,46978901,42256901,43396409,43396410

These studies support efficacy claims (in various versions) against fleas, ticks, lice (chewinglbiting), mites (aids in control of sarcoptic mange), mosquitoes, and repe lIence of biting flies.

Claims are not supported for sand flies, for killing/control of mites (only 'aids in control'), or sucking lice.

IV. RECOMMENDATIONS:
(I) Labeling: (a) What pests and site/pest combinations may be added asfollows to the label based on the sllbmitted ar cited data?

Fleas: Killing within 6 hours and control for up to one month. Also repellence of fleas. Ticks: Killing and controlling for up to one month. Also repellence of fleas. Mosquitoes: Killing and controlling for up to one month, also repeJlence and prevention of blood feeding for up to one month Biting Flies: Repellence Lice (chewing/biting); Killing and controlling for up to one month Mites: Aids in control of sarcoptic mange/mites that may cause sarcoptic mange, etc. (b) Whatpests and site/pest combinations mllst be removed ji·01ll the label? Any and all claims against sandflies Any claims ofcontrol offleas or ticks beyond one month (given that waterproof claims are included) Killing/controlling claims against mites (only aids in control is supported) Any and all claims against 'sucking' lice (c) List changes to the directiansfor lise:

None required (d) List changes to the optional marketing claims:

The following marketing claims must be deleted from the label (pages 4-7)

All references to sandflies, killing/controlling of mites, and 'sucking' lice must be removed from all marketing claims and from the entire label. References to the word 'effective' are deemed inappropriate, as this implies a heightened comparative efficacy claim (a decision on the suitability ofthis claim is deferred to the product 5manager). Finally, any and all claims of 'breaking the flea life cycle' must be deleted, as this product does not kill flea eggs or larvae. On a line-by-line basis, the claims marked with strikethrough text below must be deleted,

"For convenient, quick-acting, long-lasting effective control offleas ticks, ,,"

"" ,(biting, chewing and sucldRg) lice and mites" ," All variations ofthese kill claims must be deleted throughout the label. Claims against mites may be expressed as 'aids in contro\.'

"Kills fleas, ticks, lice, mites and mosquitoes, repels biting flies and mosquitoes"
"Repels fleas, ticks, biting flies, sandflies and mosquitoes"

"Research has sho,

....n that flea, tick, (sl;lcking, biting, aRd chewing) lice and mite infestations can be completely cORtrol!ed witH montaly applicatiORs ofEFFITIXTM Topical Sollllion for Dogs," The claim 'research has shown' is unacceptable and the claim 'can be completely controlled' implies 100% efficacy, which is also unacceptable.

"Effective monthly application against fleas, ticks, and mosquitoes"

"Fleas: EFFlTIXn1 Topical solution for dogs can kill adult fleas in 6 hours fur up to taree months, Apply monthly ifyour dog" ,"

"Effective monthly application against fleas"

"Effective monthly control offleas"
"Easy to apply (effective) control, , ," "Effectively breaks the flea life cyele"

"Effective monthly application against ticks" "Repels and inhibits blood feeding by biting flies, sandflies and mosquitoes" (delete all other references to sandflies)

"Lice: EFFITlXTM Topical Solution for Dogs can kill sucking, biting and chewing lice for., ," (delete all other references to sucking lice)

"Mites: When applied monthly, BFFITIXT'lJ Topical Sohllion for Dogs kills mites"

"Mites (Cheyietiella yasguri): "Vllen applied monthl) , , , ,"

"Kills mites (that may cause sarcoptic maRge)" Can be revised to 'aids in control of mites that may cause, "

"Sold By yeterinarians"

"VeteriRarian recommeRded"

Page 6 of6

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 485107·01. Fourie, J.J. Efficacy Study Against Fleas (Ctellocep/talidesJe/is) on Dogs: Onset of Action. December 9, 2009. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT 

### Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30
Primary Reviewer: 

### Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.

Robert Ross, M.S

.. Program Manager


### Quality Assmance: Jennifer Goldberg. B.S. Signature: Date:


### Signature: Date:
Signature: Date:


### Signature: Date:

Disclaimer

# J~;;:;~

# 0~T.~_

# ~*i/dkt~

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP-W-JJ-OI4

### DATA EVALUATION RECORD
{primary 

### Reviewer's Name] 

### STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE
485107-01. Efficacy Study Against Fleas (Ctenocephalides/elis) on Dogs: Onset ofAction. Fourie, 

### J.J. 2009. 391921
448350
897940
VIRBAC SA

ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa


### J.J. Fourie, M.Sc.

S. Bonneau, Virbac SA


### 27/05/2009

None

"This study has been performed in compliance with the Swiss Ordinance relating to Good Laboratory Practice, 

### adopted May 18, 2005 [SR 813.112.1]. This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26 th

, 

### 1997 by decision of the OECD Council [C(97) 1861Fina1J. These principles are compatible with Good Laboratory Practice regulations specified by regulatory authorities throughout the European Community, the United States 

### (EPA and FDA), and Japan (MHLW, MAFF, and METI)."

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: fipronil and pennethrin CHEMICAL NAMES: Not provided. A.I %: 6.01 % fipronil and 44.88% perrnethrin 

### PC CODES: 129121 (fipronil) and 109701 (pennethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution

2

### PROPOSED LABEL MARKETING CLAIMS: PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.9Ib; 2 mL for dogs 23-44.9Ib; 4 mL for dogs 45-88.9Ib; and 6 mL for dogs 89-132 lb ACTIVE INGREDIENT APPLICATION RATE(S): Not provided.

...can start killing adult fleas within 6 

### hr and lasts for up to three months.

STUDY REVIEW
Purpose: To test the speed of effectiveness of 104.05 spot-on formulation against 

### Ctenocephalides 

### felis fleas on dogs.

MATERIALS AND METHODS

Test Location: ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa.

Test Material(s): 104.05 spot-on formulation (6.7% fipronil and 50% permethrin, wivo}).

Test Species Name, Life Stage, Sex and Age: Male and female adult dogs 

### (Canisfamiliaris) greater than 

### 6 months old.; mixed, mainly mongrel.



### Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 7 days prior to treatment and dewormed and did not harbor fleas at the initiation ofthe study. Dogs were separated by gender and ranked as follows: dogs weighing <18.14 kg were ranked first and then dogs weighing 2:18.14 kg were ranked in descending order ofindividua1**pre~treatment** 

### flea counts. Within each gender the dog weighing less than 18.14 kg with the highest**pre~treatment** 

### flea count and the dog weighing 2: 18.14 kg with the lowest**pre~treatment** 

### count were allocated to Group 2 (treatment group). The remaining 12 dogs were blocked into 6 blocks oftwo animals each and within each block were randomly allocated to Group 1 (control) or Group 2. Laboratory breed strain (ClinVet

- 2004, routinely fed on cats) of 

### Ctenocephalides fe/is were used in the artificial infestations. Each dog
was infested with 100 fleas on Day**~6** 

### and on Day**~** 

### 1. After treatment the dogs were kept in individual pens. Flea counts were conducted on Day**~5** 

### and on Day 0 (day of application) at 2, 6, and 12 hours after treatment.
Treatments, including untreated control: 0.1 mL/kg.

Number of replicates per treatment: One.

Number of individuals per replicate: Ten in the treated group; six 

### in the negative control group. Length of exposure to treatment (time in seconds. minutes or hours): Spot application between shoulder blades.



### 3

### Were tested specimens transferred to clean containers? N/A 

### Experimental conditions: 20±4°C; 12112 light cycle,

Data or endpoints collected/recorded: Flea counts were conducted on Day -5 and on Day 0 (day of application) at 2, 6, and 12 hours after treatment,

Data analvsis: Efficacy calculations were based on geometric means, and specifically on the geometric means of the flea data (count 

### +1), One was subsequently subtracted from the result to obtain a meaningful value for the geometric mean ofeach treatment group, Percent efficacy was calculated as follows:
Efficacy (%)**~** 

### 100 x 

### (Gm,

- Gm,) / Gm" where:



### Gme = 

### Geometric mean number oflive fleas on dogs in the negative control group (Group 1) at a specific time point. Gmt = 

### Geometric mean munber of live fleas on dogs in the treatment group (Group 2) at a specific time point, Descriptive statistics (mean, minimum, maximum, standard deviation, CV%, geometric mean and median) on flea counts for the various assessment days were calculated and tabulated,


## RESULTS

Raw data were not included in the study report One protocol deviation was reported; two female dogs with the lowest pre-treatment flea count in the lower weight category «18,14 kg) were excluded instead of the two female dogs with the lowest pre-treatment count per weight category because no female dog in the heavy weight category could be excluded, Flea counts for the negative control group and the treated group are shown in Table 1, Percent efficacy is shown in Table 2.



### a e 

# . T bl 

### 1 M ean 

### Fl C ea 

### oun SID 

### e 

### on ro an rea e 

### t . th C t 1 dT t dGroups. Day,hr Group 1, Ne ative Control Group 2, Treated Group Arithmetic Mean Geometric Mean Arithmetic Mean Geometric Mean -5 67.5 67.0 75.3 73.7' O. 

### + 2 hr 71.5 71.3 55.4 48.1 ' O. 

### + 6 hr 71.0 70.9 8.1 4.0" 0.+12hr 70.7 70.5 0.4 0.3



## .. . . Not statIstIcally slgmficantly (p > 0.05) dIfferent fTom the control group on Day -5 and on Day 0, +2 hr. "Statistically significantly (p < 0.05) different fTom the comrol group.



### T bl 2 P



### a e 

# . ercent Effi 

### lcacy B d 

### ase 

### on G

### eometric M 

### eans of Product 104.05 Against Fleas. Day, hr Group 2, Treated Group Arithmetic Mean Geometric Mean 0, 

### + 2 hr 22.5 32.5 0, 

### + 6 hr 88.6 94.4 0, +12 hr 99.4 99.6

4

### Study Author's Conclusions

The test product (104.05) killed >90% of the fleas on the treated dogs within 6 hr and >99% within 12 hr following administration.


### Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended perfommnce standard was met within 6 

### hr post administration. Note: the reported a.i. concentrations in the product tested (6.7% fipronil and 50% permethrin wtlvol) do not exactly match the label concentration (6.01 

### % fipronil and 44.88% permethrin, presumably on a 

### wtlwt basis). The concentrations ofthe active ingredients in the test product were not verified or supported by a Certificate ofAnalysis. The
use ofthe geometric means in the data analysis was not adequately explained, although it could be argued that the results for each dog can be considered independent variables.

The study author stated that the application was one spot between the shoulder blades. The body weight ofthe study animals ranged between 10.2 kg (22.5 Ib) and 20.2 kg (44.5 Ib). On the label it is stated to apply the product evenly to tlrree spots on the dog's back for medium (22-44.9 lb) or large dogs (45-88.9Ib).


### Reviewer's Recommendations
Acceptable ifthe registrant can verify that the concentrations ofthe a.i. in the test product are the
same as those on the label for "Effitix Topical Solution for Dogs" or are within the certified upper and lower limits ofthe product as specified on the CSF. Results support the label claim that the product starts killing fleas within 6 lrr.

Note: The reported test concentrations (6.7% fipronil and 50% permethrin) were expressed on a wtlvol basis (p. II of36 in MRlD 485107-01). Other MRlDs in Task 2-3030 (e.g., MRlD 484671-26) indicate that 6.7% w/v fipronil and 50% w/v pem1ethrin are equivalent to 6.01% w/w fipronil and 44.88% w/w permetlrrin, the label concentrations.

5

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-22. Fourie 

### J.J. 104.05: Efficacy Study Against Rhipicephalus sunguineus in Dogs: Duration of Action. December 9, 2009. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30 

### Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.

Robert Ross. M.S., Program Manager


### Quality Assurance: Jennifer Goldberg. B.S. 

### Signature: Date:


### Signature: Date:
Signature: Date:
Signature: 

### Date:

Disclaimer



### This review may have been altered subsequent to the contractors' signatures above.

Summitec corp. for the U.S. Environmental Protection Agency under Contract No.EP·W-11-014

### DATA EVALUATION RECORD

[Primary 

### Reviewer's Namel 

### STUDY TYPE:

MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE

484671-22. 104.05: Efficacy Study Against Rhipicephalus sanguineus in Dogs: Duration of Action. Fourie, J.J. December 

### 9,2009.

391921
448350
897940
S. BOlmeau, Virbac SA

ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa.
1.1. Fourie, M.Sc.

S. Bonneau, Virbac SA


### 09112/2009

None

"This study has been performed in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted May 18,2005 [SR 813.112.1]. This Ordinance is based on the 

### OEeD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26 th

, 1997 by decision ofthe OECD Council [C(97)186/Fina1]. These principles are compatible with Good Laboratory Practice regulations specificed by regulatory authorities throughout the European Commlmity, the United States (EPA and FDA), and Japan (MHLW, MAFF, and METI)."

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: fiproni1 and permetbrin CHEMICAL NAMES: Not provided. AJ %: 6.01 % fipronil and 44.88% pennethrin PC CODES: 129121 (fiproni1) and 109701 (pennethrin) CAS NO. Not provided



### 2PROPOSED LABEL MARKETING CLAIM: FORMULATION TYPE: Topical solution

PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.91b; 2 mL for dogs 23-44.91b; 4 mL for dogs 45-88.91b; and 6 mL for dogs 89-1321b ACTIVE INGREDIENT APPLICATION RATE(S): Not provided.

...can kill ticks for at least a month.

STUDY REVIEW
Purpose: To test the duration of action of I 04.05**spot~on** formulation against 

### Rhipicephalus sanguineus ticks in dogs.

MATERIALS AND METHODS

Test Location: 

### elinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa

Test Material(s): 104.05 spot-on formulation (6.7% fipronil and 50% pennethrin).

Test Species Name, Life Stage, Sex and Age: Male and female adult dogs 

### (Canisfamiliaris) older than 6 months old; mixed, mainly mongrel.



### Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 7 days prior to treatment; dewonned and "did not harbor ticks at the initiation of the study." Dogs were kept in individual pens 1.9 m by 2.97 m. Laboratory breed strain (French) of

### Rhipicephalus sanguineus were used in the artificial infestations. Immature ticks were fed on rabbits. Adult ticks at least one week old were used in the infestations (50% male and 50% female). Each dog received 50 unfed adult ticks on Day -6, Day 0 (2 hr ±15 min prior to treatment), and on Days +7, + 14, +21, +28, +35, +42, +49, +56 and +63. After treatment, the dogs were kept in individual pens. Tick counts were conducted on Day4, +1 (in situ), +2, +9, +16, +23, +30, +37, +44, +51, +58, and +65.
Treatments, including untreated control: 0.1 mL/kg

Number of replicates per treatment: One

Number of individuals per replicate: Six in the treated group and six in the control group. Length of exposure to treatment (time in seconds, minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? 

### N/A

3

### Experimental conditions:**~20** ± 

### 4°C; 12112 light cycle

Data or endpoints collected/recorded: Tick counts were conducted on Day -4, +1 (in situ), +2, +9, +16, +23, +30, +37, +44, +51, +58, and +65. The ticks were categorized as being alive or killed and in three subgroups: free, attached and unengorged, or attached and engorged (the latter category was not included during the 24 hr in situ count on Day 1. The ticks counted and removed during the 48 hr assessments were categorized according to gender. Dogs were sedated with medetomidine hydrochloride (1.0 mg/mL ) to facilitate tick infestation.

Data analysis: Efficacy calculations were made for each treatment group at each assessment day. Efficacy was based on geometric means ofthe tick data (count 

### + 1). One was subsequently subtracted from the result to obtain a meaningful value for the geometric mean of each treatment group. Percent efficacy was calculated as follows:
Efficacy (%)**~** 

### 100 x (Gm,

- Gm,) 

### I Gm" where:

Gme = 

### Geometric mean number oflive ticks on dogs in the negative control group (Group 1) at a specific time point Gmt = 

### Geometric mean number of live ticks on dogs in the treatment group (Group 2) at a specific time point.
Descriptive statistics (mean, minimum, maximum, standard deviation, CV%, geometric mean and median) on tick counts for the various assessment days were calculated and tabulated.


### RESULTS

Raw data sheets were included in the study report No deviations from the study protocol were reported. Mean tick COlU1ts for the negative control group and the treated group are shown in Table L Percent efficacy is shown in Table 2. The immediate efficacy assessed after 24 hr was 47.1 %; at 48 hr it was 86.6%. Greater than 90% efficacies were recorded up to 51 days post treatment with the exception ofDay +37 when it was 87.3%.

a el. 

### T hI M can Tick Counts in the Control and Treated Groups Day Group 1,**Ne~ative** 

### Control Group 2, Treated Group Arithmetic Mean Geometric Mean Arithmetic Mean Geometric Mean -4 25.5 24.0 25.2 24.8 

### +1!l 18.0 17.7 11.3 9.3" +2 18.7 16.9 3.0 2.3 

### b +9 20.2 19.3 0.0 0.0 +16 25.8 23.5 0.0 

### O.Ob +23 27.5 26.8 0.0 0.0 +30 27.0 26.4 1.7 1 

### ,b .) 

### +37 34.2 32.3 6.2 4.1 +44 25.5 23.3 2.0 1.0" +51 27.2 26.3 3.0 1.6 +58 34.8 34.6 8.2 4.2" +65 29.7 29.2 12.2 7.2' " In SItu counts bGroup 2 differed statistically significantly (p < 0.05) from Group I. 4

### Tab e 2. Percent Efficac'\ Based G 

### on 'M 

### eometnc eans 0 

### fP d ro uct 

# . \.R:amst 

### Ie 104 05 A' T' 

### ks Day GrouD 2, Treated GrouD Arithmetic Mean Geometric Mean
+ l' 37.0 47.1 +2 83.9 86.6 +9 100.0 100.0 +16 100.0 100.0 +23 100.0 100.0 +30 93.8 94.2 +37 82.0 87.3 +44 92.2 95.5 +51 89.0 94.0 +58 76.6 87.8 +65 59.0 75.2 

### • In Situ counts



### Study Author's Conclusions

A 7-week duration of action (>90%) was recorded against Rhipicephalus sanguineus 

### ticks in dogs. No treatment related adverse effects occurred.


## Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended performance standard was met. The reported a.i. concentrations in the test product (6.7% fipronil and 50% permethrin) do not exactly match the label concentration (6.01 % fipronil and 44.88% permethrin). The concentrations ofthe active ingredients in the test product were not verified or supported by a Certificate ofAnalysis.


## Reviewer's Recommendations
Acceptable ifthe registrant can verify that the concentrations ofthe aj. in the test product are the
same as those in "Effitix Topical Solution for Dogs" (see NOTE below). Results support the label claim that the product kills ticks for at least a month.

NOTE: Although not specifically stated in the study report, the reported test concentrations (6.7% fipronil and 50% permethrin) may have been based on weight per volume measurements. Other MRIDs in Task 2-30 indicate that 6.7% 

### w/v fipronil and 50% 

### w/v pennethrin are equivalent to 6.01% 

### w/w fipronil and 44.88% 

### w/w pennethrin, the label concentrations.

5

### TASK 2 DATA EV ALUA TION RECORD

STUDY TYPE: Product Performance

MRID: 484671-23. Fourie, J.J. 104.05: Efficacy Study Against Dermacelltor variabilis on Dogs: Duration of Action. December 9, 2009. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30 

### Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.



### Robert Ross, M.S

.. Program Manager
Quality Assurance: Jennifer Goldberg, B.S. 

### Signature: Date:



### Signature: Date:

Disclaimer

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP-W-II-O 14DATA EVALUATION RECORD 

### !primary Reviewer's Name}
STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE
484671-23. 104.05: Efficacy Study Against 

### Dermacentor variabilis on Dogs: Duration of Action. Fourie, LT. December 9.2009. 391921
448350
897940
S. Bonneau,Virbac SA

ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa


### 1.1. Fourie, M.Sc.

S. Bonneau, Virbac SA

09112/2009
None

"This study has been perfonned in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted May 18.2005 [SR 813.112.1]. This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26th

, 1997 by decision 

### of the OECD 

### Council [C(97) I 86/Final]. These principles are compatible with Good Laboratory Practice regulations specified by regulatory authorities throughout the European Community, the United States (EPA and FDA). and Japan (MHLW. MAFF. and METI):'

PRODUCT NAME: Effitix 

### Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: fipronil and permethrin CHEMICAL NAMES: 

### Not provided. A.I %: 6.01 % 

### fipronil and 44.88% pennethrin PC CODES: 129121 (fipronil) and 109701 (permethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution

2PROPOSED LABEL MARKETING CLAIMS: PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.91h; 2 mL for dogs 23-44.9 Ib; 4 mL for dogs 45-88.9 Ib; and 6 mL for dogs 89-132 Ib ACTIVE INGREDIENT APPLICATION RATE(S): Not provided.

.. can 

### kill ticks for at least a month.

STUDY REVIEW
Purpose: To test the duration of action of 104.05 spot-on formulation against 

### Dermacentor variabilis ticks on dogs.

MATERIALS AND METHODS

Test Location: ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa.

Test Material(s): 104.05 spot-on formulation (6.7% fipronil and 50% pennethrin).



### Test Species Name, Life Stage. Sex and Age: Male and female adult dogs (Canisfamiliaris) greater than 6 months old; mixed, mainly mongreL



### Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 7 days prior to treatment; dewonned and "did not harbor ticks." Dogs were kept in individual pens 1.9 m by 2.97 m. Dogs were separated by gender and blocked per gender in blocks of animals weighing <18.14 kg and animals weighing**~18.14** kg in descending order of individual pre-treatment tick counts. Laboratory breed strain of 

### Dermacentor variabilis were used in the artificial infestations. Immature ticks were fed on rabbits. Adult ticks at least one week old were used in the infestations (50% male and 50% female). Each dog received 50 unfed adult ticks on Day -6, Day 0 (2 hr prior to treatment), and on Days +7, + 14, +21, +28, +35, +42, +49, +56 and +63. Tick counts were conducted on Day -4, + 1 (in situ), +2, +9, +16, +23, +30, +37, +44. +51. +58. and +{i5.

Treatments. including untreated control: 0.1 mLlkg.

Number of replicates per treatment: One.

Number of individuals per replicate: Six treated and six controls.
Length of exposure to treatment (time in seconds, minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? N/A
Experimental conditions:**~20±4°C;** 12112 light cycle; relative humidity 21.4-68.0% in room C of unit 20.

3

### Data or endpoints collected/recorded: Tick counts were made on Day -4, +1 (in situ), +2, +9, +16, +23, +30, +37, +44, +51, +58, and +65. The ticks were categorized as being alive or killed and also in three subgroups: free, or attached and unengorged, or attached and engorged (the latter category was not included during the 24 hr in situ count on Day 0). The ticks counted and removed during the 48 hr assessments were categorized according to gender. Dogs were sedated with Domitor (1.0 mg medetomidine hydrochloride/mL) to facilitate tick infestation.

Data analysis: Efficacy calculations were made for each treatment group at each assessment day. Efficacy was based on geometric means ofthe tick data (count 

### +1). One was subsequently subtracted from the result to obtain a meaningful value for the geometric mean ofeach treatment group. Percent efficacy was calculated as follows:
Efficacy (%)**~** 

### 100 x (Gm,

- Gm,) 

### I Gm" where:

Gme = 

### Geometric mean number of live ticks on dogs in the negative control group (Group I) at a specific time point. Gml = 

### Geometric mean number of live ticks on dogs in the treatment group (Group 2) at a specific time point. Descriptive statistics (mean, minimum, maximum, standard deviation, CV%, geometric mean and median) on tick COW1ts for the various assessment days were calculated and tabulated.



### RESULTS

Data sheets with the individual animal results were included in the study report. Mean tick counts for the negative control group and the treated group are shown in Table 1. Percent efficacy is shown in Table 2. The immediate efficacy assessed after 24 hr was 0%; at 48 hr 

### it was 49.4%. Efficacy values (based on geometric means) >90% were recorded from Day +9 to Day +44.



### a e 

# . T bl 1 M ean 

### T' 

### kC Ie 

### oun s III 

### e on ro an rea e 

### t' th C t 1 dT t dGroups Day Group 

### I, Ne ative Control Group 2, Treated Group Arithmetic Mean Geometric Mean Arithmetic Mean Geometric Mean -4 27.3 26.3 28.7 27.2 +1 ' 15.5 14.8 25.3 24.4' +2 19.2 15.5 11.7 7.9 +9 26.2 20.3 0.0 0.0' +16 23.8 21.5 0.0 0.0 +23 28.7 24.9 0.2 0.1 ' +30 23.7 19.8 0.2 0.1 +37 26.0 23.4 2.0 1.4' +44 17.5 14.6 1.8 0.8' +51 13.3 10.9 4.0 2.0 +58 20.0 18.7 5.5 4.4' +65 14.0 12.0 3.5 3.0'



### ,In Situ counts bGroup 2 differed statistically significantly (p < 0.05) from Group 1.

4

### T hI 2 P a 

### e 

# . ereentEffi 

### Jeae B d G 

### ase on t' M come rIC 

### eans 0 

### fP d tl0405A

. tT" ks 

### ro uc 

# .**~eams** Ie Day 

### Group 2, Treated GrouD Arithmetic Mean Geometric Mean
+ l' 0.0 0.0 +2 39.1 49.4 +9 100.0 100.0 +16 100.0 100.0 +23 99.4 99.5 +30 99.3 99.4 +37 92.3 94.0 +44 89.5 94.8 +51 70.0 81.3 +58 72.5 76.7 +65 75.0 74.8 

### • In SItu counts



### Study Author's Couclusions
Efficacy reached 100% at Day +9. A 6-week duration of action (>90%) was recorded against 

### Dermacentor variabilis ticks in dogs. No treatment related adverse effects occurred.


### Reviewer's Conclusions

Results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended performance standard was reached at Day 9 post-treatment and lasted to Day +44. The reported a.i. concentrations in the test product (6.7% fipronil and 50% pennethrin) do not exactly match the label concentrations (6.01% fipronil and 44.88% permethrin). The concentrations ofthe active ingredients in the test product were not verified or supported by a Certificate of Analysis.



### Reviewer's Recommendations
Acceptable, if the registrant can verify that the concentrations of the a.i. in the test product are the
same as those in "Effitix Topical Solution for Dogs" or are within the certified upper and lower limits ofthe product as specified on the CSF.

Note: Although not specifically stated in the study report, the reported test concentrations (6.7% fipronil and 50% pennethrin) may have been based on weight per volume measurements. Other MRIDs in Task 2-30 30 (e.g., MRID 484671-26) indicate that 6.7% 

### w/v fipronil and 50% 

### w/v pennethrin are equivalent to 6.0 I % w/w fipronil and 44.88% w/w pennethrin, respectively, the label concentrations.

5

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-24. Fourie, J.J. Efficacy Study Against the Brown Dog Tick (Rhipicephalus sanguineus) and the Cat Flea (CtenocepflaJidesJe/is) on Dogs: Effects of Shampooing and Periodic Water Immersions. December 9, 2009. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30


### Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: 

### Gene Burgess. Ph.D.

Robert Ross. M.S

.. Program 

### Manager
Quality Assurance: Jennifer Goldberg. B.S. 

### '7 t) 

### Signature:

__

# \-_~---;=:-;--c~="'=-_'I;_,"".!:JY,:;-~-. Date: 

## OCT 

## J 9 

## 2011

# ~!t;I,/kt/- Signature: Date:

Disclaimer

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract**No.EP~**W - 11 -0 14DATA EVALUA TION RECORD 

### [Primary Reviewer's Name)
STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE

MRID: 484671-24. Efficacy Study Against the Brown Dog Tick (Rhipicephalus sanguineus) and the cat Flea (Ctenocephalidesjelis) on Dogs: Effects of Shampooing and Periodic Water Immersions. Fourie, J.J. December 9, 2009.

391921
448350
897940
S. Bonneau, Virbac SA

ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa
1.1. Fourie, M.Sc.

S. Bonneau, Virbac SA

09112/2009
None

"This study has been performed in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted May 18,2005 [SR 813,112.1]. This Ordinance is based on the DECO Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26 1h

, 1997 by decision ofthe OECD Council [C(97)186/Final]. These principles are compatible with Good Laboratory Practice regulations specified by regulatory authorities throughout the European Community, the United States (EPA and FDA), and Japan (MHLW, MAFF, and METI)."

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTfVE INGREDIENT NAMES: fipronil and permethrin CHEMICAL NAMES: Not provided. A.I %: 6.01 % fipronil and 44.88% permethrin PC CODES: 129121 (fiproni1) and 109701 (pennethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution

2PROPOSED LABEL MARKETING CLAIMS: PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.91b; 2 mL for dogs 23-44.91b; 4 mL for dogs 45-88.91b; and 6 mL for dogs 89-1321b ACTIVE INGREDIENT APPLICATION RATE(S): Not provided.

..can 

### kill ticks for at least a month

....can start killing adult fleas within 6 hr and lasts for up to three months.

STUDY REVIEW
Purpose: To test the effects of shampooing and periodic water immersion on the efficacy of fonnulation 104.05 against the brown dog tick 

### (Rhipicephalus sanguineus) and the cat flea 

### (Ctenocephalides felis) on dogs.

MATERIALS AND METHODS

Test Location: ClinVet International, Uitsig Road, Bainsvlei, Bloemfontein, South Africa.

Test Material(s): 104.05 topical spot-on formulation (6.7% fipronil and 50% pennethrin).

Test Species Name, Life Stage, Sex and Age: Male and female adult dogs 

### (Canisfamiliaris) greater than 6 months old; mixed, mainly mongrel.

Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 7 days prior to treatment; dewonned and did not harbor ticks at the initiation ofthe study. The 24 dogs used in the study were blocked within gender and weight groups (dogs weighing <18.14 kg and dogs weighing 

### '2: 18.14 kg) in six subsequent blocks offour dogs each in descending order of individual**pre~treatment** flea counts. Study groups were assigned to the blocks using randomization through minimization. The block which was not gender balanced was allocated to the control group. The remaining three groups
were randomly assigned to the three treatment groups. Group #1 was the negative control (shampooed and water immersed, n=6). Group #2 was treated with the test substance (n = 6). Group #3 was treated with the test substance and shampooed (n = 6). Group #4 was treated with the test substance and water immersed (n = 6). After treatment on Day 0, the dogs were kept in individual pens (1.9 m x 2.97 m). Dogs were infested with 100 fleas on Days -4, 0 (4 

### hr prior to treatment); +7, + 14, +21 and +28. Dogs were also infested with 50 ticks on Days**~5, ~**  1, +6, +13, +20, and +27. Shampooing occurred on Day + 12; water immersion on Days + 12 and +26. Tick and flea counts were conducted on Days**~2,** +2, +9, + 16, +23, and +30. Ticks were categorized as alive or killed, as free or attached, and as engorged or unengorged.
Treatments, including untreated control: 0.1 mL for dogs weighing 2 to 10 kg; 2 mL for dogs weigbing > 1 0 kg up to 20 kg; 4 mL for dogs weighing >20 kg up to 40 kg.



### 3

### Number of replicates per treatment: One per treatment type and one control group.
Number of individuals per replicate: Six.
Length of exposure to treatment (time in seconds, minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? N/A


### Experimental conditions: 20±4°C; 12/12 

### light cycle

Data or endpoints collected/recorded: Tick and flea counts were conducted on Days -2, +2, +9, +16, +23, and +30. Ticks were categorized as alive or killed, as free or attached, and as engorged
or unengorged.

Data analysis: Efficacy calculations were based on geometric means ofthe tick or flea data (count 

### +I). 

### "One" was subsequently subtracted from the result to obtain a meaningful value for the geometric mean of each treatment group. Percent efficacy was calculated as follows: Efficacy (%) = 

### 100 x (Gme

- Gmt) 

### I Gme , where:

Gme = 

### Geometric mean number of live fleas (or ticks) on dogs in the negative control group (Group 1) at a specific time point. Gmt = 

### Geometric mean number oflive fleas (or ticks) on dogs in the treatment groups (Groups 2, 3 

### and 4) 

### at a specific time point.
Descriptive statistics (mean, minimum, maximum, standard deviation, Cv%, 

### geometric mean and median) on tick and flea counts for the various assessment days were calculated and tabulated. The groups were compared pair-wise using ANOVA with a treatment effect after a logarithmic transformation on the tick or flea data (count 

### +I) 

### on each assessment day. In addition, the baseline counts were compared in the same way by an ANOVA across all groups. 

## RESULTS

Tick counts for the negative control group and the treated groups are shown in Table 

### I. Percent efficacy for the three treated groups is shown in Table 2.



### Table 1. 

### Mean Tick

; 

## ". in the

III I 

# .,

4'I'.h.o 

### 2. Efficacy Values

" '



### Flea counts for the negative control group and the treated groups are shown in Table 3. Percent efficacy for the three treated groups is shown in Table 4.



### Table 3.**~ean** 

### Flea**Count~** 

### in the Control Group and the Three Treatment Groups

# rT~a~blle===~~~v=a~l~u=e=s**~~~~~F~le=a=s** for the Three Treatment Groups

IIA \' mU:lIJP1-**i~lIl~b'~II{~ (l~U~)**  <lROl1l'3.. Tt1I:f11t::1li1a{,**(I~OJJiSM'!Ilp»I'd**



### Study Author's Conclusions

Ticks: Efficacy values based on geometric means were considered primary. Therapeutic efficacies for Groups 2, 3, and 4 were 75.3%, 64.6% and 85.4%, respectively on Day +2. All treatment groups had >90% efficacy against ticks for the duration ofthe assessment period.



### Fleas: Efficacy values based on geometric means were considered primary. Therapeutic efficacies for Groups 2, 3, and 4 were 99.0%, 97.0% and 98.4%, respectively, on Day +2. All treatment groups had 100% efficacy against fleas for all other assessment periods.



### Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when

5

### tested under simulated or actual field conditions." Although the efficacy value for ticks on Day +2 were less than 90%, the recommended performance standard was reached in all three treatment groups by Day +9.


### Reviewer's Recommendations
Acceptable, if the registrant can verify that the concentrations ofthe a.i. in the test product are the
same as those in "Effitix Topical Solution for Dogs" or are within the certified upper and lower limits ofthe product as specified on the CSF. Results for ticks support the label claim that the product "kills ticks for at least a month". Results for fleas do not support the label claim "lasts for three months;" however, they can support a claim of efficacy for up to one month. Label does not have any claims concerning the efficacy against ticks or fleas after treated dogs are shampooed or are immersed in water.

Note: although not specifically stated in the study report, the reported test concentrations (6.7% fipronil and 50% pennethrin) may be based on weight per volume measurements. Other MRIDs 

### in Task 2-30 (e.g., MRID 484671-26) indicate that 6.7% w/v fipronil and 50% w/v pennethrin are equivalent to 6.01 % 

### w/w fipronil and 44.88% w/w pennethrin, the label concentrations.

6

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-25. Moran, C. The Duration of Efficacy of a Single Application of 104.05 (Fipronil 6.7%, Permethrin 50%) Compared to a No Treatment Control Against Artifically Induced Infestations of Ticks (Amhlyoma americanum) on Dogs. October 28, 2010 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pefs

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30 

### Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.

Robert H. Ross, M.S., Program Manager
Quality Assurance: 

### Angela M. Edmonds. B.S.

Disclaimer 

### Signature: Date:
Signature: Date:


### Signature:

# ~ 

# fit**fi4~** Date:OCI 

## J 9 

## 2011

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP-W-II-OI4

### DATA EVALUATION RECORD

[Primary 

### Reviewer's NameI STUDY TYPE:
MRID:

DPBARCODE:
DECISiON NO:
SUBMISSiON NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE

484671-25. The Duration of Efficacy of a Single Application of 104.05 (FiproniI6.7%, Permethrin 50%) Compared to a No Treatment Control Against Artifically Induced Infestations of Ticks (Amblyoma amer;canum) on Dogs. Moran, C. October 28, 

### 20[0

39[92[
448350
897940


### I. Villard, Virbac SA

Charles River Laboratories Preclinical Services Ireland Ltd., Glenamoy, Ballina, Co. Mayo, Ireland
C. Moran, BSc, MAnSe



### I. Villard, Virbac SA

28110/2010

None



### "The study was conducted in compliance with 

### the OEeD Principles of Good Laboratory Practice 

### [ENV/MC/CHEM/(98)17j."

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RlT 

### ACTIVE INGREDIENT NAMES: Fipronil and pennethrin CHEMICAL NAMES: Not provided. A.I 

### %: 6.01% fipronil and 44.88% pennethrin 

### PC CODES: 129121 (fipronil) and 109701 (pennethrin) CAS NO. Not provided FORMULATlON TYPE: Topical solution

PRODUCT APPLlCATlON RATE(S): 1 mL for small dogs and puppies 8 weeks old and older, up to 22.91b; 2

2

### PROPOSED LABEL MARKETING CLAIMS: mL for dogs 23-44.91b; 4 mL for dogs 45-88.91b; and 6 mLfordogs 89-1321b ACTIVE INGREDIENT APPLICATION RATEeS): Not provided

.



### ..can 

### kill ticks for at least a month

STUDY REVIEW
Purpose: To detennine the duration of efficacy of a single application offormulation 104.05 against infestations ofticks 

### (Amblyoma americanum) on dogs.

MATERIALS AND METHODS

Test Location: Charles River Laboratories Preclinical Services Ireland Ltd., Glenamoy, Ballina, Co. Mayo, Ireland



### Test Material(s): 104.05 spot-on formulation (nominal 6.7% w/v fipronil and 50% w/v pennethrin). Two Certificates ofAnalysis was included in the study report (actual concentrations: 6.71 and 6.68% w/v fipronil and 50.26% and 50.23% w/v pennethrin, respectively).

Test Species Name, Life Stage. Sex and Age: Male and female adult beagle and mixed breed dogs 

### (Canisjamiliaris),**~** 

### 6 months old.

Test containers. chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimatized for seven days. Dogs were grouped within
one oftv.ro 

### body weight bands; ::;17.9 kg or**~18.0** 

### kg based on Day**~2** 

### body weight measurements. Dogs**~18.0** 

### kg were ranked in decreasing order of Day**~5** 

### tick counts, irrespective of sex. The first two dogs 2:18.0 kg fonned a block and were assigned to either the treatment group or the control group using random order numbers. The next two dogs 2:18.0 kg were blocked and assigned to groups in the same way, as was the third two dogs**~18.0** 

### kg. All remaining dogs were then ranked in decreasing order ofDay**~5** 

### tick count, within each sex. The first two female dogs were assigned to one ofthe wo groups using the same method as described above, followed by the second and third pair offemales and then the remaining males until there were three males and three females in the treatment group and in the control group. Dogs were infested with approximately 50 ±4 viable, unfed adult 

### Amblyoma americanum ticks (approximately 50% male and 50% female) on Days**~7,** 

### 0, 7, 14,21,28,35, and 42. On Day**~5,** 

### about 48 hr 

### post infestation, ticks were counted and removed from the dogs. On Day 1, ticks were counted, categorized by gender, attadunent status, viability and location, but not removed. On Day 2, ticks were counted categorized and removed from the dogs approximately 48 hr after treatment. On Days 9, 16,23,30,37 and 44, ticks were counted, categorized, and removed from the dogs approximately 48 hr 

### post infestation.
Treatments, including untreated control: 0.1 mLlkg.

Number of replicates per treatment: One and one control group.
Number of individuals per replicate: Six.



### 3

### Length of exposure to treatment (time in seconds, minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? N/A


### Experimental conditions: IS-22°C; 53-80% RH

Data or endpoints collected/recorded: On Day 1, ticks were counted, categorized by gender, attachment status, viability and location, but not removed. On Day 2, ticks were counted categorized and removed from the dogs approximately 48 hr after treatment. On Days 9, 16,23, 30,37 and 44, ticks were counted, categorized, and removed from the dogs approximately 48 hr post infestation.

Data analvsis: Primary efficacy was defined as the geometric mean live tick reduction when compared to the untreated control group. Efficacy was declared at ::::90% tick count reduction compared to the control group.

To calculate efficacy the number oflive attached ticks was added to the number oflive free ticks. This count was calculated after totaling male and female ticks over all locations from which ticks
were collected.

Arithmetic and geometric mean tick counts were calculated for each assessment day and used to calculated percent reduction. The geometric mean was calculated by first applying a natural logarithmic transfonnation. In cases where the data sets included a zero, geometric means were calculated by adding I to all numbers before applying the transfonnations. The arithmetic mean was calculated for the transfonned data. This was then anti logged and 1 was subtracted (if the data sets contained a zero).

Percent efficacy was calculated from Abbott's fonnula as follows:
Efficacy (% reduction)**~** 

### 100 x [(Me

- Mt) I 

### Me], where:

Mc = 

### Geometric mean count in the control group (Group I) at a specific time point. Mt = 

### Geometric mean count in the treatment group (Group 2) at a specific time point.

The test and control groups were compared using ANOVA for Days 1,2, 16,23,30,37, and 44. For study Day 9 the comparisons were on the basis ofthe numbers of animals with tick present using the non-parametric Fisher's Exact test. All tests were two-tailed with a 5% level of significance.



### RESULTS

Results for each individual test animal are included in the study report. Deviations from the study plan are listed below:

41. The Study Ptan stated that for the duration of the study the dogs \voutd be housed in Unit 2 at the Glenamoy facilities of Charles River Laboratories Preclinical Sorvices Ireland Ltd. The animals

were housed tn Unit 1 at the Glenamoy facilities of Charles River LaboratOries Preclinical Services tretand Ltd. The deviation arose due to a mistake In the Sludy Plan, which was subsequently corrected by amendment. Slnce the pens used were of the corred size, as stated in Section 

### lU of Ihe Study Plan, and lhe environmental conditions were the same in Unit 1 and Unit 2, there was no impact on the study.

2. Amendment 1 stated that only fOUf femate and five mate dogs should weigh ;;:18.0 kg on Study Day -7, and that six female and five male dogs should weigh :517.9 kg on Study Day -7. tn fact four female and four mala dogs weighing**~18.0** kg on Study Day**~7** and six female and six male dogs weighing :::;17.9 kg on Study Day-7 were included In the study, The deviation arose due to

an oversight on the part of the Study Director. Since the correct number of animals of each weight band were assigned to groups on Stody Day Mi. there was no impact on the study.

3. The Study Plan staled that for the duration of the study the temperalure should remain between 1S'C and 21"C and the relative humidity between 30 0/ 11 and 70 

### %. On 19AUG09the temperaiL..u-e reached 22**~C** and the relative humidity reached 73 %. On 20AUG09 Ihe relative humidity reached up to 75 % in the morning, and 76% in the afternoon, 01121AUG09 the relative humidity reacned 77 % in the morning j and on 25AUG09 the relative humidity reElched 75 % in the moming. On 01 SEP09 the relative humidity In the study unn reached 80%. Since there was no indication of discomfor1 or jJlness in the study animals, and ticks <Ire comfortable in humid conditions there was no impact on the study.

4. As a consequence 

### 'Of the unforeseen occurrence (see Section 14,0 Unforeseen Occurrences above) which took place 

### on 10SEP09 (Study Day 30) some tick count data for animals 15019, 28572. 59347 and 33610 on 03SEP09 (Study Day 23) was lost. As these data had been entered into Excel files and checked and the summary results of all tick counts for all animals are still ava'ilable, tho study Director is satisfied that there is no impact 'On Ihe study.



### 55. The Study PlEIn stated that during trck infestations all animals would remain in containment boxes for 1 hour (!: 5 m'ln) post infestation. On Study Day 1 (18AUG09) animal no. 33610 (Group 2, Test Item) was infested with ticks at 

### 15:27 and removed from the tick containment box at 16:20-

a deviation of 

### 2 minutes. The devlat10n occurred due to an oversight on the part of the technician who removed the animals from the tick containment boxes, Since the animal was kept in the tick conla'lnment box for 53 Instead of 55 m'lnutes. and as the atlachment rates of ticks In the other animals assigned to Group 

### 2 were similar to 

### those- for animal 

### no. 33610. the Study Director is satisfied that this deviation would have had no impact on the study.

6, The Study Plan specified that the ticks would be stored between 85-100% RH at the Entomology Dept. at Charres RIver Laboratories Precllnlcat Services Ireland Ltd. White the tickS were stored in Ihe Entomology Dept. at Charles River laboratories PreclinIcal Services Ireland Ltd., the relative humidity range was 68% to 99%. As all ticks. remained viable and as the attachment rate of the ticks was >25% on 6/8 infestation timepoints (mean % attachment rates ware 22.3% and 24.4% on Study Days 1 and 9 respectively). the Study DIrector fS satiSfied that the tow RH values during the- storage period in the Entomology Dept, had no impact on the viabilily of the ticks or
on the study.

7. Blinding was broken on One occasion (Study Day 16: 27AUG09) when the Individuat who checked the allocation 

### to groups data, and who checked the target volume and dose times and witnessed administration of tast Item, also performed the tick count of animal no. 54047, As the tick count data from this animal were simJlar to those recorded for other animals assigned to Group 1 (untreated control) at this timepoint. and similar to the tick counts recorded at other timapoints for this animal. the Study Director is satisfied that the tick count performed on this animal was performed in an unbiased way. that the data are valid and Ihat this deviatIon had no impact on the intel1ityofthe study.
8, The Study Plan specilled that the study would continue only if the efficacy of the test item remained above 80%. On Study Day 30, the efficacy of the test item was 79% but following consultation with the sponsor, it was agreed to continue the study. An amendment was not prepared by the Study Diredor to allow for the contlnuaUon of the study When the efficacy of the test item reached 79%. In the opinion of the Study Director. there was no impact of this deviation

on the study as at a timepoint subsequent to Study Day 30 (Le, Study Day 37, the efficacy of the test Rem increased to 88%.



### Tick counts for the negative control group and the treated group are shown in Table 1.

6

### Table 1. Tick Counts in the Control and Treated Groups

Grllup NIl. ;)nd Tre41mcnt '_____ StlXtyOay Animal I

-**~-f-** 

## ---:---=::::-:""---'--,,-

-

# r "

No. i ! li29iHi-i2J

er..nlml
INo RJ.tmenl} 

# ",., 5<10·11
593:23 S;l5!J 111$**4~113** 2"'"

:2 016711 1(M.05**2~1lOO (O.lrn~g**  b:Jdywcighl) 1-5019 111572.

33510 

# " " 

# , '" 

# " 

# " 67 

# " 

# " " 

# " 

# " " " 91



# , 20 Ie



# , 

# , 2 

# ,
, 

# " " 15 

# " " 

# "

,
o o
o m 

# " 

# " " 22 

# " 112



## , 2 o
: 1

# ~ , I , 11l-2



# , , , 

# , ,
o 12 21 

# " 

# " " " "

7 

# " "
, 

# , " 17 

# " 15

25 

# " '"


# • 

# , f2


# , 

# , , " "


# , " 25 

# " "



# ,
, 

# " ,
7
o



### The percent efficacy of the test product against Amblyoma americanum 

### ticks, based on geometric and aritlunetic means, for each assessment day was as follows:



### .. -3% (geomet.ric 

### means) and**~9%** 

### (ijrilhrnctic means) on 

### study day 1


### • 70% (geomelTic mean,) and 62% 

### ("itb,net;. ,"can,) on smdy day 2
• 98% (geometric me.",) and 97% 

### (.ritlune!ic mean,) Oil 

### smdy day 9
• 96% (geometric means) and 94% (arithmetic means) ou study day 16


### • 91% (goomelTie me.ns) and 88% 

### (,rithmetic means) on 

# ,may day 23
• 79% (ge(Hnetl'ie 

### means) 

### and 69% (ilri!hmetic mean$) on study day 

### 30


### • 88% (gcomclTie me.ns) and 79% 

### (arid,metie meMS) "" 

### smdy day 37
• 69% (geometric means) and 57% (ildlhmetic means) on study day 44

Statistically significant differences between the control and treated group in number of live ticks
were seen on Days 

### 2,16,23,30,37, and 

### 44.



### Study Author's Conclusions

The results of this study demonstrate that a single adminislralion of the Test Jtem (104.05: fipronil 6.7% 

### wlv, permethrin 50% w/v) 

### at a dose rate of 0.1 mLll<g bodyweight, to beagle and mixed breed 

### dogs l was effective (efficacy 

## z:. 90%) against 

### A. 

### americanum on Study Days 9. 16 and 23 

### post treatment. with some residual control of trcks (efficacy was approximately 80%) 

### on Study Day 

### 30 and Study 

### Day 37. A single topical application of the Test Item (104.05) was well tolerated,

7

### Reviewer's Conclusions

The results support the conclusions ofthe study author. Although adequate efficacy against 

### Amblyoma americanum ticks was demonstrated on Days 9, 16 and 23, efficacy was only 79% on Day 30. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions."



### Reviewer's Recommendations
Unacceptable. The label claim that the product kills ticks for at least a month, is not fully supported.

Note: The reported nominal test concentrations were 6.7% 

### w/v fipronil and 50% 

### w/v pennethrin. Other MRIDs in Task 2-30 (e.g., MRID 484671-26) indicate that 6.7% wiv fipronil and 50% wiv pennethrin are equivalent to 6.01 % 

### w/w fipronil and 44.88% 

### w/w permethrin, respectively, the label concentrations.



### 8

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRlD: 484671-26. Moran, C. The Duration of Efficacy of a Single Application ofl04.05 (Fipronil 6.7% w/v, Permethrin 50% w/v) Compared to a No Treatment Control Against Artifically Induced Infestations of Ticks (Ixodes scapu/aris) on Dogs. December 1, 2010 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460 Prepared by Summitec Corporation Task Order No. 2-30 

### Primary Reviewer: 

### Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.

Robert Ross. M.S

.. Program Manager Quality Assurance: 

### Angela M. Edmonds, B.S. Signature: 

### Date:
Signature: Date: Signature: Date:
Signature: Date:

Disclaimer

# ~i3tNl~,H€

.., "OCT I 9 2011

. j


## OCT 192011

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP- W-11-014

### DATA EVALUATION RECORD
(EPA Primary 

### Reviewer's Name] STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE

484671-26. The Duration of Efficacy of a Single Application of 104.05 (FiproniI6.7% w/v, Permethrin 50% w/v) Compared to a No Treatment Control Against Artifically Induced Infestations of Ticks (Ixodes scapu/aris) on Dogs. Moran, C. December 1, 2010.



### 391921
448350
897940
I. Villard, Virbac SA

Charles River Laboratories Preclinical Services Ireland Ltd., Glenamoy, Ballina, Co. Mayo, Ireland


### C. Moran, BSc, MAnSe.

I. Villard, Virbac SA


### 22103/2010
None



### "The study was conducted in compliance with the OEeD Principles afOood 

### Laboratory Practice 

### [ENVIMC/CHEM/(98)17]."



### PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: fipronil and pennethrin CHEMICAL NAMES: Not provided. A.I %: 

### 6.01% fipronil and 44.88% pennethrin 

### PC CODES: 129121 (fipronil) and 109701 (pennethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution

PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.9Ib; 2 mL for dogs 23-44.9 Ib; 4 mL for dogs 45-88.9 Ib; and 6 mL for dogs 89-132 Ib ACTIVE INGREDIENT APPLICATION RATE(S): Not

2

### PROPOSED LABEL MARKETING CLAIMS: provided

.

..can kill ticks for at least a month.



### STUDY REVIEW
Purpose: To determine the duration ofefficacy of a single application offormulation 104.05 against infestations ofticks 

### (Ixodes scapu!aris) on dogs.



### MATERIALS AND METHODS

Test Location: Charles River Laboratories Preclinical Services Ireland Ltd., Glenamoy, Ballina, Co. Mayo, Ireland

Test Material(s): 104.05**spot~on** 

### formulation (Nominal 6.7% 

### w/v fipronil and 50% 

### w/v permethrin 

### w/v; equivalent to 6.01 % 

### w/w fipronil and 44.88% 

### w/w permethrin). Actual concentrations oftwo analyses: 6.75% 

### w/v fipronil 

### w/v and 51.36% 

### w/v permethrin, and 6.68% 

### w/v fipronil 

### w/v and 50.23% 

### w/v permethrin. Certificates ofAnalysis included in study report.

Test Species Name, Life Stage, Sex and Age: Male and female adult beagle and mixed breed dogs 

### (Canisfamiliar;s), 2: 

### 6 months old.

Test containers. chambers and/or apparatus (include site description and location) and how experiment was conducted: Animals were housed singly in rooms measuring approximately 2 In X 

### 2 m x 2 m and acclimatized for seven days prior to testing. Animals were grouped within one of two body weight bands; :'S17.9 kg or 2:18.0 kg based on Day -2 body weight measurements. Dogs 2:18.0 kg were ranked in decreasing order ofDay -5 tick counts, irrespective of sex. The first two dogs 2: 18.0 kg formed a block and were assigned to either the treatment group or the control group, using random order numbers. The next two dogs 2:18.0 kg were blocked and assigned to groups in the same way, as was the third two dogs 2:18.0 kg. All remaining dogs were then ranked in decreasing order ofDay -5 tick count, within each sex. The first two female dogs were assigned to
one ofthe two groups using the same method as described above, followed by the second and third pair of females and then the remaining males until there were three male and three females in the treatment group and in the control group. Dogs were infested with approximately 40 ±4 viable, unfed adult ticks 

### Ixodes scapu!aris (25 ± 2 females and 15 ± 

### 2 males) on Day**~7,** 

### and with 50 ±4 ticks (30 ± 2 females and 20 ± 2 males) on Days 0, 7,14,21,28,35, and 42, and with 35 ±4 (30 ± 2 females and 5 ± 1 males) on Day 49. On Day 0, the dogs were infested with ticks 2 hr ± 

### 10 min prior to being treated. Dogs were sedated to facilitate tick infestation and tick counting. Group #2 dogs were treated once on Day 0 (2 hr ± 

### 4 min post infestation). Group #1 dogs were not treated. Ticks were counted, categorized and removed from the dogs on Days -5, 2, 9, 16,23,30,37,44, and 51, approximately 48 hr post infestation. Ticks were counted and categorized but not removed from the dogs on Day 1. 

### The number, sex, attachment status, viability and location on the dog of each tick were recorded at each assessment time.
Treatments, including untreated control: Maximum of0.1 mLlkg.

3

### Number of replicates per treatment: One.

Number of individuals per replicate: Three males and three females in the treated group and the
same numbe rof each in the control group. Length of exposure to treatment (time in 

### seconds. minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? N/A
Experimental conditions:**15~20°C;** 

### 25-65% relative humidity.

Data or endpoints collected/recorded: The number, sex, attachment status, viability and location
on the dog ofeach tick were recorded at each assessment time.

Data analysis: Efficacy calculations were based on geometric means, and specifically on the geometric means ofthe live free and attached female tick COWltS. The geometric mean was calculated by first applying a natural logarithmic transformation. In cases where the data set contained a zero, a "1" was added to all numbers before applying the transformation. The arithmetic mean was calculated for the transformed data. This was then anti-logged and "1 " was subtracted (ifthe data sets contained a zero).
Efficacy was calculated using Abbott's formula as follows:

Percent reduction (Efficacy = 

### 100 x (Gme

- Gmt) / Gme , where:

Gme = 

### Geometric or arithmetic mean cmmt in the control group (Group 1) at a specific time point. Gmt = 

### Geometric or arithmetic mean count in the treatment group (Group 2) at a specific time point. The test and control groups were compared using ANOVA for Study Days 1, 2, 30, 37, 44, and 51. For Study days 9,16, and 23, comparisons were on the basis ofthe numbers of animals with ticks present using the non-parametric Fisher's exact Test.


## RESULTS

Data for each individual test animal and control are included in the study report. Data were adjusted for control mortality using Abbott's formula. Deviations from the study plan included:

1. On Study Day 37 sedation was reversed in two dogs before the 90 min time period specified in the protocol 2. The minimrun relative hrunidity in the tick storage cabinet on most days was less than the 85% specified in the protocol, but with the exception of9 data points it was >75% (within 10% of the acceptable range). 3. The maximum relative hrunidity was below the specified range on two occasions when it was 36 and 84%.

Tick counts for the control group and the treated group for each time interval are shown in Table 1. Percent efficacy for each time interval is shown in Table 2.

4

### Table 1. 

### Total Live Female Tick Counts

Group H::>.**,;~.,n:1\: Sl~()~**  D;;1**;,~J** ;,t:f,lmen: No, 

# , ,-3 21 .10 :':'T**~.l** :';1

";·:il51l7 

# " ", 2/ 

# " 22 

# " :':\ 21 I" C.::onl:ol**:"'~f,1** 

# " 

# " 1,", 1·1 2(; :1:1 ?? 

# , I"**,I~~** tri?Jl'l1e"H, ,(!F? 

# "**1~ ,~n**  :0 

# "**\~** /\**~f'** 21 .:4iY,;> ::3 23 ?II 

# " 23 "

... ) ?O '" 21l " 71:,",77 15 

# '" !;l 10 22 7.1 22 T'_, 

# "**2~3·1J** 

# " '" 

# " >G 

# " H 23 )I; ;H
rOi.11 Sf 116 141 

## I !OJ 

## I**\:\~** 

## I Hi) 

## ! 13, 

## I**~J~** 

## I n!)"

2**9~~G1** 

# , " 0 

# , " " " :(j.{'::;::i 0:7019 " 0 0 

# " 0 

# , ;) 

# " 5 :0**''''l·~;; CQ~Y."Qlgr:l:**  ild!'·:' m 

# , " 0 

# , " 

# "**~~8:1j?** 

# , 2 

# " (; 0 0 () '" 

# , nEi21 " 

# , " " 

# " ., 

# " , J?,em G s 

# " 

# , 0 0 

# , TO!JI -11 

### I W 

# " I 

# " I 

## I 

# , I 1;:' n 

## I ;: 

# .

•**F.9u'~'~** ;-""".(t[,I",<I in Ih$**l~bk1** 'nckldc te:n Lue Alklchea**F"'T"~k;** 4nd Li';L' FIQ':!**F~msle** T:h:i.. E,,:'.**~nirl'.=I·.~21'" ;'If!:'~:eo**  ;.'.Ih :tH:!**(;",,~,i¢** II:'J'/us $(;;"-;"/;;.'1, CD**Sl~dl'** [}.1Y$ (), T, :.1, Z1. 2e. 3G.:l-:' and ,;!1



### Table 2. Percent Efficacy Based on Arithmetic and Geometric Means of 104.05 Against 

### ld Z'Tks xo es scapu arzs Ie


# . Day Arithmetic Mean (%) 

### Geometric Mean (%) 

### 1 56 59 2 

### 91 94 9 100 100 16 100 100 23 99 99 30 95 96 37 89 93 44 76 83 51 80 85



### Study Author's Conclusions
Analysis ofhomogenity indicated that there were no differences between the control and test groups in terms ofbody weight or tick counts on Study Day**~5.** 

### The test product was effective (2':90% efficacy) against 

### Ixodes scapularis ticks on Study Days 2, 9, 16,23,30, and 37, with some residual control on Days 44 (83%) and 51 (85%).

5

### Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended perfonnance standard was reached for over one month.


### Reviewer's Recommendations
Acceptable. Results support the label claim that the test product, fonnulation 104.05, kills ticks for at least one month, although lOO% 

### mortality was only achieved at two time intervals.

6

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-27. Monzali, C. 2011. Determination of of a Combination of Fipronil and Permethrin in Topical Solution Against Mosquitoes 

### (Aedes aegyptl) on Dogs. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30 Primary Reviewer: Dennis M. Opresko, Ph.D.


### Secondary Reviewers: Gene Burgess. Ph.D.

Robert 

### H. Ross. M.S

.. Program Manager


### Quality Assurance: Angela M. Edmonds. B.S. Signature: Date:
Signature: Date: 

### Signature: Date: 

### Signature: Date:



### Disclaimer 

## OCI 192011'" 

# 6w---**13~,** 

# 1\£ OCT 192911

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP-W-II-OI4

### DATA EVALUATION RECORD


### (EPA Primary Reviewer's Name]
STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE
484671-27. Determination of of a Combination ofFipronil and Pennethrin in Topical Solution Against Mosquitoes 

### (Aedes aegypti) on Dogs. Monzali, C. April 6, 2011. 391921
448350
897940
S. Bonneau, Virbac SA
Avogadro, Pare de 

### Genibrat, 31470 Fontenilles, France

C. Monzali.

S. Bonneau, Virbac SA
06/04/2011



### None

"This study

... was perfonned in accordance with

....and the Plinciples of Good Laboratory Practices including: 

### Ee principles of Good Laboratory Practices (Directive 

### 20041l0/EC ofthe European Parliament and Council ofthe II FEB 2004)

... "
PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RlT ACTIVE INGREDIENT NAMES: Fipronil and pennethrin CHEMICAL NAMES: Not provided. A.I %: 6.01 % 

### fipronil and 44.88% permethrin PC CODES: 129121 (fipronil) and 109701 (permethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution
PRODUCTAPPLICATIONRATE(S): I mLforsmall dogs and puppies 8 weeks old and older, up to 22.91b; 2 mL for dogs 23-44.9Ib; 4 mL for dogs 45-88.9Ib; and 6 mL for dogs 89
H 

### 1321b ACTIVE INGREDIENT APPLICATION RATE(S): Not



### 2

### PROPOSED LABEL MARKETING CLAIMS: provided.

"

... (prevents blood feeding by) (and) (kills) (and) (repels)

... mosquitoes for up to 4 weeks (a(oneJ month). Kills mosquitoes for up to four weeks (a(oneJ month)."

STUDY REVIEW
Purpose: To test the efficacy of 104.05 topical solution against Aedes aegypti mosquitoes on dogs.

MATERIALS AND METHODS

Test Location: Avogadro, Parc de Genibrat, 31470 Fontenilles, France

Test Material(s): 104.05 topical solution (6.7% w/v 

### fipronil and 50% w/v pennethrin). A Certificate ofAnalysis for the test product was included in the study report.

Test Species Name, Life Stage, Sex and Age: Short hair Beagle dogs and long hair Golden retriever cross dogs (10 males,S short hair and 5 long hair) and 4 females (short hair); age 8.8-15.3 months; weights 9.0-11.3 kg for the beagles and 20.8-27.4 kg for the retrievers.

Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 12 days prior to treatment during which time they were tested for ability to host mosquitoes by being exposed for 30 min to 40-67 unfed female mosquitoes (A. aegypti) at least 2 days old. Dogs allowing a feeding rate of>40% were considered good hosts. Twelve animals were randomly allocated into two groups: one control group of six animals (2 long hair males, 2 short hair males and 2 short hair females); and one test group of treated animals (2 long hair males; 2 short hair males and 2 short hair females). Six blocks of animals were fonned based on body weight, and one animal from each block was randomly assigned to one ofthe two groups. Two animals were swapped in order to balance the groups with respect to the results of the infestation received during acclimatization. The test product (0.1 mLlkg) was administered to the dogs in the treatment group (between the shoulder blades) on Day 

### O. After treatment the dogs were kept in individual pens. The dogs in both groups were exposed for 28-35 min to unfed female mosquitoes on Day 1 (91-114 mosquitoes), Day 7 (88-108), Day 14 (51-121), Day 

### 21/22 (44-110), Day 28 (87-111) and Day 35-37 (89-136). Dogs were sedated during infestations. Afterwards, the mosquitoes were collected, the dogs removed from the exposure cages and returned to their housing, and at 52-92 min after the beginning ofthe exposure, dead and alive mosquitoes were cOW1ted. The mosquitoes were frozen, crushed to determine if they had a blood meal and then the number offed and unfed mosquitoes was detennined.
Treatments, including untreated control: 0.1 mLikg.

Number of replicates per treatment: One.

Number of individuals per replicate: Six in the treated group and six in the control group.

3

### Length of exposure to treatment (time in seconds, minutes or hours): Topical application between shoulder blades.

Were tested specimens transferred to clean containers? N/A
Experimental conditions: 14.4-21.0°C; 16-80% RH; 12/12 light cycle.

Data or endpoints collected/recorded: Mosquito mortality rate (%) as well as mosquito blood feeding rate (%) were deterrnined.

Data analysis: Efficacy calculations were calculated from Abbott's formula, by comparing the geometric mean number ofblood fed mosquitoes from the treated group to the geometric mean of the number ofblood fed mosquitoes from the control group: Anti-feeding Efficacy (%)**~** 

### 100 x [(FC - FT)/FC], where:

FC = 

### geometric mean ofthe number ofblood fed mosquitoes from the control group FT = 

### geometric mean number ofblood fed mosquitoes from the treated group

The killing efficacy was determined by comparing the mortality ofmosquitoes between the control and treated groups after the 3D-min exposure period:
Killing Efficacy (%)**~** 

### 100 x [(LC

- LT)/LC], where:

LC = 

### geometric mean number oflive mosquitoes in the control group. FT = 

### geometric mean number of live mosquitoes in the treated group.

RESULTS

Individual animal results were presented in the study report. Deviations from the study protocol
were as listed below:

4The two animals n05.160612 and 251448 WCr!} hotlSed in the trc<lted b'fOUP room since 09 FEB 2010 but were treated 8 days Inter, on 17 FEB 2010,
During aeclimatisntion: dogs were exposed to 40

- 67 unfed felOnle mosquitoes (,;/, 4e:gypli) nf at least 2 d,'lYs old inslead of 50 ± 5. During the other infestations, tiogs.
were exposed to**~7** - 136 unfed fernnlc mosquitoes instead of 100 ± 10 nnd 44**~** 63 unfed fcrnalc mosquitoes instead 

### of 50 ± 

### 5 al 

### Day 14, for the 

### 4 dogs nos.25 

### 1092, 251448,258217 and 160612 and J)ay21 for the & dogs nos.251561, 258329, 251819, 258l175, XII'AL2, X2PAC9, X IP'\C6 and X2PAIl2. Dog no,258.329, from Day 10 to Day 37, received iiOOg pf food daily in tvw times instead of 300g once daily. bC¢iluse he lcst wcighL Times (If the second tood distribution were not recorded in the raw dala. Dogs were fcd between 3 hours 07 minutes and 7 houl's 52 minutes instend or UbDllt four hours post exp<)surc.

Some dogs received an anti-parasitic treutment within IWO llinnths befotc Day 0: shon hair dog no.25 1 092 rct:eived an anthelminthic treatment (fenbcndazolc) on**2~1** DEC 2009 and the live long hair dogs nos.2GHP252, X1PAL2, X21:l.>\C9, X IPAC6 and X2PAD2 recel\'ed lin car antiwpamsitic treatment (tipronil**IO'~,f~** approximately 1 mg/kg) on 18 JAN 20 I

## o. Tbese treatments Itld no rept!lk·nt or killing impact on mosquitoes.
M;lximum and minimum temperatures and relative hurnidity of treated dogs ro')l1)
were I(ot recorded on the last day orthc in-life phose (27**~'~AR** 2010).

The 4 dogs nos.251092, 251448,25&217 and 160612 were infested at Day 22 instead of Day 21 rind Day 3-7 instcild of Day 35 because of an insufficienl number of unfed female mosquitoes of at least 2 days old. Nevertheless, we can consider that Day 22 wus equivalent to Day 2 I and 

### Da.y 37 was equivalent to Day 35.

Por dog no.25 (819, the tcst item dose volume was rounded to the nearest 0.05 mL, instead onlle ncarC.'it 0.1 mi.,.**Temper.~turc** in the exposition room was maintained between 23,2"C unti 3 t.2¢C) instead of 24QC and 30°C. and relative humidity was mftintained between 40 and 95%, inste;H.l of40 and 800'/0.
Dogs were exposed to female mosquitoes for 28 to 35 minutes instca<1 of 30 minutcs and dead a'nd alive l110squitocs were eoonted at 52 minutes to Ih32 (correspondiug to 92 minutes) po.!;t beginning ofexposure, instead of60 I'ninutes.

Mosquito mortality rates are shown in Table 1. Mosquito blood feeding rates are shown jn Table 2. Mosquito anti-feeding efficacy and mosquito killing efficacy of Product 104.05 are shown in Table

o o.



### 5

### Table 1. Mosquito Mortality Rates (%) 

### in Control and Treated Dogs Long 

### + short I.air dogs**~ ~~...**  

# .**~~'I** Mosquito Group i mortality I rate (%) Time

# ~~~:::ti 

# I):y I

# ["~ay 7 I,i' 

# I)oy 14lnay**2llZ2r~ay** 28 I , 

### 0.0 

# I 0.0 

# I 0.0 

# I --c----f---. 

## i 0.0'1 0.0

untrClitcd 

### SD 0.0 

### 0.4

i ::: II

# ·:::i···~~.o

treated geometric 1,' 0.0 mean 

### 0.1 I aritlimetie 

# I I 

### I 0.0 33.5 ,27.9 31.2'1 meaD " 22.2



### 51) ,-0.0

# _,_25~7J**1-2~~'** 20.8

_ ..... 

# 24.8_

..

'-

__

# .....J._g_e'"~m",~"'~'-ri_'...cI_o_._o_L**24.6_~~I~-_-_~-_-~t_-_-_-_-_-_:I-_-_-13~._5-_-ir_-_-2_2-_.-9_.,-** 13.0 

# J

Table 2. Mosquito Blood Feeding Rates in Control and Treated Groups

LOn!! 

### + short (mir dOES Time 

# i Mosquito**~-~-..** . .. __ . 

### "1"

..**.~.~.** 'I h100d**A('clim~Hi~** Group fccdingrutc!, sation Day 1 Day 7 Day l4
1 DaY21122 Day28 Dlly35/37! (%) 

# iii

Jlrirhmetie 

### 1 

# I 1 I 72 

# I

untreated

# r-"m"':"'~":-;--::-·5_9.~ ....

# -~**~-;~~_::-_.'1**__

# ~:_:4_8**-,-~-~-::_-·~;~Lr. ..::::.-r-::·~**  geometric I 

# I me;ln ; 72.1 43.4 67.6 69.6 49.5: 69.4 ) 34.2

arithmetic 1**~** 

# I

mean 6S.9 10.6 9.1 18.8 i 11.1 

# ! 24.1 1 28.2 

### treat,d, SII ,-

## i-~2·-6'-5-f--5-.4--il--8'-6-+--1-4'-4-li-**;~~-.--;;;-** 14.8



# ' I ,i geometric 63.4"""

# ------~~~" -- 6.2 

# 13.T;.7 22.6" 25.3 _" mean

___**~**____ '**_l",~~**

6

### Table 3. Mosquito 

### Anti-Feeding Efficacy and Mosquito Killing Efficacy 

### of Product 104.05

_

# I-~ae;~~~ I 

# Day
I

# T~~;7r**D;::>.!,~;~:"'l:~; 1'~.::/.3**  .....

# 7Jl 

# L Shorthairj 87.4

.... 96,2 

### ! .u , 

### Anti-feeding 

# I Longhair

# ~: 43.1 I' 

### 65.2 55.9

... ng=. 

### 84.5 I 39

..

# 6_1_156.71' 

# r- '

cffic<lcy 

# I Glob", I ",,' 79.2 

# I . L- ..- . .



### . .. 91.7 79.3 79.8 

# I 69.1 

# I 17.1 !

: i 

# , !

__ ,m6

## ~**B91~.4I~AI~~:**

# c~~!~~;**!-~LOng** lIair 

# fl1.5'u-6.9 .8,01 ·5.5

# ;~f;**T25~1** 

# I**",~I~IObnl** L. 

### 40.0., 

# 1 46.5 38,6 

# r 30A 37.1 

# I 17.5J



### StudY Author's Conclusions

Short-haired dogs were more susceptible to mosquitoes than long hair dogs. The test product had a more effective anti-feeding (repellency) action than a killing action, especially in short hair dogs. Killing efficacy was no greater than 59.5% (Day 7 for short hair dogs). Anti-feeding efficacy for 

### short and long hair dogs combined was only greater the 90% for one time interval (Day 7).


### Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 810.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended perfonnance standard for killing efficacy was not reached in this study. Anti-feeding efficacy (repellency) reached 90% at only one time interval, Day 7.


### Reviewer's Recommendations
Unacceptable. The study results do not support the label claim that the product "

... (prevents blood feeding by) (and) (kills) (and) (repels) ." mosquitoes for up to 4 weeks (a [one] month), 

### Kills mosquitoes for up to four weeks (a[oneJ month)."

7

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-28. Fourie, J.J. Repellence Efficacy Study of 104.05 Against Ticks (Dermacentor variabilis and Rhipicephalus sanguineus) on Dogs Under Laboratory Conditions. November 3, 2010. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFF1TIX TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 

### DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30 

### Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: Gene Burgess. Ph.D.

Robert Ross, M.S

.. Program Manager
Quality Assurance: 

### Jennifer Goldberg. B.S. Signature: Date:
Signatme: Date:
Signature: Date:

Disclaimer 

## OCT 192011

# GtuB~ At OCT 

# i92ri1I'

OCT I 920U

This review may have been altered subsequent to the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract No.EP-W-l1-0l4DATA EVALUATION RECORD 

### (Primary Reviewer's Name]
STUDY TYPE:

MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE

484671-28. Repllence Efficacy Study of 104.05 Against Ticks (Dermacentor variabilis and Rhipicephalus sanguineus) on Dogs Under Laboratory Conditions. Fourie, U. November 3, 2010.

391921
448350
897940
S. Bonneau, MD, Vlrbac SA

ClinVet International, Uitzich Road, Bainsvlei, Bloemfontein, Republic of South Africa
J.J. Fourie, M.Sc.

S. Bonneau, Virbac SA


### 21107/2010

None

"This study has been performed in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted May 18, 2005 [SR 813.112.1]. This Ordinance is based on the 

### OEeD Principles afGood Laboratory Practice, as revised in 1997 and adopted November 26 1h

, 1997 by decision ofthe OECD Council [C(97) I 86lFinalJ. These principles are compatible with Good Laboratory Practice regulations specified by regulatory authorities throughout the European Community, the United States (EPA and FDA), and Japan (MHLW, MAFF, and METI)."

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: Fipronil and permethrin CHEMICAL NAMES: Not provided. A.I %: 6.01% fipronil and 44.88% pennethrin PC CODES: 129121 (fipronil) and 109701 (pennethrin) CAS NO. Not provided



### 2

### PROPOSED LABEL MARKETING CLAIMS: FORMULATION TYPE: Topical solution

PRODUCT APPLICATION RATE(S): I mL for small dogs and puppies 8 weeks old and older, up to 22.91b; 2 mL for dogs 23-44.9Ib; 4 mL for dogs 45-88.9 Ib; and 6 mL for dogs 89-132 Ib ACTIVE INGREDIENT APPLlCATION RATE(S): Not provided.

.. can kill ticks for at least a month.

STUDY REVIEW
Purpose: To test the repellence efficacy, tick killing effect, and tick viability impact of 104.05 spot-on formulation against 

### Dermacentor variabilis and 

### Rhipicephalus sanguineus ticks on dogs.

MATERIALS AND METHODS

Test Location: ClinVet International, Uitzich Road, Bainsvlei, Bloemfontein, Republic of South Africa

Test Material(s): 104.05 spot-on formulation (6.7% w/v fipronil and 50% w/v pennetlrrin, equivalent to 6.01% w/w firpronil and 44.88% w/w pennethrin).

Test Species Name, Life Stage, Sex and Age: Male and female sub adult and adult dogs 

### (Canis familiaris) greater than 6 months old; mixed, mainly mongrel.

Test containers, chambers and/or apparatus (include site description and location) and how experiment was conducted: Dogs were acclimated 7 days prior to treatment (Day**~**

### 7 to Day -1); dewonned and "did not harbor ticks." Dogs were kept in individual pens 1.9 m by 2.97 m. Twelve dogs were used in the study; 8 dogs <18.14 kg and 4 dogs 2::18.14 kg. The 8 dogs of the smaller weight were blocked into four blocks oftwo dogs each, and the large dogs were blocked into two blocks oftwo dogs each. Within each block the dogs were randomly assigned to either Group #1 (negative control) or Group #2 (treated group). Dogs were dosed with 0.1 mL ofthe test product
on Day 

### O.
Laboratory breed strains of

### Dermacentor variabilis and 

### Rhipicephalus sanguineus ticks were used in the artificial infestations. Immature ticks were fed on rabbits. The dogs were infested with 30 unfed adult ticks in an infestation chamber on Day**~6** 

### (R. sanguineus only), and Days + 1, +3, +7, +14, +21, +22, and +28. In situ tick assessments were conducted on Days + 1, +3, +7, + 14, +21, +22, and +28, 3 hours after infestation. Tick counts, and removals were conducted on Day -5, +2, +4, +8, + 15, +22, +23, and +29,24 hours after the infestations.
Treatments, including untreated control: 0.1 mL/kg.

Number of replicates per treatment: One treated group and one control group.



### 3

### Number of individuals per replicate: Six treated and six controls.
Length of exposure to treatment (time in seconds. minutes or hours): Spot application between shoulder blades.

Were tested specimens transferred to clean containers? N/A
Experimental conditions: -20±4°C; 12112 light cycle.

Data or endpoints collected/recorded: In situ tick assessments were conducted on Days 

### +I, +3, +7, +14, +21, +22, and +28, 3 hours after infestation; tcks were counted but not removed. Ticks
were counted and removed on Day -5, +2, +4, +8, +15, +22, +23, and +29, 24 hours after the infestations. The ticks were categorized as being alive or killed and also in three subgroups: free,
or attached and unengorged, or attached and engorged (the latter category was not included during the in situ observations). The ticks counted and removed during the 24 hr assessments were categorized according to sex. Ticks found in the infestation chamber after removal ofthe dogs
were categorized as alive, moribund or dead. Dogs were sedated to facilitate tick infestation.

Data analysis: Efficacy calculations were made for each treatment group at each assessment interval. Efficacy was based on geometric means ofthe tick data (count 

### + 1) because ofthe anticipated low and possibly zero counts at some time period and the likelihood that a normal distribution would not be seen. One was subsequentlY subtracted from the result to obtain a meaningful value for the geometric mean ofeach treatment group.

In situ tick count efficacy was calculated as follows:
Efficacy (%)**~** 

### 100 x (Gm,

- Gm,) 

### I Gm" where:

Gme = 

### Geometric mean number oflive ticks (alive, free and attached) on dogs in the negative control group (Group I) at a specific time point. Gmt = 

### Geometric mean nwnber oflive ticks (alive, free and attached) on dogs 

### in the treatment group (Group 2) at a specific time point.

The groups were compared using an ANOVA with a treatment effect after a logarithmic transformation on the tick data (count +1)

24 hour tick count and removal efficacies were calculated for each species oftick as follows:
Efficacy (%) = 

### 100 x (Gme

- Gmt) / Gme, where:

Gme = 

### Geometric mean number oflive ticks (alive, free and attached, unengorged and engorged)
on dogs in the negative control group (Group I) at a specific time point. Gmt = 

### Geometric mean number of live ticks (alive, free and attached, unengorged and engorged)
on dogs in the treatment group (Group 2) at a specific time point.

The groups were compared using an ANOVA with a treatment effect after a logarithmic transfommtion on the tick data (count +1)

4

## RESULTS

Data sheets with 

### the individual animal results were included in the study report. Amendments to and deviations from the test protocol are shown below:

Protocol amendment Amendment#1:

Reason for 

### changEr

lmpact on study:



### Protocol deviation DevIation #1:

Reason for deviation: Impact on study:



### Deviation #2:

Reason for deviation: Impact on study: Effective date 13 July 2010, to the effect that the Day +21 tick (Dermacentorvariabiiis and Rhipicephalus sanguineus} infestations and subsequent as.sessments were repeated on Day +22, The attachment 

### of Dermacentor v8rfabilis ticks 

### to- the dogs were less than expected resultlng in low tick counts on the study groups. The [ow number of ticks which attached could be due to a decrease in lick viability and it was decided to repeat the infestations with a dirferent batch of Dermacentor variabi/is ticks. 

### No foreseen negative impact. Addilional results for 

### the week 3 assessments were obtained from the repeated infestalion and subsequent assessments.

Effective date 20 Aug 2010 to the effeci that temperatures in Unit 19 SecUon E deviated from 01 Jui to 04 Jul2010 between 0.6

- 1.6 

## "c from the ranges specified in the protocol. Air conditioning unit malfunction
No negative impact

Effeclive date 22 June to 21 July that the maximum temperatures recorded in the temperatLire controlled room with the humidity containers containing the ticks forviabilily assessments exceeded the protocol specified maximum temperature of 26DC with up to 1(!C on a number of occasions. Air condit1on·mg unit malfunction
No negative impact



### Results for Rhipicephalus sanguineus:
Twenty-four hour tick counts are shown in Table 1. Twenty-four hour killing efficacy values are shown in Table 2. Three-hour in situ tick counts are shown in Table 3, and 3-hr efficacy values in Table 4. Repellency data for 10-min exposures are shown in Table 5 and tick viability after the 10 min exposures is shown in Table 6.

5DAY



### Table 2. 24-hr Efficacy of Product 104.05 Against 

### Rhipicephalus sanguineus

DAY



### Table 3. 3-hr Counts of

### Rhipicep/talus sanguineus in Control and Treated Groups

DAY



### Table 4. 3-hr Efficacy ofProduct 104.05 Against 

### Rhipicepltalus sanguineus

DAY

+1 +3 +7 '''14 +21 +22 +28 ArIthmetic mean 72.2 70A 94.3 93.8 82.2 87.3 77.S EFFICACIES % GROUP 2 -IVP (104,.05)

6 Geometric mean 77.1 SO.3 95.7 95.9 88.2 90,0 7B.4

### Table 5. Repellency Effect of Formulation 104.05 Against 

### Rhipicephalus sanguineus



# , , Day

", . .',.,.-

InltfaJfy illfest(J{J.

1. ':. ' 2.5

5.4 .,1:1

3.3
.6.4. '.



### Table 6. Viability of

### Rhipicephalus sanguineus After lOw min Exposures to Formulation 104.05

Treatment Group 

# 3", 24 Hr 48H(



# ,
j Group (p<O.05) from



### Results for Dermacentor variabilis
Twentywfour hour tick counts are shown in Table 7. Twenty-four hour killing efficacy values are shown in Table 8. 

### Threewhour in situ tick counts are shown in Table 9, and 3

w 

### hr efficacy values in Table 10. Repellency data for 10

w 

### min exposures are shown in Table 11, and tick viability after the IO-rnin exposures is shown in Table 12.

7

### Table 7. 24-hr Counts ofDermacentor variahilis 

### in Control and Treated Groups

DAY GROUP 1 - No atlve control GROUP 2 -IVPl104.0m Arithmath:: mean Geometrle meolln Arithmotlc mean Ge:ometric.ml::an +2 19.8 18.4 0.7 0.4 +4 19.0 17.4 0.0 0.0 +8 ·14.7 14.0 0.0 0.0 +15 3.2 2.5 0.0 0.0 +22 5.0

. 4.2 (}.O 0.0 +23 3.0 2.7 0.0 0.0 +29'. 12;'3 , ·11.2

. 0.3 0.3 Group 2 differed statisticallYs/gnr{icimlly (P<:O.05) from the nogrJ/iva control Group on all days.



### Table 8. 24-hr Efficacy of Product 104.05 Against Dermacentor variabilis

DAY

+2 +4 +8 +15 +22 +23 +29 Arlthmttt!c moan 96,6 100,0 100.0 100.0 100.0 100.0 97.3 EFFICAClfS (%) GROUP 2 -IVP 1fl4.05 Geometric**m~an** 97.6 100.0 100.0 100,0 1flO,0 100.0 97.7



### Table 7. 3-hr Counts ofDermacentor variabilis 

### in Control and Treated Groups

DAY

+1 +3 +7 +14 +21 +22 +28 Arlthmetlc m-fran 69.6 87.3 91.4 86.5 91.2 94.6 79.1 EFFICACIES %) GR.OUP 2-IVP 104.05 GcomQltlc mean 7S.2 91.S 94,3 91,5 95.2: 96.S 80.2



### Table 8. 3-hr Efficacy of Product 104.05 Against_Dermacentor variabilis,



### DAY GROUP 1- He ativeconlool GROUP 2-IVP 104.05 Arlthmotlc mean Geomolril:: mean Arithmetic mean Goometrlc maan**~. ~**  

### _**~** 

### U**~** 

# = _ U ,.**~ 1~**  

## ru ,.**1~** +14 a.7 8.2 '1.2 0.7**~** 

### U U U M 

## m U U M U

_ 1U**~** U U Group 2 dIffered statiMrCalIy sigllifict.mlly (p<Q,Q5) from 1119 negative con/ror Groop t on all days.

8

### Table 9. Effect of Formulation 104.05 Dermacentor variabilis



# .,

•• 0"

{p<Q,OO) from Group 1.



### Table 10. Viability ofDermacentor Formulation 104.05 variabilis After 

### lO-min Exposures to

Treatment Group 48Hr

- .',,::-'



## ,

J GrolJP 1.



### Study Author's Conclusions

Results ofthis study indicate that dogs treated with Formulation 104.05 at a dosage of0.1 mLlkg
were protected from infestations of

### Dermacentor variabilis and 

### Rhrpicephalus 

### sangurneus for up to 

### 29 days post treatment. Efficacy against 

### Rhipicephalus sanguineus was 99% at Day +2 and 100% on all other assessment days. Efficacy against 

### Dermacentor variabilfs was 97.6% on Day +2 and 100% on every other assessment day except Day +29 when it 

### was 97.7%.

9

### Tick counts conducted 3-hr post treatment indicated that the test product was effective against both species throughout the study. Three-hour efficacy values ranged from 77.1 to 95.9% for Rhipicephalus sanguineus 

### and from 78.2 to 96.6% for Dermacentor variabilis.



### The repellent effect offonnulation 104.05 after 10-min exposures was S 16.7% for Rhipicephalus sanguineus 

### and 26.6 to 48.0% for Dermacentor variabilis.



### Unattached Rhipicephalus sanguineus 

### tick viability values after the lO-min exposures were very variable due to the small numbers ofticks repelled (mean values of

### O. 7 to 5.2 were recorded for the treated group); however, a marked difference in the percentage ofticks found dead and moribund was observed between the ticks exposed to the test product and the controls (statistically significant by 3 hr on Days +7 and + 14, and by 24 hr on Day +3 and +7). For Dermacentor variabilis 

### similar results were obtained, with statistically significant differences from controls seen by 3 hr on Day +1, +3, and +7 and by 24 hour on Day +14.


### Reviewer's Conclusions

The results support the conclusions ofthe study author. OCSPP Test Guideline 8] 0.3300 states that the product should "Provide 90% reduction in pest infestation through a killing action when tested under simulated or actual field conditions." This recommended perfonnance standard was reached for both species oftick for all assessment periods. The concentrations ofthe active ingredients in the test product were not verified or supported by a Certificate ofAnalysis.


### Reviewer's Recommendations
Acceptable. However, the concentrations ofthe active ingredients in the test product were not verified by the registrant. Results support the label claim that the test product kills ticks for at least a month.

10

### TASK 2 DATA EVALUATION RECORD

STUDY TYPE: Product Performance

MRID: 484671-29. Villard, I. Summary of Efficacy Data for EffitixTM Topical Solution for Dogs (Fipronil 6.01 % and Permethrin 44.88% End Use Product). April 20, 2011. 

## ocspp 810.3300. Treatments to Control Pests of Humans and Pets

Product Names: EFFITIX'M TOPICAL SOLUTION FOR DOGS EPA Reg. No.: 2382-RIT Decision number: 448350 DP number: 391921

Prepared for Registration Division (7505) Office of Pesticide Programs U.S. Environmental Protection Agency Washington, DC 20460
Prepared by Summitec Corporation Task Order No. 2-30
Primary Reviewer: Dennis M. Opresko. Ph.D.
Secondary Reviewers: 

### Gene Bmgess. Ph.D.

Robert Ross, M.S., Program Manager


### Quality Assurance: Jennifer Goldberg. B.S. 

### Signatme: Date: 

### Signature: Date:

Disclaimer



### This review may have been altered subsequent to 

### the contractors' signatures above.

Summitec Corp. for the U.S. Environmental Protection Agency under Contract**No.EP~W~ 11~014** DATA EVALUATION RECORD



### [primary Reviewer's Name)
STUDY TYPE:
MRID:

DPBARCODE:
DECISION NO:
SUBMISSION NO:
SPONSOR:

TESTING FACILITY:

STUDY DIRECTOR:

SUBMITTER:
STUDY COMPLETED:
CONFIDENTIALITY CLAIMS:
GOOD LABORATORY PRACTICE:

TEST MATERIAL: PRODUCT PERFORMANCE
484671-29. Summary of Efficacy Data for EffitixTM Topical Solution for Dogs (Fipronil 6.0 I % and Permethrin 44.88% End Use Prodlict). Villard, I. April 20, 20 II.

391921
448350
897940
C. Parks, Virbac SA

NIA

NIA

C. Parks, Virbac SA
20104/2011

None

"This docwnent is a compilation document and is not subject to the requirements of40 CFR Part 160,"

PRODUCT NAME: Effitix Topical Solution For Dogs EPA REGISTRATION NO.: 2382-RIT ACTIVE INGREDIENT NAMES: fipronil and permethrin CHEMICAL NAMES: Not provided. A.I %: 6.01 % fipronil and 44.88% permethrin PC CODES: 129121 (fipronil) and 109701 (permethrin) CAS NO. Not provided FORMULATION TYPE: Topical solution

PRODUCT APPLICATION RATE(S): 1 mL for sma1l dogs and puppies 8 weeks old and older, up to 22.9 Ib; 2 mL for dogs 23-44.91b; 4 mL for dogs 45-88.91b; and 6 mL for dogs 89- 132 lb ACTIVE INGREDIENT APPLICATION RATE(S): Not

2provided.



### PROPOSED LABEL MARKETING CLAIMS: Fleas:

...can start killing adult fleas within 6 hr and lasts for up to three months

... Ticks:

..can kill ticks for at least a month

... Lice: can kill sucking biting and chewing lice for a month
or longer

.. . Mites:

...kills mites

... Biting flies and mosquitoes:

...(prevents blood feeding 

### by)(and)(kills)(and)(repels) biting flies and mosquitoes for up to 4 weeks (a[one] month). Kills mosquitoes for up to 

### four weeks (a [one] month).

STUDY REVIEW
Purpose: To review the efficacy data for EffitixTM Topical Solution for Dogs against fleas, ticks, mites, lice, mosquitoes, biting flies and sand flies.



### BACKGROUND

EffitixTM Topical Solution for Dogs contains two active ingredients: 6.01% w/w fipronil and 44.88% w/w permethrin. The registrant proposes using three types of efficacy data in support of its application for registration of EffitixTM Topical Solution for Dogs: I) data previously submitted, reviewed and accepted by the Agency for fipronil spot on products and for certain permethrin**spot~** on products; 2) data published in the open literature on certain permethrin spot on products; and 3)
new efficacy studies using EffitixTM Topical Solution for Dogs (MRID numbers were not provided for these studies).

NOTE: In MRlD 484671-29 the registrant does not present any ofthe quantitative data given in the previously submitted and accepted MRIDS for fipronil and permethrin. The published information on permethrin is discussed briefly and copies ofthe published articles are included in
an Appendix to MRID 484671-29. Studies conducted on EffitixTM Topical Solution for Dogs are summarized in MRID 484671-29 in a condensed format.



### RESULTS

Data on Efficacy Against Fleas

Data on the efficacy of EffitixTM Topical Solution against fleas on dogs is summarized in Table 1.



### Tabl 1 S e 

# . umma

### rvo

## rEm lcacy Data f 

## Em or ItixTM 

### T opical 

### Solution 

### A \.gamst Fleas on 

### Dogs Test Species Citation Result Cat flea Fourie j J.J. 2009. Efficacy Study Against Fleas Kills >90% of fleas within 6 hr and (Ctenocephalides (Ctenocephalidesfelis) on Dogs: Onset of Action. >99% within 12 hr I felis) December 9, ?009.

Cat Flea Fourie j J.J. 2009. Efficacy Study Against the Brown The use ofshampoo or water (Ctenocephalides Dog Tick (Rhipicephalus sanguinells) and the Cat Flea immersion had no etfect on the felis) (Ctenocephalidesfelis) on Dogs: Effects of efficacy of the product; efficacies Shampooing and Periodic Water Immersions. were 100% after shampooing and



### 3I water immersions.



### Data on the efficacy ofpennethrin against fleas in dogs are summarized in Tables 2 and 3. Data on the efficacy of fipronil against fleas in dogs are summarized in Table 4.

Table 

### 2. Published Data on the Efficacy of Permethrin Against Fleas
EPA Re2.# Publication MRID# 773-73 Endtis, R. 

### el aT: Efficacy of two 65% permethrin 5pot- unlrnown 

### on fonnulations against induced infestations 

### of Ctenocephnlides felis (Insecta: Siphonaptera) and Amblyomma americanum (Acari: Ixodidae) on beagles. Vet Ther. Spring 2003;4(1);47-55 773-73 Emiris. R. el al: Efficacy of three dose volumes of 

### unknown topically applied 

### 65% pennethrin agaiost Cteuooephalides fclis and Rhipicephalus sanguinetlS on dogs weighing 30 kg or more. Vet Ther. Winter 2002;3(4);435-40 773·73 

### Endris. R. e! al: Efficacy of nvo 65 % pennethrin spot- unknown 

### on formulations against canine 

### infestations 

### of Ctenocephalides fclis and Rhipicephalus sanguineus. Vet Ther. Fall 2002;3(3):326·33 270-278-43591 Ross, D. eI 

### aT: Efficacy 

### of a pennethrin 

### and 46006002 pyriproxyfen product for control of fleas. ticks and**mo~quitoes** On dQgs:. Canine Pmc!' 1997' 22(2):53-58 Not applicable Tilley L.P. and Smith W.K.: Tularemia in Blackwell's 

### Unknown**five~minute** veterinary consult: canine and feline, fourth edition, 2007 Blackwell Publishing Professional, n.1365.

Table 3. Unpublished Data on the Efficacy of Permethrin Against Fleas

4

### Table 4. Unpublished Data on the Efficacy ofFipronil Against Fleas



# . ID# 

## 143 14 

## I Fie

.., 

## 143 121115 

# i I'

# ~ 12lJ21 

## 18] 121122 

## I F1eas I Fleas

# ~**14~T** leas 11 

### leas 

## 8 144!

# ~ 'Ie" 

## 18 145

# ~ 18

### ~I04 !105 

# tie

Data on Efficacy Against Ticks

Data on the efficacy ofEffitixTM Topical Solution against ticks on dogs are summarized in Table 5.

Table 5. Summa rv of Efficacy of EffitixTM Topical Solution A ainst ticks in DOffs Test Species Citation 

### Result Brown dog tick Fourie 1.1. 2009. Efficacy Study Against Rhipicephaills The duration of>90% efficacy was 7 (Rhipicephaills sangllineus in Dogs: Duration ofAction. weeks sany;uineus) American dog tick, Fourie,1.1. 2009. Efficacy Study Against The duration ofefficacy was 6 weeks (Dermacentor Dermacentor variabilis on Dogs: Duration of Action. variabilis) Lone star tick, Moran, C. 2010. The Duration of Efficacy of a Single The duration ofefficacy was between (Amblyoma Application of 104.05 (Fipronil 6.7%, Permethrin 50%) 4 and 5 weeks americanum} Compared to a No Treatment Control Against ArtificaJly Induced Infestations ofTicks (Amblyoma americanum) on Dogs. Deer tick Moran, C. 2010. The Duration of Efficacy ofa Single The duration ofefficacy was at least 5 (Ixodes scapularis) Application of 104.05 (FiproniJ 6.7%w/v, Permethrin weeks 50% w/v) Compared to a No Treatment Control Against ArtificaJJy Induced Infestations ofTicks (Ixodes sCQoularis) on Doos. Dog ticks, (D. Fourie, J.J. 2010. RepeJJence Efficacy Study of Effective for alleast one month. 24-hr variablis and R. 104.05 Against Ticks (Dermacentor variabilis and efficacy against R. sanguineus was sanguineus) Rhipicephalus songuineus) on Dogs Under Laboratory 100% on day 4,99% on day 9 and Conditions. November 3, 2010. 100% on alJ other days; 24 hr efficacy against D. variabilis was 97.6% on day 2,100% on day 4, and?97.7% on alJ other days



### 5Brown Dog Tick Fourie, J.J. 2009. Efficacy Study Against the Brown The use of shamopoo or water (R. sanguinells) Dog Tick (Rhipicephalus sanguineus) and the cat Flea immersion had no effect on the (Ctenocephalidesjelis) on Dogs: Effects of efficacy ofthe produC1; efficacies Shampooing and Periodic Waler Immersions. were 2:99.5% after shampooing and after water immersions.



### Data on the efficacy of perrnethrin against ticks in dogs are summarized in Tables 

### 5 and 

### 6. Data on the efficacy offipronil against ticks in dogs are summarized in Table 7.



### Table 

### 5. Published Data on the Efficacy ofPermethrin Against Ticks

EPA Reg. # Publication MRID# 

### 773·73 Endris, 

### R. et 01: Efficacy of two 65% permethrin**spot~** 

### Unknown On formulations against induced infestations of 

### Ctenocephalides fclis 

### (Insecta: Siphonaptera) ,nd Amblyomma americanum {Acari: Ixodidae) on beagles. 

### Vet Ther. Sorin_ 2003:4(1):47·55 773·73 Budris, R. el al: 

### Efficacy of three 

### dose volumes of 

### Unknown topically applied 65% permcthrin against Ctenocephalides fe-lis and Rhipicepbalus sanguineus 

### on dogs**:37:~;ghing** 30 kg or more. Vet Ther. Winter 

### 2002;3 4 ;435-40 773-73 Endris, R. el ai: 

### Efficacy of two 

### 65 % 

### pennethrin spot- Unknown 

### on fonnulations against canine infe-stations of Ctenocephalides**fel~~3~d** Rhipicephalus sanguineus. 

### Vet Thcr. Fall 2002;3 3 :326·33 270·278-43591 Ross, 

### D. ot al: 

### Efficacy 

### of • pennethrin and 

### 46006002 pyriproxyfen 

### product for control of 

### fleas, ticks 

### and mosQuitoes on dOf!.$. Canine Pract.**1997~** 22(2):53-58 

### 773-73 Endris, 

### R. et al: Repellency and efficacy of 65% 

### Unimown permethrin and selameetin spot-on fonnulations 

### against**lxod~(rici,ms** ticks 

### on dogs. 

### Vet Ther. Spring 2002:3 1):64·71



### Table 6. 

### Unpublished Data on the Efficacy ofPermethrin Against Ticks

Guideline 

### MRID# Claim 810.3300 41683903 Ticks 8103300 43111607 Ticks 

### 810.3300 43396409 

### Ticks 810.3300 43396410 

### Ticks

6

### Table 7. Unpublished Data on the Efficacy of Fipronil Against Ticks

Guideline MRlD# Claim 810.3300 43577712 

### Ticks 810.3300 43121114 Ticks 810.3300 43121115 

### Ticks 810.3300 43121117 

## I Tick, 810.3300 43121122 

## I Tick,



### Data on Efficacy Against Mosquitoes

Data on the efficacy of EffitixTM Topical Solution against mosquitoes on dogs are summarized in Table 8.



### Table 8. Summary of Efficacy Information for EffitixTM Topical Solution Against Mosquitoes . D III 

### og, 

### Test Snecies Citation Result Mosquito Monzali, C. 20!!. Detennination of a Combination Anti- feeding efficacy on short hair (Aedes aegypti) ofFiproni! and Permethrin in Topica! Solution Against dogs ranged from 52.5% on day 35/37 Mosquitoes (Aedes aegypti) on Dogs to 96.2% on day 7. Anti-feeding efficacy on long hair dogs ranged from ·156.7% on day 35/37 to 84.5%
on day 21122. Killing efficacies were 50·60% up to day 2! in short hair dogs, and < !2% up to day 28 in long hair docrs.



### Data on the efficacy ofpennethrin against mosquitoes in dogs are summarized in Tables 9 and 10. Data on the efficacy of fipronil against mosquitoes in dogs are summarized in Table 11.

Table 9. Published Data on the Efficacy ofPermethrin Against Mosquitoes
EPA Rcg.# l'ubfieatioD MRID#

773·73 Meyer et af.: Repellency and Efficacy ofa 65 % Permethrin Unlmown Spot-on Formulation for dogs againstAedes aegypli (Diptera: Culicidne) Mosquitoes. v.et TIler. Summer 2003;4(2):l35- 143. 270-278-43591 Ross, D. et .al: Efficacy of a permethrin and pyriproxyfen 46006002 product for control**o~{~;~,** ticks and mosquitoes on dogs. Canine Pract. 1997; 22 2**:53~58**



### Table 10. Unpublished Data on the Efficacy of Permethrin Against Mosquitoes

Guideline EPA Re2. 

### # MRID# Claims supported 810.3300 773·73 42256901 

### Kills and repel mosquitoes (4 weeks) 810.3300 

## I 43396409 810.3300 

# , 43396410

7

### Table 11. Unpublished Data on the Efficacy of Fipronil Against Mosquitoes Guideline 

### MRID# Claim 810.3300 45866902 Mosquitoes 

### 810.3300 46019202 Mosquitoes 

### 810.3300 46019201 Mosquitoes



### Data on Efficacy Against Mites

Data on the efficacy ofEffitixTM Topical Solution against mites on dogs are not available. Pennethrin data are summarized in Table 12, 

### fipronil data in Table 13.



### Table 12. Published Data on the Efficacy of Permethrin Against Mites
EPA Rcg. # 

### Publication MRID# 

### 773·73 Endris el al.: Efficacy of 65 % Permetbrin Applied as a 

### Unknown Topical**Spot~on** Against Walking Dandruff Caused by the Mite, Cheyletielln yasguri in Dogs. Vet Ther. Fall 2000'1(4):273·279



### Table 13. 

### Unpublished Data on the Efficacy ofFipronil Against Mites
810.3300 43577701 

### Mites 810.3300 43951701 

### Mites 810.3300 45612701 Mites 

### 810.3300 45620503 

### Mites 810.3300 45866901 Mites



### Data on Efficacy Against Lice

Data on the efficacy of 

### EffitixTM Topical Solution against lice on dogs are not available. Pennethrin data are smnmarized in Table 14; fipronil data in Table 15.

Table 14. Published Data on the Efficacy ofPermethrin Against Lice
EPA Reg. # Publication MRID# 773·73 Endris e/ al.: Efficacy of a Topical Spot-<>D containing Unknown 65 % Penncthrin against the Dog Louse Trichodectes 

### canis (Mallophaga: Trichodectidae). Vet 

### Ther. Spring 2001:2(2): 135.139.

8

### Table 15. Unpublished Data on the Efficacy ofFipronil Against Mites Guideline 

### MRID# Claim

810.3300 45620501 

### Lice 810.3300 45628101 

### Lice 810.3300 45628102 

### Lice 810.3300 45628103 

### Lice 810.3300 45628201 

### Lice

Data on Efficacy Against Biting Flies

Data on the efficacy ofEffitixTM Topical Solution against biting flies on dogs are not available. Permethrin data are summarized in Table 16; 

### there are no data for tipronil.

Table 16 Unpublished Data on the Efficacy ofPermethrin Against Biting Flies



# . Guideline EPA Re•. # MRID# Claims sunDorted

810.3300 

### 11556-132, 46978901 Repe1s biting flies fbr three weeks 

### 133, 134 135 (2004)



### Data on Efficacy Against Sandflies

Data on the efficacy ofEffitixTM Topical Solution against sandflies on dogs are not available. Permethrin data are summarized in Table 17; there are no data for fipronil.

Table 17. Published Data on the Efficacy of FiproniI Against Sand Flies
EPA Reg. # Publication MRID# 173-73 Molina et 01.: Evaluation of a topical solution containing 65 % P¢IDlethrin against the Saudily (Phtebolomusperniciosus) in DOl!s. Vet Ther. Summer 2001;2(3):261-267.



### Study Author's Conclusions

The study author's conclusions are presented in Table 18.

9

### Table 18. Summary of Data Available on the Efficacy of EffitixTM Topical Solution, Permethrin and Fipronil Against Target Organisms on Dogs Fleas (C.je/is) Repels and kills fleas forup tn three months. Renel nnd kills fleas in sLx hours Tieks (It sallgUilll!Us. A. americanlllll. J. scapu[cris. 1. Repels and kills ticks for at least one month rldmlS, D,**variabil~)** Kills 90% ofthe ticks in 3 hours Lice Kills and repels Trichadectes canis for up to 4 weeks Kills sucking, biting and c-hev.ing lice for a month 

### or lon2':cr Mites (C yasguri, S. scobie! va! canis) Kills mites (c. yasguri) for up to four weeks Aids in the -control ofsarcontic**man~e** mite infestation Mosquitoes (A. aegyptJ.) Prevents- blood feeding, kills, repels mosQUitoes for up to one month Biting flies (S. caldtrans) Prevents blood feeding and repels biting flies: for up tn three weeks Sandflies (P. pernie/osus) Pte\'ents blood feeding and repels sand flies fnr up to one month



### Reviewer's Conclusions

Infonnation on the efficacy on EffitixTM Topical Solution for Dogs was adequately reviewed. Although the use ofpennethrin and fipronil efficacy data in support ofthe registration of EffitixTM Topical Solution for Dogs is justified, the infonnation provided was inadequate. 

### It could not always be determined ifthe dose rates used in the previously accepted studies were less than
or equal to the dose rates proposed for EffitixTM Topical Solution for Dogs. Furthennore, the use of data from products that contain more than one active ingredient was not always clearly justified. For example, data for K9 Advantix is used to support biting fly claims for EffitixTM Topical Solution; however, the presence ofimidacloprid in the product, in addition to pennethrin, may have affected the results (although the author ofMRID 484671-29 claims that imidacloprid "is not itself effective on biting flies"). Study author uses data for a 65% pennethrin product to support claims ofefficacy against sandflies, and states that the dose rate by kg or lb is equal to or below that for EffitixTM Topical Solution; however, no quantitative data were presented to support this claim.


### Reviewer's Recommendations
Unacceptable, but upgradable. The reviewer did not have access to infonnation needed for the supporting permethrin and fipronil studies on lice, mites and biting flies. Sandflies are not listed
on the label.



### 10Virbae

- 2382-RlT Wade Britton 

### to: 

### jbarron 11107/201107:13 PM Ce: brenton. smith, Kimberly Nesci, Richard Gebken, Bonaventure Akinlosotu Hide Details From: Wade BrittonIDC/USEPAIUS

To: 

### j barron@exponent.com

Cc: brenton.smith@virbacus.com, Kimberly NesciIDC/uSEP A/US@EPA, Richard GebkeniDC/USEP AlUS@EPA, Bonaventure Akin[osotnIDCIUSEPAIUS@EPA

1 Attachment 

### r--'

# ~ Image.imageOO l.jpg@OlCC9783.3764E1DO.PLAIN Page 1 on

Mr. Barron - I am writing in confirmation of our discussion this morning regarding Virbac's pending registration, 2382-RIT. Due to the short time frame from the mailing of the letter outlining the recommended label changes to the November 19, 2011 PRIA date for the pending registration, the Agency will not be requiring that these changes be addressed prior to product registration. However, please note that EPA does anticipate the submission of amended labeling incorporating the recommended changes within 6 months following product registration.
We are continuing to consider the specific questions/rationale provided by Virbac following our Oct 13,2011 meeting,

Best Regards, Wade

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tv Wade Britton, MPH Industrial Hygienist; Health Effects Division Office of Pesticide Programs, US EPA (703)308-0139

-----"Jim Barron" <jbarron@exponent.com> wrote:

-----



# I To: Wade Britton/DC/USEPA/US@EPA From: "Jim Barron" <jbarron@exponent.com>

file://C:IDoeuments and SettingslBAkinloslLocal SettingsITemplnotes87944BI-web3825.... [119/2011

### Date: 10/31/2011 

### 09:54AM Cc: "Brenton Smith" <brenton,smith@virbacus.com> 

### Subject: 2382-RIT
Wade, 

### Page 2 on

Hope you had a good weekend. Any decision taken by your team on our proposed labeling for Effitix topical solution for dogs.? Also, did you receive the proposed printed labeling which we had sent to Bonaventure and Richard Gepken?

Thanks for your help.

Jim Barron, Ph. D.
Managing Regulatory Consultant

1000 Centre Green Way Suite 200
Cary, NC 27513

Office Telephone (919)**228~6479** Mobile Telephone (919)**534~6018** Facsimile (919)**228~6501** Email Addressjbarron@exponent.com

CONFIDENTIALITY NOTICE: This electronic transmission (including any files attached hereto) may contain information that is privileged, confidential and protected from disclosure. The infonnation is intended only for the use of the individual or entity named above and is subject to any confidentiality agreements with such party. If the reader of this message is not the intended recipient or any employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any disclosure, dissemination, copying, distribution, or the taking of any action in reliance on the contents of this confidential information is strictly prohibited. If you have received this communication



### file:IIC:IDocurnents and SettingslBAkinloslLocal SettingsITemplnotes87944BI-web3825.... 11l9!2011in error, please destroy it immediately and notify the sender by telephone. Thank you



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which may be a computer program. This attached computer program could contain a computer network, and data. virus which could caUSe harm to EPA' s The attachment has been deleted. computers,

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### file:IIC:IDocuments and SettingslBAkinloslLocal SettingsITemplnotes87944BI-web3825.... 1119/2011Effitix- CRP questions Jim Barron to: Bonaventure Akinlosotu 

### llI03/201111:19AM Cc: melissa.lum, "Brenton Smith" Hide Details From: "Jim Barron" <jbarron@exponent.com>



### To: Bonaventure AkinlosotulDC/uSEPAlUS@EPA 

### yage 1 01 L

Cc: <melissa.lum@virbacus.com>, "Brenton Smith" <brenton.smith@virbacus.com>

1 Attachment 

# d
image003.jpg
Bonaventure,
Rosalind and I have this morning discussed by phone her concerns about the proposed Effitix text label (6-21-11) version as well as the mock-up artwork label we submitted 10v5-11. Bonaventure, I believe that Rosaling will be talking to you and summarizing the actions for you. My main action is to provide you with revised text labeling where we have moved the bullets describing proposed illustrations that now appear on page 4 to the end of the "Marketing Claims" sections on page 9. This is the location where we listed the proposed illustrations on the now approved Effipro label (2382-185). Addressing the last bullet statement in that group (the bullet that proposes an illustration of the applicator tube), Virbac will also either provide a proposed picture of the applicator tube or we will strike that statement for now. I have to obtain confirmation from Virbac first on that mattern.
The only other CRP related question that Rosalind and I discussed and which you and I should touch base on now is the incorrect arrow placement on opening instructions that Rosalind noticed in the mock up draft artwork label submitted 10-5-11. My suggestion is to handle this by instructing Virbac in the NOR to make sure that those opening instruction diagrams (especially the arrows) in the final printed labeling (artwork) are drawn identically to the opening instructions in the text label that you will stamp.
If you need to discuss this with me further, let me know.
I am back in the office. The phone number is 919 462-9860. Thanks,

file:IIC:\Documents and Settings\BAkinlos\Local**Settings\Temp\notes87944B\~web5512....** 1113/2011Jim Barron, Ph. D. Managing Regulatory Consultant

### EXponen~, 

### Inc. 1000 Centre Green Way Suite 200 Cary, NC 27513

Office Telephone (919) 228-6479 Mobile Telephone (919) 534-6018 Facsimile (919) 228-6501 Email Addressjbarron@exponent.com 

### Page 2 of2

CONFIDENTIALITY NOTICE: This electronic transmission (including any files attached hereto) may contain information that is privileged, confidential and protected from disclosure. The information is intended only for the use of the individual or entity named above and is subject to any confidentiality agreements with such party. If the reader of this message is not the intended recipient or any employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any disclosure, dissemination, copying, distribution, or the taking of any action in reliance on the contents of this confidential information is strictly prohibited. If you have received this communication in error, please destroy it immediately and notify the sender by telephone. Thank you

llnnnl1

### October 5, 2011

Bonaventure Akinlosotu, PM Team 10 

### Office ofpesticide Programs (7504P) U.S. Environmental Protection Agency Document Processing Desk 

### Room S-4900, One Potomac Yard 2777 South Crystal Dlive Arlington, VA 

### 22202

Subject: Efftix@ Topical Solution for Dogs (EPA Reg. No 2382-RlT); Proposed Labeling.

Dear Bonaventure,



### Please find enclosed proposed printed labeling for Effitix (2382-RIT) for referencing during our October 13 teleconference.

In addition, here are Virbac questions/comments resulting from the September 30, 2011 Lois Rossi Letter that the company would like to discuss during the teleconference:

In order ofimportance:

1. We do not believe 

### it should be necessary to add the phrase

- HMAY BE FATAL".



### 2. We do not want to increase the size of the word "Dogs" for the product name. The word "Dogs" is stated at least 12 times on the one-pack alone, so we feel that this should be very clear on this package. Increasing the font size would require us to remove other important infonnation from the package. This is an even greater issue with the request to increase the size ofthe !tcat prohibition icon".

3. We do not think it should be necessary to place a 'cat prohibition' icon in the lower right hand corner

- we feel we already have this icon multiple places throughout the packaging (front panel, back panel, package insert, blister and pipette). We consider the placement ofthe icon closer to the middle ofthe package to be better in terms ofvisibility for the pet
owner.

3200 Meacham Blvd .• Fort Worth, TX 76137 Telephone; (817) 831·5030 • (800) 338-3659 Fax (817) 831-8327

### 4. Increasing the size of the cat icon to 1.5 cm x 1.5 cm is a reasonable request on the l(1rger package presentations (3, 6 and 36-packs) because there is more room to meet't:l';se dimensions. However, on the one-pack this will be very hard to accOl.lflr'lJ-lte. We 'also believe that there is an inherently lower need for this adjustment baseq on the one use nature of a one-pack, which we do not expect pet owners to take home and**~tore** 

### for future use. We feel there shouldn't be any confusion about which pet**;"1t\;~e** 

### prodlLcts ill 

### the one-pack should be applied to.

5. Changing the colors of the "cat prohibition icon". The colors were chosen to starcl ,('ut against the background colors of the different packages. We believe the presence of this icon is in 

### enough places that there shouldn't be any confusion (front panel, back panel, package insert, blister and pipette).

6. "Keep cats away from treated dogs for 24 hours"- This seems to only be a necessary warning for 'Keep cats that groom dogs away'. This should be more specific as this is a very rare Issue.

7. Expanding the toxicity warnings to be broken down by active ingredient is a concem based on the amount of space that this would require. The listing of side effects is complete based on the total product so this duplicated effort would negatively impact the amount of space for other warnings that are necessary for these packages.

We look forward to discussing these questions with you during the October 13, 2011 teleconference.

Sincerely, 

# ;3riiilcA

# ~**l~f5-r**
Brenton Smith, Ph.D, PMP Product Development Manager Research and Development

3200 Meacham Blvd .• Fort Worth, TX 76137 Telephone: (817) 831'·5030. (800) 338·3659 Fax (817) 831-8327UNITED STATES ENVIRONMENTAL PROTECfION AGENCY WASHINGTON, D.C. 20460

FILE SYMBOL No.: 2382-RIT ACTION CODE: R 31 0 OFHCE**OFCIIt~IlCAL** SAfETY**A~D POLLtJTIO~** **PREVENTIO~** OFFICE OF PESTICIDE PROGRAMS

I{EGIS'mATION DIVISION 17$051')

DECISION No.: 448350 DP BARCODE No.: 0390814 PC CODES: 109701,129121 FOOD USE: No PRODUCT NAME: Effitix Topical Solution for Dogs

DATE OUT: October 25, 2011
SUBJECT:

FROM: End Use Product Chemistry Review Product Name: Effitix Topical Solution for Dogs.**~** Bruce F. Kitchens, Chemist

# ~ 

# ':j**X~** Product Chemistry Team 

## c}::)' (!)&G 

### 7.&// Technical Review Branch/RD (7S0SP) 

### (AIt_. "- 

# l,n2--6!')

RM 10, Richard Gebken/Bonaventure Akinlosotu 

# ?5 '(5V'-"

- \J \ Insecticide Branch I RD (7S0SP) TO:

Company Name: Virbac AH, Incorporated Liquid Formulation Type:
INTRODUCTION:

The registrant has submitted an application for the registration of the new end use product, Effitix Topical Solution for Dogs. The active ingredients in this product are Fipronil and Permethrin at label nominal concentrations of6.01 and 44.88% a.i., respectively. The fipronil source is not registered. This product is intended for use as a topical insecticide for dogs. In support of the registration application, the registrant has submitted a Confidential Statement of Formula (CSF) dated 21 Mar 2011, a draft label and 830 Series Group A and B product chemistry data contained in MRID#s 484671-01, -02, -03, -04, -OS, -06, -07, -08, -10 and 484873-01. During the course of this review, the registrant submitted a revised basic CSF dated 21 Oct 2011 to correct a calculation. The Technical Review Branch (TRB) has been asked to review this submission.
SUMMARY OF FINDINGS:

1. Name of Active Ingredients: Fipronil (6.01% a.i.) Permethrin (44.88% a.i.)

2. Has the registrant claimed substantial Similarity to a registered product? [I Yes; [XI No

3. All of the source materials of the active ingredient are derived from registered sources- [ 

### 1 Yes [Xl No
The fipronil source of the active ingredient is not registered. The purity of the unregistered source is as stated by the registrant.

4. All inert ingredients have been screened by IIAB and found to be approved for the proposed labeled uses.FILE SYMBOL No.: 2382-RIT ACTION CODE: R 310 DECISION No.: 448350 DP BARCODE No.: 0390814 PC CODES: 109701, 129121 FOOD USE: No PRODUCT NAME: Effitix Topical Solution for Dogs

5. Confidential Statement of Formula:
[Xl Basic

- Dated: 21 Mar 2011 ; Re-submiUed

- Dated: 21 Oct 2011

6. Product label

a. Ingredient statement: Nominal concentration of AI listed on CSF concurs with product label (PR Notice 91-2).

[Xl Yes, if not, explain below:

Is the sub statement in compliance with PR Notice 97-6 (inert ingredient vs other ingredient) [Xl Yes; [] No; if not, explain below

Metallic equivalent: Soluble arsenic: [ [Yes [X] NA; [)Yes [X]NA Isomeric ratios: Acid Equivalent [X[Yes [ 

## 1 NA Permethrin cis/trans ratio: max 55% (2:.) cis & min 45%(2:.) trans [ ] Yes [X] NA
b. Health related sub statements: Product contains?

Petroleum distillate at > 10%: Methanol at > 4%: Sodium nitrate/sodium nitrite [ [Yes; [ [ No; [XI NA [[Yes; [[No; [X[NA [[Yes; [[No; [X] NA

c. Physical chemical hazard statement: Product label requires a statement per40 CFR §156.78 for: flammability, explosive potential or electric insulator breakdown? [] Yes [XI No

Is the sub statement in compliance with PR Notice 98-6 (Total Release Fogger)? [ [Yes; [ [ No; [Xl NA; if not, explain below

d. Label requires an additional Storage and Disposal statement [ [Yes [Xl No; if yes explain below:FILE SYMBOL No.: 2382-RIT ACTION CODE: R 310 DECISION No.: 448350 DP BARCODE No.: D390814 PC CODES: 109701, 129121 FOOD USE: No PRODUCT NAME: Effitix Topical Solution for Dogs

7. Group A: Product Chemistry Data

TRS's determination of the acceptability for the proposed product is listed in the tables below.
Data submitted Guideline TR8's No. Study Title Assessment MRID Nos. of Data Ves No 830.1550 Product Identity & Com osition X A 484671-01 Description of Materials Used to 830.1600 Produce the Product X A 484671-01 Description of Formulation 830.1650 Process X A 484671-01 Discussion of the Formation of 830.1670 Impurities X A 484671-01

830.1700 Preliminary Analysis X A 484671-02 Standard Certified Certified Limits X limits (158.350) Proposed Limits Justification for 830.1750 wider limits seecsf10/21i11

830.1800 Enforcement Analytical Method X A 484671-03

A = Acceptance, N 

# = Not Acceptable, G 

## =Data Gap, W = Waiver Request, I 

## =In Progress, NA 

## =Not Applicable; U 

## =Upgradeable.DP BARCODE No.: 0390814 PC CODES: 109701, 129121 FOOD USE: No

8. Group B:
Guideline Study Title No.

830.6303 Physical State
830.6315 Flammability

830.6316 ExPlodability
830.7000 pH
830.7300 Density (units) FILE SYMBOL No.: 2382-RIT ACTION CODE: R 3 I 0 DECISION No.: 448350

PRODUCT NAME: Effitix Topical Solution for Dogs

Value or Qualitative TRB's MRID Nos. Description Assessment of Data

Yellow odorless liquid A**484671~O4** 96.28'C (flash point) A 484671-06 Product does not have explosive components NA 5.30@22'C A**484671~O8** 1.114 (relative density) A 484671-10

A = Acceptance, N = Not Acceptable, G = Data Gap, W 

## = Waiver request, NA = Not applicable, I 

## =In progress; U = Upgradeable.

9. The registrant referenced product chemistry data for the unregistered source of fiproni!. This source is a component of EPA Reg. Nos. 2382-185 Effipro Topical Solution for Dog 2-186 Effipro Topical Solution for Cats. The stated purity of the unregistered source is The producer of the unregistered source used in this proposed product is the same as the producer for the registered**end~use** products mentioned above. This data was reviewed and it was determined that the data was acceptable and supported the registrations for the currently registered**end~use** products. See the confidential appendix for a summary of the product chemistry data requirements for the unregistered source of the active ingredient fipronil.DP BARCODE No.: D390814 PC CODES: 109701, 129121 FOOD USE: No

CONCLUSIONS: FILE SYMBOL No.: 2382-RIT ACTION CODE: R 310 DECISION No.: 448350

PRODUCT NAME: Effitix Topical Solution for Dogs

The TRB has reviewed the product chemistry data submitted for the proposed end-use product and has concluded that:

1, The basic formula CSF for the proposed end-use product, Effitix Topical Solution for Dogs dated 21 Oct 2011 is acceptable.

2. This submission satisfies the data requirements as specified in 40 CFR 158.155, 158.160, 158.165, 158.167, 158.175, and 158,180 with respect to product identity and composition, description of materials used to produce the product, description of formulation process, discussion of formation of impurities, certified limits, and enforcement analytical method.
3. This submission satisfies the data requirements as specified in 40 CFR 158.190 with respect to physical and chemical properties.DP BARCODE No.: D390814 PC CODES: 109701, 129121 FOOD USE: No FILE SYMBOL No.: 2382-RIT DECISION No.: 448350 ACTION CODE: R 310 PRODUCT NAME: Effitix Topical Solution for Dogs

CONFIDENTIAL APPENDIX
The product chemistry data submitted for the unregistered source of fipronil is summarized in the following tables.



### COMMON NAME: Fipronil

CHEMICAL NAME (CAS): IH-PyrazoIe-3-carbonitrile, 5-amino-I-[2,6-dichioro-4- (trifluoromethyI)phenyI]-4-[(trifiuoromethYI)suifinyI]-
(IUPAC): 5-amino-I-[2,6-dichioro-4-(trifluoromethyIJphenyI]-4-(1,R,S)- (trilluoromethyisuifinyl)-1 H-pyrazoIe- 3-carbonitri Ie

CAS No.: 120068-37-3

PC CODE NO.: 129121

EMPIRICAL FORMULA: C 12

### H,CI,F,N,OS

MOLECULAR WEIGHT: 437.15

STRUCTURAL FORMULA:



## I

# ~

# ~

# ~

# ~;"o I 

## ; I Prod", "",,'"**~d,** A iwiJIn 

# '" J A II available

&301600 Descripticm orlTllltcriah used to 1:.o2--10} Additional MSDS '$**hll~** A J J i A 830.1670 Discussion Df lbrmation of i 

## I 83'.1700 

# .**~.,".** A


### I 81'17" A 

## , i i .

. .-. 

## I 83'18'" i A

A'" " ",.iml) 

# ,'" '·N,' J = Dlita sap: I '" In progress or 

# '**v,..~,**DP BARCODE No.: D390814 PC CODES: 109701, 129121 FOOD USE: No
CONFIDENTIAL APPENDIX: FILE SYMBOL No.: 2382-RIT DECISION No.: 448350 ACTION CODE: R 31 0 PRODUCT NAME: Effitix Topical Solution for Dogs

830 Series Subgroup B**(pbysical~Cbemical** Properties)

Table 2: Ph**$i~l** MId Chemical PI rtit:i cl': TGAIfMUP
GLN RequirellWnl MRJD 

## S."" Rcsuhot Deficiency

UO.6302 Color 4S09S2--i() A While
330.630] Physical stale 480952-40 A Crystullinc powder

830.6304 Cd" NA

11306313 Siability 10 normal and LeUerdlle<! W Waiver lteCjl(cJ elevnted temperaturt'S. melllis, IUld**m~1lI1** ions 1l-02·IO

830.63 (4 Oxidation/reduc(ion: 480952·39 A Incompatible with mong bilS1:S, strong acid$, and strong chemical incompatibiUIy oxidizing =gclIl.'l

830.6315 Flammability 480952.39 A Nal flammable

B30.6316 ExpJodability 4809S2·39 A Nol explosive

830.6317 Storage stllbilily 4S(I9S1-43 U Stable after \4 Jays al**54~C** 830.6319 MiscibiHIy NfA NOI intended to be mixed wilh petroleun, solvents

330.6320 Corrosian charaeleristics G No data provided
830,7000 pH 48095247 A 6.05 lit 22·C
830,7050 UVNisiblc absorplion 480952-48 A UVNlS $PCCtrll**wc~** very similar al pH 0.6, pH 6.7,**~nd** pH 13.2

830.7100 Vi.;co:;ity NiA Ploducl is II solid
830,7200 Melling poinl 480%2-49 A 203.9± o.l·e
S3().7220 Boiling poinl NJA Product is l solid

830.7300 Density 

# I 48[}9S2-50 A DiO ", 1.716

830.7370 

# IDissociation consla/1ls in 430952-5 I w Nol an aeiJ, hilS no organic functionality; no dissocialiot\ wlltcr(DC) is expeeted

830.7550 Partition coefficient 480952-44 A Log Paw'" 2.96

830.7840 Water solubility 480952-45 A U9 mg/l..t**20~** 8JO.79S0 Vape.r pressure 4809S246 A LO x 10-6 at25"C

2.0 x 10-3 Pa It**80~** 2.S l( \0',2 Put lOOCC

4.8 x 10.2 Pa as IIO'C

A'" Aw:ptlble; N '" un&(:c<;plllble (see Deficiency); NfA" NO! Applicable; G "" Data gap; I = In progress 01**n~d** upgrade; U '" Up-grade (adJitienal inOmn:tiom requiled); W -'waiversDP BARCODE No.: D3908I4 PC CODES: 109701, 129121 FOOD USE: No

CONFIDENTIAL APPENDIX:

Chemica] Fipronit

CD Number 

# , FILE SYMBOL No.: 2382-RIT DECISION No.: 448350 ACTION CODE: R 310 PRODUCT NAME: Effitix Topical Solution for Dogs

Registration No. 2382-??? DP Bar.;odc D379877

ProduclT 

# , m$((:licidc Test**Sub~Ulnce** TOAIJMUP Group A-GLNS 830.1530.830.1600,830.1620, 830.1650, 830. 1670. 830.1700, 830.1 750, & 830.1 800: Comprui1iOfl (CSF), lmpurilies, fuJimifllU)' ;maly5;is. and Analytical Methods

Com \lillI/Com 

## "' , Lower Ctrlifi«l Upper Cenified Preliminary

T""

# -I NOminll Jimi1 coneenlnilion limit cQnccnlr1ltion Anillysis No Name**Co~::~on** (%wtw) (% wtw) Mean±s. d. %wIW %w/wl**FiprOll~** CAS No. 120068-37-3 AI

## CHEMICAL NAMEIPESTICIDE CRE' "l:CAL CODE (pCC) REQUEST FORN! CR#

___ _
REQUESTOR NAME

### ~"we 

# K;.**tc0.~,-,,-** Request date: 

## 2if 

# tif Zfl 

## /I
Tel: 

## .31?l'; 

# -Ci312 

# I ORG.:,R.o,h 

### ,I 

### CUBE::5-733j MAIL CODE: 

# 7sz;sP

, CSF ATTACHED:**~YES** IfCSF is attached complete Item A and the chemical name in item C. [] NO IfCSF is not attached complete Item A through C.

A INFORMATION REQUmED: .Q CheckApplicahle Category [J Provide 

### PCC and Tolerance Exemption Status ForFood-Use Inert ingredient (s). 

### ":H: Provide PCC for Non-Food Use inert Ingredient (s).



### [ J Provide PCC for Active Jngredient (s). [J Provide PCC fur Dye. [J Detennine ifFragrance is Acceptable for Use In Fonnulation. [J Olher(Describe):

__________ _
B. PESTICIDE PRODUCT INFORMATION:

EPA Reg. NoJFileSymbol: 

# viRBIk-M,u. Produo< Nrune: 

## H,;4k 

## To7/;uJ 5#/,;1;". ,fp 

## o"'},

. Registrant: 

## 2"382

- 

## J?J.T Food-Use Pesticide: [] Yes**~Nu** Percent in Fonnulation (For Fragrance !Dyes )

C. INGREDIENT INFORMATION: Ingredient No.1 INFORl'dATION REPORTED;

Chern. Name: PCC:**~** Trade Name: TaL. STATUS;
CAS Reg. No.: OTHERINF.: 

# I

PCC:

# ~OLSTATUS: QlliERrnF.:
Ingredient No3 

# I
Ch=Nrun, Trade Name:
OTHERINF.:
Ingredi ntNo4· 

# , .. Chern. Name: 

### pcc:
nadeName: TOL. STATUS:
CAS Reg. No.: OTIIERThIf".:
Completed By: 

# \L1,**{~** Date Completed: / '11 

### SII/ 

### / 

## /UNITED STATES ENVIRONMENTAL PROTECTION ,\GEI\CY WASHINGTON. D.C. 20460

OFFICE OF CllDIlO\L SAFETY ,\"D POLlXTIO:,\ PREVEKTIO'"

OFFICE OF PESnClDl, I'llOGRk\IS**I~EGISTnATIO:X** DIYISIO."I\**(750~P)** 

### October 13,2011

MEMORANDUM

Subject: Name ofPesticide Product: EPA Reg, No./File Symbol: EFFlTlXTM TOPICAL SOLUTION FOR DOGS 2382-RIT DP Barcode: Decision No.: Action Code: PC Code: DP 390818 448350 R310 109701 (Permetbrin: 44.88%) 129121 (Fipronil: 6.01%)

From: Byron T. Backus, Ph.D., Toxicologist Technical Review Branch Registration Division (7505P) 

## (3 

# ---T ()**~ ~**  

### - LJ 'Lol...\ 

### 00£·(,<-- 

# rt**~-f/.,b'**

# Lr:;-;;t~ To: Bonaventure AkinlosotuiRichard Gebken, RM 10 Insecticide Branch Registration Division (7505P)
Registrant: VIRBAC AH, INC.

FORMULATlON FROM LABEL:

Active Ingredient(s): 129121 Fiproni1 109701 Permetbrin Other Ingredients: TOTAL

ACTION REQUESTED: The Risk Manager requests: bywt. 6.01% 44.88% 49.11% 100.00%

"For your review: MRID Nos. 484671-17 to 20, and 48487302; for an R310, new fipronil/permethrin containing spot-on for dogs

... "



### 1

### BACKGROUND:

The material received includes three companion animal safety studies: MRlD 48467117 (a companion animal safety study in adult beagles); MRID 48467118 (a companion animal safety study in approximately 8 week old beagles); and MRID 48487302 (a second companion animal safety study in 

### approximately 8 week old beagles). There is also a report (in MRID 48467119) titled "Summary of Companion Animal Safety Data for EffitexTM. 

### In addition, there is a proposed label (indicating a dose rate of 1.0 mL for small dogs and puppies 8 weeks of age and older weighing up to 22.9 lbs; 2.0 rnL for dogs weighing between 23 and 44.91bs; 4.0 mL for dogs weighing between 45 and 88.91bs; and 6.0 mL for dogs weighing between 89 and 1321bs) 

### with application at 3D-day intervals.



### COMMENTS AND RECOMMENDATIONS:

1. The three companion animal safety studies were reviewed by a contractor (Summitec Corporation). The resulting DERs were secondarily reviewed by TRB and revisions were made as appropriate.

In the study in adult beagles (MRID 48467117) it is concluded that the margin of safety in 10- to 20-kg adult beagle dogs administered 104.05 [End-use Product: EffitixTM Topical Solution for Dogs] is at least 5x the recommended dose (2.0 mLldog). This companion animal safety study in dogs is Acceptable/Guideline and does satisfy the guideline requirement for a companion animal safety study (OPPIS 870.7200) in adult dogs.

In a study with 8 week old beagle puppies (MRID 48467118) effects were seen that were doserelated. At the 5X dose level there were increased incidences of vomiting and abnormal feces, i.e. feces that were liquid, loose, mucoid, with traces ofblood, and/or discolored (seen in 4-5 5X animals vs. 0 controls). The 5X animals ofboth sexes had decreased weight gain during days-l to 7 (51 % 

### and 55% less than controls for males and females, respectively). During days 1-5 ofthe study, the daily food consumption ofthe 5X animals was 32-50% less than that ofcontrols (p<O.OI), and there were 26 occasions (involving nine 5X puppies) in the period from Day 1 to 9 when a 5X puppy consumed less than 100 g of food in a single day (this occurred only twice in the IX group and once in the 3X group during this period). Two 5X animals also exhibited abnormal neurological signs, considered treatment-related. These included salivation, ataxia, inability to walk properly, trismus (inability to properly open the mouth), walking in a circle to the right, resting head against the wall, generalized tremors, one episode of seizures (clonic convulsions), "dullness," and regular retropulsion ofthe neck in one animal and salivation, ataxia, Wlsteadiness
on hind limbs and gait incoordination due to weakness, and slight generalized tremors in the other 

# I

animal. There were no apparent treatment-related effects on clinical chemistry parameters or 

# l

serum thyroxin and thyroid stimulating hormone concentrations. '

This companion animal safety study with 8 week old puppies does not demonstrate an adequate margin of safety. In particular, some ofthe effects observed in 3 ofthe 5X animals were severe and required veterinary intervention (these 5X puppies received IV saline treatments as well as other treatments and one ofthese was also treated with oxygen by face mask for 30 minutes on ) Study Day 4). This study in puppies is classified as Unacceptable/Guideline. It does not satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in juvenile dogs.

2

### 4. In the other companion animal safety study with 8 week old puppies (MRID 48487302) one 5X female exhibited profuse salivation on the morning ofday 3, exhibited ataxia, generalized tremors, "dullness," and lateral recumbency on days 3-4, and was subsequently euthanized for humane
reasons on day 4. There were no gross or microscopic findings to account for the neurological signs; chronic active inflammation with hemorrhage was present in a localized area ofone lung, but the study pathologist did not consider these changes extensive enough to cause clinical signs. The 5X males gained less weight than controls during days -I to 7 (49% less than controls), and 5X animals ofboth sexes had biologically and statistically significantly decreased mean food consumption on days 1-3 (25-29% less than controls; p<O.Ol).

It 

### is concluded that toxicity was evident at the 5X dose level as abnormal neurological clinical signs (ataxia, generalized tremors, and profuse salivation) were observed in one female along with decreased food consumption in both sexes on Days 1 through 4 and decreased body weight gain in males. therefore, an adequate margin of safety has not been demonstrated in 8-week-old puppies.

This companion animal safety study in 8 week old puppies does not demonstrate an adequate margin of safety and is classified as Unacceptable/Guideline. It 

### does not satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in juvenile dogs.

5. Refer to the attached DERs for additional comments regarding these studies.

6. The material in MRID 48467119 includes a comparison ofdosage rates of other existing pennethrin-containing spot-on products and fipronil-containing spot-on products. However, there is no registered spot-on product which contains both ofthese active ingredients, and it is not known whether there is any additive and/or synergistic toxicity when permethrin and fipronil are combined.



### 3

### DATA EV ALUA TION RECORD
PERMETHRIN, FIPRONIL [104,05 (EFFITIX'M TOPICAL SOLUTION FOR DOGS)]

OPPTS 870,7200 STUDY TYPE: COMPANION ANIMAL SAFETY STUDY- ADULT DOGS MRID 48467117

--------

Primary Reviewer: Donna 

### L. Fefee, D.V.M.
Secondary Reviewers: Prepared for Registration Division 

### Office ofPesticide Programs U.S. Environmental Protection Agency One Potomac Yard 2777 

### South Crystal Drive



### Arlington, VA 22202


### Prepared by Summitec Corporation 9724 Kingston Pike, Suite 602

Knoxville, Tennessee 37922



### Task Order No_ 3-C-03

Signature: Date:
Virginia A. Dobozv. V.M.D

.. M.P.H. 

### Signature: Date:

Robert H. Ross. M.S

.. Group Leader Signature: Date: 

### Quality Assurance: Angela M. Edmonds. B.S. Signature: Date:

Disclaimer

# ~Ot-- 

# t- Fet-u-, M3 

## SEP 142011

# fbtMrn-~**~~p** 

## 1 42QU

This review may have been altered subsequent to the contractor's signatures above.

### EPA Reviewer: Byron T. Backus, Ph.D. Signature: 

# \l 1'::::::T _**~..J------.** 

# _'V 1...-1 

# {1... 0 '-, 

### Technical Review Branch, Registration Division (7S0SP) Date:

EPA Secondary Reviewer: Kit Fanvell, D.V.M., D.A.B.T. Risk Assessment Branch VII, Health Effects Division (7509P) Signature:

# _-JI!=J-n-J!"-1'-c-h-~~ Date:
__

# r;td;L'/)"-,-;~~';)",o,,,(-,I-c- 

# ,c::-c-=-cc==-:-c=-:-::======- Template version 02/06 

## I DATA EVALUATION RECORD 

## I

STUDY TYPE: Companion Animal Safety Study

- Adult Dogs; OPPTS 870.7200

PC CODES: 109701, 129121 DP BARCODE: 390818

TEST MATERIAL (PURITY): 104.05 (6.71 

### gil 00 mL Fipronil and 50.26 

### g/lOO mL Permethrin; Batch No. CGA 09007-1)

SYNONYMS: EffitixTM Topical Solution for Dogs

CITATIONS: Smith, D. (2010) 104.05:Target animal safety study by dermal administration to beagle dogs. Huntingdon Life Sciences, Cambridgeshire, U X. Study Number VRBOOI7, February 5, 2010. MRID 48467117. Unpublished.

SPONSOR: Anonymous (2011) Summary ofcompanion animal safety data for EffitixTM Topical Solution for Dogs (Fipronil 6.01% and Permethrin 44.88% end use product). Virbac, lere Avenue, 06Sl1 Carros Cedex, France. Study number Virbac 104.0S-2, 

### April 10, 2011. MRID48467119. Unpublished.
Ballantine, A (2010) Validation of an immunoassay method for the measurement of TSH in canine serum. Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Cambridgeshire, U.K. Study number HLS0715, May 24, 2010. MRlD 48467120. Unpublished.

Virbac S.A, 13 eme 

### Rue LID, BP27, Carros, F-06511, France.

EXECUTIVE SUMMARY: In a 14-day companion animal safety study (MRID 48467117), 104.05 

### (6.71 gllOO mL Fipronil and 50.26 

### gllOO mL Permethrin; Batch No. CGA 09007-1) was applied topically to the skin on the dorsal midline at the base ofthe head to the mid back. Groups of six male and six female adult beagle dogs (9-10 months old; Day -1 weights: males: 11.8-14.6 kg; females: 10.1-13.1 kg) were treated at IX (2.0 mLidog) or 5X (l 

### 0.0 mLidog) the total dosing volumes for the end llse product in dogs weighing 10-20 kg. "104.0S 

### Placebo" was applied to a control group of 6 male and 6 female animals at a dosing volume of 10.0 mLidog. Animals were treated on day 0 and observed for 14 days. Dogs treated with 10.0 mL of the test material or placebo received two separate S.O 

### mL applications, spaced at approximately 4 hours apart.

There were no treatment-related effects on mortality, body weight or body weight gain, food consumption, hematology, clinical chemistry, or coagulation parameters, or serum thyroxin and thyroid stimulating hormone concentrations. Treatment at 

### SX the recommended therapeutic dose resulted in an increased incidence ofloose feces within 4 to 8 hours of dosing; three 

### SX dogs exhibited a total of seven incidences compared to no incidences in controls. In the absence of


### 5

### correlated effects on body weight or other end points, at this low incidence, the loose feces are not considered adverse. There was no local irritation (erythemaJedema) or discoloration of the skin at the dose sites. Cosmetic effects, such as greasy appearance to the hair coat, deposits, spiking, and clumping, were transient and resolved within**7~8** 

### days ofdosing.

It 

### is concluded that the margin of safety in 10- to 20-kg adult beagle dogs administered 104.05 [End-use Product: EffitixTM Topical Solution for DogsJ is at least 5x the recommended dose (2.0 mLldog).

This companion animal safety study in dogs is Acceptable/Guideline and does satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in adult dogs.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements
were provided for the study report (MRID 48467117). Signed and dated GLP and Data Confidentiality statements were provided for the companion animal safety summary (MRID 48467119); the GLP Compliance Statement consisted of a declaration that, as a compilation document, the volume "is not subject to the requirements of40 CFR Part 160."



### I. MATERIALS AND METHODS

A. MATERIALS:

1. Test material: Description: Batch #: Purity: Compound Stability:

CAS#:



### 2. Vehicle control: Description: Batch #: Purity:
Compound Stability:

CAS#: 

### I 04.05**[End~use** 

### Product: EffitixTM Topical Solution for Dogs] Clear, slightly yellow solution CGA**09007~1** 6.71 g/100 mL Fipronil and 50.26 g/100 mL Permcthrin
Re-Iest datc: September 2009; stored in original packaging, at ambient temperature (S 25" C), dry conditions. Not Provided



### 104.05 Placebo Liquid NDE 10132 0.02% (lv/v) Butylhydroxyanisole, 0.01 % (w/v) Butylhydroxytoluene, and Ethylene diethylene glycol (QSP 100 mL) Re-test date: Scptember 2009; slored in original packaging. at ambient temperature (:::: 25" C), dry conditions. Not Provided



### 6

### 3. Test animals: Spccies: Breed: Age/weight at study initiation: Source: Dog Beagle Approximately 9- I 0 months old! Males: 11.8-14.6 kg; Females: JO. 1-13.1 kg Harlan Laboratories UK Ltd. Housing: Diet: Individually, in partitioned kennels with underfloor heating (dimensions not providcd) 400-450 g ofTeklad 2021 Dog Maintenance Diet, moistened with an equal amount of water.

Water: Environmental conditions:

Acclimation period:



### B. STUDY DESIGN: Dogs were allowed acccss to the food for at lcast one hour. Ad /ibitllm water from thc public supply Temperaturc: Humidity: Air changcs: Photoperiod: Four weeks. 15-24° C. Generally 40-70%, with occasional excursions to (35-92%) Approximately 12lhour 12 homs lightfl2 hours dark



### 1. 

### In life dates: Start: July 2, 2009; 

### End: July 16,2009.

2. Animal assignment: Study design is given in Table 1. The animals were assigned to 

### groups according to body weight on day -23, using a stratified pseudo-random procedure, such that inclusion of litter-mates within the same group was avoided to the extent possible and the group mean body weights for each sex were approximately equal.

TABLE 1: Study design 

## "

Test Dosing volume (mUdog) Dose (mg/dog) Dosc (mg/kg) 0 Number assigned Group Fipronil Permethrin FiproniJ Permethrin Males Females
l. Control 10.0 mL 0 0 0 0 6 6 (2 applications of 5.0 mL of control item)
2.IX 2.0mL 134 1000 9.2-12.9 69.0-96.2 6 6 (I application of2.0 mL oftcst item)
3.SX 10.OmL 670 5000 46.2-64.4 342.5-495.0 6 6 (2 applications of 5.0 mL oftest itcm) 

## " Data takcn from pp. 14, 18, and 106-107 MRID 48467 I I 7. b Calculated by rcviewer, using day -I body weight ranges of JO.4- I4.5 kg and 10. I - 14.6 kg for the I X and 5X groups, respectively.


### 3. Dose selection rationale: According to the study report, a 2-mL dosing volume is the intended recommended therapeutic dose for this product for dogs that weigh 10-20 kg. Doses were selected to comply with OPPTS 870.7200. The exaggerated doses were achieved via two 5.0 mL applications (spaced approximately 4 hours apart) of the end-use product or the control item.

4. Treatment: The control or test material, as appropriate, was applied topically on day 0, using a syringe without a needle. The application site was from the dorsal cervical area at the base ofthe head"to the mid back. To achieve the exaggerated 5x doses, the control or test material was 7

### applied on two occasions with 4 hours between applications. There was no mention of parting the hair or making a particular effort to apply the materials directly to the skin.

5. Statistics: Body weight gain (days -1 to 7, days 7 to 14, and days -1 to 14), mean food consumption (over days 0-14), and hematology and clinical chemistry parameters were analyzed as follows. For clinical pathology data, if greater than 75% ofthe values were identical, Fisher's exact test was used. Otherwise, the data were first analyzed using Bartlett's test for homogeneity ofvariances. Data with homogenous variances were analyzed using the F I 

### approximate test, followed by Dmmett's test (if significant) or Williams' test (if not significant). Ifthe variances were nonhomogenous, logarithmic and square root transformations were done, and the transfonned data
were analyzed as above ifthe variances were stabilized; if not, the untransfonned data were analyzed using the non-parametric HI test, followed by Steel's test (if significant) or Shirley's test (if not significant). The individual animal was considered the basic experimental unit, and the data for each sex were analyzed separately. Differences from the control were considered significant at the 5.0% and 1.0% probability levels.

The reviewer, in general, considers the above-mentioned analyses to be appropriate; however, it would have been preferable for investigators to analyze the absolute body weight and daily food consumption data in addition to the body weight gains and cumulative food consumption.



# c. METHODS:

1. 

### Observations:

a. General health observations: During acclimation, the animals were observed at least once per day. From at least day -14 through the end of the study, the animals were visually inspected at least twice daily for abnonnal clinical signs, including the presence ofvomitus, blood, diarrhea, etc., in the pens. On day 0, detailed observations were made 11-33 minutes prior to each dose application, during and immediately after each dose application, and approximately hourly after the first dose application until 8 hours after the second dose application (for the control and 5X groups) or approximately hourly for 4 hours and at 7 and 12 hours after dosing (for the IX group). The post-dosing detailed observations included observation for any behavioral indications of irritation or other reaction to treatment, such as pawing or scratching at the application site. These included evaluation ofthe animals while the animals were standing or walking around in order to discern any ataxia, loss ofcoordination, or localized or generalized tremors.

b. Clinical assessments: All animals received detailed physical examinations on days -3,1,7, and 14. The examination included assessment of general appearance, color ofmucous membranes, behavior, appetite, stool characteristics, eyes, ears, and the respiratory, cardiovascular, gastrointestinal, musculoskeletal, neurological, and integumentary systems. Respiratory rate, heart rate, and temperature were recorded.

c. Application site observations: After treatment, the application site was observed daily for changes to the skin and fur. Any erythema/eschar and edema were scored according to the Draize scale, and the presence or absence ofchanges to the hair, such as matting (tangled mass of hair), greasy appearance, clumping (areas of compact clusters or lumps), spiking (hair coming together 

### 8

### in narrow, sharp points), discoloration, and deposits (areas oftest item visible on the surface),
were also recorded.

2. Body weight: The animals were weighed twice weekly during acclimation (except once weekly during week -3) and on days -1, 7, and 14.

3. Food consumption: Food consumption was measured and recorded daily.

4. Clinical pathology: On day -8, day 1 (approximately 22-24 hours after the first application), and day 7, blood for hematology, clinical chemistry, coagulation evaluation, and thyroid function evaluation was collected from thejugular vein or another suitable vein. On sampling days, food
was not offered to the.m1imals until after blood sampling was performed. The CHECKED (X) parameters were examined.

a. Hcmatology:

X Hematocrit (HCT)* X Leukocyte differential eount* (absolute and percentage) X Hemoglobin (HGB)* X Mean corpuscular HGB (MCH)* X Leukocyte count (WBC)* X Mean eorpuse. HGB conc.(MCI-IC)* X Erythrocyte count (RBC)* X Mean eorpuse. volume (MCY)* X Platelet count X RetiCUlocyte count Blood clotting measurements X Morphology (if indicaled) X (Thromboplastin time)* X Heinz body formation (Clolting time) X (Prothrombin time)*



### , * Recommended for compamon allimals safety evaluation based on or PTS 870.7200


### h. Clinical chemistry:

ELECTROLYTES OTHER X Calcium* X Albumin* X Chloride* X Creatinine* Magnesium X Urea nitrogen (BUN)* X Phosphorus* Cholesterol X Potassium* X Globulins* X Sodium* X Glucose* ENZYMES X Total bilirubin* X Alkaline phosphatase (ALK)* X Direct bilirubin* Cholinesterase (ChE) Indirect bilirubin Creatine phosphokinase X Total prolein (TP)* Lactic acid dehydrogenase (LOB) Triglyeerides X Alaltine aminotransferase (ALT/also SGPTY Serum protein electrophoresis X Aspartate aminotransferase (AST/also SGOT)* Albumin/globulin ratio Sorbitol dehydrogenase Gamma glutamyl transferase (GGT) Glutamate deltydrogenase 

### * Recommended for a compallion allimal safety evaluation based on OPPTS 870.7200.



### c. Thyroid function: Serum thyroxin (T4) and thyroid stimulating hormone (TSH) immunoassays
were done. The separated serum was stored at approximately _20 0 

### C until analysis. Where
9

### possible, the test samples were run in duplicate, and the calculated mean T4 and TSH concentrations were reported. For both parameters, any test results with duplicate results greater than ±20% from their mean result were reanalyzed, provided there was a sufficient volume of
serum remaining; ifreanalysis could not be accomplished due to insufficient sample remaining, then the initial mean result was reported "for information only." Due to sample volume limitations, some samples could only be analyzed for TSH as single measurements, and, in some ofthese instances, TSH analyses were run using a 1 in 2 dilution. The results from diluted samples were also reported "for infonnation only."

5. Urinalysis: Urinalysis is not required for companion animal safety studies and was not done as part ofthe current study.

6. Sacrifice 

### and pathology: There were no deaths or moribund sacrifices during the study. Tenninal sacrifices and gross necropsies were not done and are not required under OPPTS 870.7200.



### II. RESULTS

A. ACTUAL DOSES ADMINISTERED: The mg/kg doses ofthe active ingredients are given in Table 1.



### B. OBSERVATIONS:

1. 

### Clinical signs of toxicity: Selected clinical signs data are given in Table 2. The incidences of loose feces from 5X animals between 4 and 8 hours after the second dose are considered potentially treatment-related, although the observed incidences are fairly low. One 5X female (#362) had five occurrences ofloose feces in the post-dosing period (4, 5, 6, 7 and 8 hours after the second dose). The incidences ofvomiting from IX and 5X animals later in the course ofthe study (between days 4 and 13) are not considered treatment-related.

The most common observation from the physical exams was nervous behavior, which was noted in 1-5 animals per group, including controls, without evidence of a dose response pattern. Other observations mainly included cutaneous lesions, scabs, dennatitis, scars, scale on the teeth, and other observations that are common in laboratory beagles.

10TABLE 2: Vomiting and loose feces from ad u[t bcag[cs trcatcd with 104.5 or 104.05 Placebo 

# ,
Dosage Observation Control IX 5X

Loose fcces : Day 0, post-dosing 0 0 3 dogs b [7 incidencesl Days 1-14 [ dog [2 incidences] 4 dogs [5 incidencesl 2 dogs [3 incidences] Tota[ [ dog [2 incidencesl 4 dogs [5 incidencesl 4 dogs [[0 incidcncesl Vomiting: Day 0, [lOst-dosing 0 0 0 Days 1-14 0 2 dogs [3 incidenccsl 3 dogs [3 incidences] Tota[ 0 2 dogs [3 incidcnccsl 3 dogs [3 incidcnces]



## , Data compiled from Appendix 5, pp. 100- [02, MRID 484671 [7. b One female (#362) had five occurrenccs of[oosc fcces in lhc post-dosing period (4, 5, 6, 7 and 8 hours aftcr second dosc).


### 2. Quantitative physical signs parameters: There were no treatment-related effects On respiratory rate, pulse rate, or body temperature. Mean values ofthe treated males and females were generally similar to those oftheir respective controls, and the differences that were seen were present prior to treatment or did not follow a dose response pattern.

3. Local effects at the application site: Prior to the application ofthe second dose to One 5X female (#366), it was noted that the material from the first application had spread towards the lower back and extending down to the lower right hind leg.

There were no observations oferythema, edema, or matting. On day 0, all ofthe animals had a greasy appearance to the hair coat, and most also had deposits, while four controls, seven ]X animals, and nine 5X animals had spiking. Cosmetic effects with onset on day I included clumping on two controls and six 5X animals and the appearance of spiking on an additional 5X animal. Controls were free ofcosmetic effects by day 3, and the 3x and 5X animals were free of cosmetic effects by days 7-8.

3. Mortality: There were no deaths or moribund sacrifices.

C. 

### BODY WEIGHT AND WEIGHT GAIN: Body weight data are given in Table 3. There were no treatment-related effects on body weight or body weight gain.

II

# ,

b TABLE 3: Body weight and food consumption data from adult beagles treated with 104.5 or 104.05 Placebo 

## "

Parameter! Dosage Study day or interval Control 

# I IX 5X

Mllies Body weight (kg): DllY -7 13.5=0.68 13.5±0.78 13.5±1.03 Dlly -1 13.4±0.62 13.4±0.93 13.7±0.75 Dlly7 13.5±0.62 13.6±0.86 13.7±0.75 Day 14 13.5±0.70 13.6±0.92 13.9±0.67
BW change (kg): Days_7to_1° -0.1 -0.1 0.2 Days -1 to 7 0.03±0.163 0.18±0.172 0.03=0.103 Days 7 to 14 0.05±0.187 -0.03±0.151 0.18=0.098 Day -1 to 14 0.08±0.248 0.15±0.084 0.22±0.147 Mean overall food consumption 448±2.7 424±41.2 435±37.0 (days 0-14) in glanimal/day
Females Body Weight (kg): Day-7 10.9=1.16 10.8±0.57 1O.5±0.90 Day -1 11.1=1.10 10.9±0.49 10.9±0.75 Day 7 11.2±1.I4 11.0±0.42 11.0±0.74 Day 14 11.4±1.21 11.1±0.50 II.2±O.76
BW change (kg): Days_7to_I o 0.2 0.1 0.4 Days-Ito7 0.05±0.055 0.15±0.207 0.12±0.160 Days 7 to 14 0.20±0.200 0.07±0.121 0.23±0.151 Day-1to14 0.25±0.217 0.22±0.214 0.35±0.152 Mean overall food consumption 408±39.1 417±36.8 419=26.8 (days 0-14) in glanimallday



### - Data taken from rabies 2 and 3, pp. 43-44 and 4)-50, respectively, MRID 48467117. Values are Mean ± Standard Devllltlon, with 11"'"6 for all groups. Calculated by reviewer using group mean absolute body weight values.



### D. FOOD CONSUMPTION: Mean overall food consumption over the study interval (days 0-14) is given in Table 3. The mean overall food consumption and daily food consumption values ofthe treated males and females were similar to their respective controls.



### E. BLOOD ANALYSES:

1. Hematology and coagulation parameters: Statistically significant differences were found for
some hematology parameters at one or more time points, including decreased mean monocyte counts in 5X males on days 1 and 7 and increased mean neutrophil counts in 5X females on day 7. However, none ofthe statistical findings were considered biologically significant or treatmentrelated because the differences were small in magnitude, with the mean values falling within two standard deviations ofthe control mean and within the background ranges ofthe testing laboratory (data not provided in the study report), The coagulation parameter values ofthe treated males and females were similar to those oftheir respective controls.

2. Clinical chemistry: Statistically significant differences were found for some parameters, but all differences were present without a dose-related trend or were of small magnitude with the mean
12

### values falling within two standard deviations ofthe control mean and/or within the background ranges ofthe testing laboratory (data not provided in the study report); thus none were considered biologically significant.

3. Thyroid function evaluation: The results ofthe thyroxin (T4) 

### and thyroid stimulating hormone (TSH) assays are given in Table 4. Six individual TSH results (from five females and one male)
were reported "for information only" because they were analyzed as a single measurement following dilution or because there was insufficient sample volume to repeat an analysis when the results from the duplicate samples were greater than 20% from their mean. However, these "for infonnation only" results were included in calculation of group mean values. No clear treatmentrelated effects were evident; however, it must be noted that, for both parameters, the data were quite variable, with most ofthe coefficients of variation for T4 >21 % and all ofthe available coefficients of variation for TSH 2: 

### 66%. Some ofthe individual results appeared abnormal: one control male had low T4 concentration on days I and 7 (9.41 and 9.25 nmoVL, respectively), without any concomitant alteration in TSH; one control male had elevated TSH concentration at all time points (0.600-0.699 ng/mL), without any concomitant alteration in T4; 

### and T4 was greater than 37 nmollL in several animals from the control and 5X groups (three control males and one control female on day I, 

### one 5X male on days -8, I, 

### and 7, one 5X male and two 5X females on day I, 

### only, and one 5X female on day 7, only).



## ,

b



## , d TABLE 4: Mean thyroxin (T4) and thyroid stimulating hormone (TSH) concentrations in adult beagles treated with 104.5 or 104,05 Placebo 

# ,
Dosage Parameter I Study day Control IX 5X

Males T4 (nmol/L): Day -8 32.6±7.0 22.8±5.6 29.0±10.0 Day 1 35.0±7.S 21.3±7.7 31.8±10.1 Day 7 27.5±4.1 17.8±5.2 31.2±10.0 TSH (ng/mL): Day-8 0.250±0.259 0.200:;;0.132 0.182±0.139 Day 1 In=6,4,and61 0.222±0.228 BLQ b «0.140) BLQ«0.140) Day 7 0.181±0.271 BLQ «0.140) c BLQ«0.140)
Females
T4 (nmollL): Day -8 23.4±9.1 23.7:!:6.3 24.9±7.7 Day 1 27.6±S.3 23.4±5.7 29.4±12.1 Day 7 26.7±S.1 25.0±4.3 28.5±6.5 TSH (ng/mL): Day-8 BLQ «0.140) 0.145±0.125 BLQ «0.140) Day 1 0.140±0.118 c BLQ «0.140) c BLQ «0.140) Day 7 BLQ «0.140) BLQ «0.140) d BLQ «0.140) c



### - Dala laken from pp. bS aud 162. MRlD 48467117. Values ore Mean ± Standard DevlallOn, with n=6 for all groups, except os indicated. BLQ = below the limit of quantification. Mean includes one value that was reported "for infOlmation only." Mean includes two values that were reporled "for information only."



### 13

### III.DISCUSSION and CONCLUSIONS

A. INVESTIGATORS' CONCLUSIONS: The study author concluded that topical application of the test substance, 104.05, at 5X the intended dosing volume resulted in an increased incidence of loose feces on the day of dosing, but that this dose level was otherwise well tolerated.

B. REVIEWER COMMENTS: The reviewer is in agreement with the study author. While 

### treatment-related, in the absence ofcorrelated effects on any ofthe other evaluated endpoints, the increased incidence of loose feces within 4-8 hours of dosing is not considered adverse.

It 

### is concluded that the margin of safety in 10- to 20-kg adult beagle dogs administered 104.05 [End-use Product: EffitixTM 

### Topical Solution for 

### Dogs1 is at least 5x the recommended dose (2.0 mL/dog).

C. STUDY DEFICIENCIES: No major deficiencies were identified.



### 14

### DATA EVALUATION RECORD

PERMETHRIN; FIPRONIL [EFFITIXTM TOPICAL SOLUTION FOR DOGS / 104.05]

STUDY TYPE: COMPANION ANIMAL SAFETY STUDY- PUPPIES; OPPTS 870.7200 MRID 48467118

Primary Reviewer: Donna 

### L. Fefee. D.V.M. 

### Secondary Reviewers: Prepared for Registration Division 

### Office of Pesticide Programs U.S. Environmental Protection Agency One Potomac Yard 2777 South Crystal Drive



### Arlington, VA 22202
Prepared by Sunullitec Corporation 

### 9724 Kingston Pike, Suite 602

Knoxville, Tennessee 37922

Task Order No. 3-C-03



### Signature: Date: 

### VirginiaA. Dobozv. V.M.D

.. M.P.H. Signature: Date:

Robert 

### H. Ross. Program Manager Signature: Date: 

### Quality Assurance: Angela M. Edmonds. B.S. Signature: 

### Date:

Disclaimer \/;

# Y-~ 

# Pt- DQb0t14-1 SEP I 42Qn

This review may have been altered subsequent to the contractor's signatures above.

### EPA Reviewer: Byron T. Backus, Ph.D. Technical Review Branch, Registration Division (750SP)

EPA Secondary Reviewer: Kit Farwell, D.V.M., D.A.B.T. Risk Assessment Branch VII, Hcalth Effects Division (7S09P) Signature: Date: Signature: Date:



## I DATA EVALUATION RECORD 

## I 

# (\ ----r: (j.........t-.. 

# !;J 1.-

# 71 "LoC\

# I~Z'1io({ Template vel'Sion 02/06



### STUDY TYPE: Companion Animal Safety Study

- Puppies; OPPTS 870.7200

PC CODES: 109701,129121 DP BARCODE: 390818

TEST MATERIAL (PURITY): 104.05 (6.62 gil 00 mL Fipronil and 50.3 gllOO mL Permethrin; Batch #NDE 10189)

SYNONYMS: EffitixTM Topical Solution for Dogs

CITATIONS: Gupta, S. (2011) A 14-day tolerance study in beagle pups when administered 104.05 (6.7% Fipronil and 50% Pennethrin topical solution) topically at IX, 3X and 5X the recommended dose. Charles River Laboratories Preclinical Services Ireland Ltd., Carrentrila, Ballina, Co. Mayo, Ireland. Study Number F004\!O-003, April 6, 201 I. 

### MRID 48467118. Unpublished.

SPONSOR: Virbac S.A.,**Pre~clinical** 

### and Clinical Unit (VB7), 13 eme 

### Rue Lid**~** 

### B.P. 27, 06511 Carros Cedex, France.

EXECUTIVE SUMMARY: In a 14-day companion animal safety study (MRID 48467118),104.05 [6.71 gllOO mL Fipronil and 50.26 glIOO mL Permethrin; Batch No. CGA 09007-1 (T3MOIS 5' C)l
was applied topically to the skin on the dorsal midline from the base ofthe head to the rump area (this is inconsistent with the proposed label which states the entire applicator contents should be squeezed onto the dog's skin at a single site for small dogs and puppies 8 weeks or older weighing up to 22.9 lbs). Groups of six male and six female 

### SO-57 day old (approximately**8-week~0Id,** 

### weighing from 1.5 to 3.4 kg) beagle puppies were treated at IX (1.0 mUpuppy), 3X (3.0 mLipuppy), or 5X (5.0 mUpuppy) the total recommended dosing volume for the end use product in puppies weighing less 10 pounds. "104.05 Placebo" was applied in identical manner to a control group of6 male and 6 female animals at a dosing volume of 

### S.O mL/puppy. The IX and 3X puppies were treated once; the 5X and placebo puppies received two divided doses of 

### 2.S mL approximately 4 hours apart. Animals were treated on day 0 and observed for 14 days.

Effects were seen that were dose-related. At the 5X dose level there were increased incidences of vomiting and abnormal feces, i.e. feces that were liquid, loose, mucoid, with traces ofblood, and/or discolored (seen in 

### 4-S SX animals vs. 0 controls). The SX animals ofboth sexes had decreased weight gain during days -1 to 7 (51 

### % and 

### S5% less than controls for males and females, respectively). During days l-S 

### ofthe study, the daily food consumption ofthe 5X animals was 32-50% less than that of controls (p<0.0 1), and there were 26 occasions (involving nine SX puppies) in the period from Day 1 to 9 when a SX puppy consumed less than 100 g of food in a single day (this occurred only twice in

16

### the IX group and once in the 3X group during this period). Two 5X animals also exhibited abnoffilal neurological signs, considered treatment-related. These included salivation, ataxia, inability to walk properly, trismus (inability to properly open the mouth), walking in a circle to the right, resting head against the wall, generalized tremors, one episode of seizures (clonic convulsions), "dullness," and regular retropulsion ofthe neck in one animal and salivation, ataxia, unsteadiness on hind limbs and gait incoordination due to weakness, and slight generalized tremors in the other animal. There were no apparent treatment-related effects on clinical chemistry parameters or serum thyroxin and thyroid stimulating hormone concentrations.

In this study, one animal tested positive for coccidia while abnormal feces consistent with coccidia (i.e. mucoid or loose with mucus and/or frank blood) were seen in what appeared to be a dose-related
manner. One animal that died during the week prior to treatment had pneumonia. Baseline blood work revealed that 1-2 animals per group had normocytic nonnochromic or microcytic hypochromic anemia on day -7, and one animal had leukopenia. Elevated WBC and neutrophils on day 7 in two 5X animals (#36094 and #87310) suggest the possibility that their serious abnormal clinical signs may have been at least partly due to infection. As a result, alterations in the hematology parameters are uninterpretable because of the possible compromised health status ofthe animals as an additional contributing factor.

This companion animal safety study in 8 week old puppies does not demonstrate an adequate margin of safety. In particular, some of the effects observed in 3 ofthe 5X animals were severe and required veterinary intervention (these 5X puppies received IV saline treatments as well as other treatments and
one of these was also treated with oxygen by face mask for 30 minutes on Study Day 4). This study in puppies is classified as Unacceptable/Guideline. It 

### does not satisfy the guideline requirement for
a companion animal safety study (OPPTS 870.7200) in juvenile dogs. It should be noted that an earlier limit test in 8 week old puppies (MRID 48487302) preceded this full study, and one 5X female
was sacrificed (for humane reasons) on Day 4 after showing neurological symptoms.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements
were provided for the study report (MRID 48467118). Signed and dated GLP and Data Confidentiality statements were provided for the companion animal safety summary (MRID 48467119); the GLP Compliance Statement consisted of a declaration that, as a compilation document, the volume "is not subject to the requirements of40 CFR Part 160."

17

### I. MATERIALS AND METHODS

A. MATERIALS:

1. 

### Test material: Description: Batch #: Purity: Compound Stability:

CAS#:



### 2. Vehicle control: Description: Batch #: Purity:

COmlJOund Stability:

CA5#: 

### 104.05 

### [EndMuse Product: EffitixTM Topical Solution for Dogs] Liquid
NDE 10189 6.62 gllOO mL Fipronil and 50.3 grlOO mL Pennelhrin EXpiration date: July 2011; stable under the storage conditions llsed in tIle study (in original packaging, at 18·22° C.) Not Provided



### 104.05 Placebo Liquid
NDE 10190 0.02% (w/v) Butylhydroxyaniso1e, 0.01% (w/v) ButylhydroxytolJlcnc, and EI1Jylcnc diethylene glycol (QSP 100 mL) Expiration date: .luly 2011; stable nnder the storage conditions llsed in the study (in original packaging, at 18_22° C.) Not Provided



### 3. Positive control: No positive control was used.

4. 

### Test animals: Speeics:
Breed: Age!weight at study initiation: Source: Housing:

Dict:

Water: Environmental conditions:

Acclimation period:



### B. STUDY DESIGN: Dog Beagle 50-57 days old! Males: 1.5-3.4 kg (on day -1); Females: 1.5-2,7 kg (on day -1) Charles River Laboratories Preclinical Services Ireland Ltd., Glenamoy, Co. Mayo, Ireland
Prior to weaning (day -7): puppies were housed with dams in two adjoining pens (each 1.7 m
x 1.4 m) with the dividiug gate opened, except during daily 2- to 3-hour intervals, during Wllic11 tIle dam was separated from the puppies to prepare them for weaning; Days -7 tIl rough -3: puppies were lJOused in groups oftwo or three; Days -2 through 14: puppies were housed individually in pens measuring 1.7 In x 1.4 m, lufrared lamps were provided wIlen deemed necessary. Pedigree pup food (Pedigree Masterfoods, Meltoll Mowbray, Leieester, U.K.), approximately 400 glpup!day Supplemental food (e.g. Welpi® milk replacer) was offered to pups when deemed necessary. Ad libitum potable water via automatic drinkers or stainless steel bowls Temperature: Humidity: Air changes: Photoperiod: Fourteen days. 16_19° C. 40-79% Not reported Not reported



### 1. 

### In life dates: Start: September 7, 2010; End: November 16,2010.

18

### 2. Animal assignment: Study design is given in Table 1. The study was conducted in five replicates, as pups ofthe appropriate age became available. Between days -3 and 0, the animals from each replicate were assigned to groups according to body weight, using a stratified randomized block design. All pups meeting the inclusion criteria were ranked within sex in order of decreasing body weight, with any same-sex pups of identical body weight ranked in order of decreasing microchip number. To the extent possible, blocks offour same-sex pups were formed and then randomly allocated to study groups using random order numbers derived from Fisher and Yates tables. When necessary, an incomplete block would be completed using pups from the subsequent set. Table 2 lists the number ofpups in each set that were assigned to each group. The study was not bl inded.

TABLE I: Study design 

## ,

Dose (mg/puppy) b Number Test Dosing volumc (mLfpuppy) Dose (mg/kg) assigned Group Fipronil Pcrmethrin Fipronil Pcrmcthrin Males Females
1. 5 mL 0 0 0 0 6 6 Cont (2 applications of2.5 mL ofvchicle col control) 2. IX I mL 66.2 503 24.5- 186.3- 6 6 (I application of 1.0 mL oftest item) 44.1 335.3 3.3X 3 mL 198.6 1509 70.9- 538.9- 6 6 (I application of3.0 mL oftcst itcm) 104.5 794.2 4.SX 5 mL 331.0 2515 97.4- 739.7- 6 6 (2 applications of2.5 mL oftest item) 18B 1397 

## " Data taken from pp. 24 and 50. MRJD 48467118. b Calculated by reviewer, using day -I body weight ranges of 1.5-2.7 kg, 1.9-2.8 kg, and \.8-3.4 kg for the IX, 3X, and 5X groups, respectively.

TABLE 2: Study dcsign 

# ,

Sets Test Group I 2 3 I. Control I M,I 

### r 2 M,2 

### r If
2. IX I M,2F 2M,2F 

### .. 3.3X I M, I F I M,2F I M,2 F 4.5X I M,2F I M,2 F I M, I F



# , Data compilcd by reviewcr using Table I, p. 49, MRID 48467118. M == male; F == female. 4 5 2M,2 

### r 1M 2M,2F 1M 2M, I F 1M
I M, I F 2M



### 3. Dose selection rationale: According 10 

### the study report, a l-mL dosing volwne is the normal recommended dose for this product for dogs, and presumably for puppies, weighing less than 10 kg. The doses used in the study were selected 10 

### conform with OPPTS 870.7200, i.e. IX, 3X, and 5X the recommended dose, and the 5X dose was achieved with two 2.5 mL applications ofthe end-use product, with the applications approximately 4 hours apart. The vehicle control substance
was also administered at 5 times the normal recommended dosing volume ofthe product (two 2.5 mL applications which were approximately 4 hours apart).

19

### . It should be noted that an earlier limit test in puppies (MRID 48487302) preceded this full study.



### 4. Treatment: The control or test material, as appropriate, was applied topically on day 0, using a syringe without a needle. For each application, the tip ofthe syringe was positioned on the dorsal cervical area at the base ofthe pup's head and used to separate the pup's hair so the material could be applied at the skin level, and the contents ofthe syringe were then applied, as evenly as possible, from the base of the head to the rump area. Following application, the pup was restrained in an upright position for at least two minutes to prevent run-off ofthe test or control substance. Syringe volumes were visually confirmed immediately prior to administration, and each syringe was checked after administration to ensure that none of the contents remained. To achieve the exaggerated 5x doses, the control or test material was applied on two occasions with 4 hours (± 10 minutes) between the two applications. There was no evidence of run-off


### 5. Statistics:
Descriptive statistics were generated for all endpoints (separately by sex and combined) at each time point.
Body weight and food consumption, hematology and clinical chemistry parameters, thyroxin and thyroid stimulating honnone values, were analyzed using repeated measures analysis of covmiance (RMANCOYA) including treatment, sampling day, sex, and the interaction tenns "treatment by sampling day (group*day)," "treatment by sex" (group*sex), "sex by sampling day" (sex*day), and "treatment by sex by sampling day" (group*sex*day) as fixed effects. The set (replicate) was also included in the model as a fixed factor but was only retained if significant (p<0.05). The individual animal was identified as the subject in the repeated statement. The covariate was the pretreatment baseline measurement or the average ofthe three pretreatment baseline measurements in the case ofbody weight.

For each analysis, the appropriate variance-covariance matrix structure was selected from among compoW1d symmetry, heterogeneous compound symmetry, first-order autoregressive, and heterogeneous first-order autoregressive, based on the Akaike Infonnation Criterion.

Ifthe group*sex*day interaction was significant (p<0.05), then the statistical analysis was considered inconclusive. Ifthe group*sex*day interaction was not significant, the interactions of group*sex and group*day were evaluated. If group*sex was significant at p<0.05 but group*day
was not significant (p>0. 10), then the statistical analysis was considered inconclusive. 

### If group*day was significant at p<O.1 0, pair-wise comparisons ofeach treated group least squares mean was performed against the control group least squares mean at each sampling day, using a two-sided Student's t-test.

"When the group*sex, group*day, and group*sex*day interactions were not significant, the "treatment" main effect was evaluated at p<O.1 O. If significant, pair-wise comparisons ofeach treated group least squares mean was perfonned against the control group least squares mean, using a two-sided Student's t-test. Ifnot significant, no further analyses were conducted on the variable. 20

### Profile plots were provided for all continuous variables and included baselines (or arithmetic
means ofpre-study data) and all data collected from day 1 through the end ofthe study. For each endpoint, the individual data were presented separately for each treatment group (with the sexes combined), and group mean values (for the sexes combined) were presented together, on a single plot.

Potential outliers were verified with the study director, and no outliers were excluded. The following defaults were used for the analyses: hemoglobin values recorded as "<6" were defaulted to 6; creatinine values recorded as "<18" were defaulted to 18; total and direct bilirubin values recorded as "<1. 

### 7" were defaulted to 1.7; thyroid stimulating honnone values recorded as "<0.14"
were defaulted to 0.14; and thyroxin values recorded as "<6.1" were defaulted to 6.1.

The clinical signs data were not subjected to statistical analysis. No animals died or were sacrificed during the study; therefore, planned statistical analysis of death or sacrifice via logistic regression was not necessary.
C. 

### METHODS:

1. Observations:

a. General health observations: Beginning on day -14 and continuing through day -1, general health observations were recorded once daily. No further details were provided conceming the evaluated parameters or whether the evaluations were cage-side or hands-oll.



### b. Clinical assessments: All pups were examined by a veterinarian on days -14 and -1, and pups belonging to sets 3 and 4 were given an additional examination on day -6 or day -12, respectively. On day 0, a veterinarian conducted clinical assessments on all animals prior to the first treatment and at 1 hour (±5 minutes), 2, 3,4, and 5 hours (±IO minutes), and 6, 7, and 8 hours (±30 minutes) after the final treatment. For the control and 5X animals, clinical assessments were also performed at 1 hour (±5 minutes), and 2, 3, and 4 hours (±IO minutes) after the first treatment. During the remainder ofthe study interval (days 1-14), clinical assessments were performed by a veterinarian twice daily, once in the moming and once in the afternoon, with at least four hours between assessments. Clinical assessments consisted of observing each animal for at least one minute and recording the presence or absence ofthe following: lethargy, ataxia, recumbency, paralysis, coma, pruritis, hyperactivity, tremors, convulsions, abnormal mydriasis, abnonnal miosis, comeal opacity, dyspnea, tachypnea, coughing, abnormal salivation, vomiting, abnol111al
mucous membranes, ocular discharge, nasal discharge, cardiovascular changes, abnormal feces, abnormal urine, abnormal coat condition, and abnormalities ofthe application site. For any fmding that was present, a brief comment further describing the condition was made at the first point of detection.

2. Bodv weight: The animals were weighed on days -14, -7, -1, 7, and 14.

3. Food consumption: From day -2 through day 13, each puppy was offered a pre-weighed, approximately 400-g quantity of food, and, on the following day, unconsmned food was removed from the pen and weighed.

21

### 4. Clinical Pathology: Each animal had blood collected for hematology, clinical chemistry, and thyroid function evaluation on day -7, day 1 (24 hours ± 

### 2 hours after the first application), and day 7. Blood was collected for thyroid function evaluation on day 14, and ifan animal had any hematology or clinical chemistry parameters outside the reference range on study day 7, an additional sample was collected from that animal on day 14 for re-evaluation ofthe particular parameter(s). On days -7, 1,7, 

### and 14, food was not offered to the animals until after blood sampling was perfonned, but there was no mention of withholding food and/or water for a specific duration oftime prior to collection, and the venipuncture site also was not reported. The CHECKED (X) parameters were examined. Coagulation was not evaluated as part of the current study, but these data are available in a previously conducted companion animal safety study in puppies (MRID 48487302).

a. Hematology:

X Hematocrit (HCT)* X Leukocyte differential eount* (absolute) X Hemoglobin**(HGB)~** X Mcan corpuscular HGB (MCH)* X Leukocyte coun! (WBC)* X Mean corpusc, HGB conc,(MCHC)* X Erythrocytc count (RBC)* X Mcan corpusc. volume (MCY)* X Platelet count Reliculocyte count Blood clotting mcasurcments Morphology (if indicated) (Thromboplaslin limc? X Heinz body formation (Clolling lime) (Prothrombin time)*



### . * Recommended for compamon ammals safcty evalual!On based on OPPl S 870.7200


### b. Clinical Chemistry:

ELECTROLYTES OTHER X Calcium* X Albumin* X Chloride* X Creatinine* Magnesium X Urea nitrogen (BUN)* X Phosphorus* Cholesterol X Potassium* X Globulins* X Sodium* X Glucose* ENZYMES X Total bilirubin* X Alkaline phosphatase (ALK)* X Direct bilirubin* Cholinesterase (ChE) Indireel bilirubin Creatine phosphokinase X Toml protein (TP)* Lactic acid dchydrogenase (LDH) Triglyeerides X Alanine aminotransferase (ALT/also SGPT)* Serum protein electrophoresis X Aspartate aminotransferase (AST/also SGOT)* Albumin/globulin ratio Sorbitol dehydrogenase Gamma glutamyltransferase (GGT) Glutamate dehydrogenase * Recommended for a compamon ammal safety evalual!on baserl on OPPTS 870.7200.



### c. Thvroid Function: Serum thyroxin and thyroid stimulating hormone assays were done using canine-specific radioactive immunoassays (Siemens), with the results counted using a gamma counter. The separated serum was stored at between _15 0 

### C and _30 0 

### C until shipment on dry ice
22to the analyzing laboratory (Charles River Laboratories, Central Laboratory Services, Edinburgh, U.K.).

5. Urinalysis: Urinalysis is not required for companion animal safety studies and was not done as part ofthe current study.

6. Sacrifice and Pathology: There were no deaths or moribund sacrifices during the study. Terminal sacrifices and gross necropsies were not done and are not required W1der OPPTS 

### 870.7200.



### II. RESULTS

A. ACTUAL DOSES ADMINISTERED: The mglkg doses ofthe active ingredients are given in Table 1.



### B. OBSERVATIONS:

1. Clinical signs oftoxicitv: Selected clinical signs data are given in Table 3. There were treatmentrelated increased incidences of vomiting and abnormal stools in 5X puppies, with a total of seven 5X puppies affected. One ofthe puppies (#36094) that exhibited both vomiting and diarrhea became dehydrated and had slightly pale mucous membranes. A fecal from this puppy was positive for coccidia, but, while other treatments were given [intravenous normal saline and amoxicillinipotassium clavulanate (3 days)] the animal was not treated for coccidia.

Two puppies exhibited neurological signs. The first ofthese (#40074) had onset of signs on day 2 and exhibited such neurological signs as salivation, ataxia, inability to walk properly, trismus, walking in a circle to the right, resting its head against the wall, generalized tremors, one episode of seizures (clonic convulsions), "dullness," and regular retropulsion ofthe neck, along with respiratory signs (dyspnea, increased respiratory sounds, rate, and intensity, green nasal discharge, froth from the mouth, and fluid sounds in the lungs and nose), vomit, slightly loose feces with traces of fresh blood, and lethargy. This puppy was treated with Buscopan compositum®, intravenous normal saline, Rimadyl injection, amoxicillinipotassium clavulanate (5 days), glucose 

### (5%w/v, Lv.), oxygen via mask administration, and intramuscular dexamethasone (given on day 3) and recovered by day 7. The second of these (#87310) had decreased appetite and had a thin appearance beginning on day 5, followed by moderate salivation, ataxia, unsteadiness on hind limbs and gait incoordination due to weakness, slight generalized tremors, preference for ventral recumbency when made to stand up, slightly pale mucous membranes with normal capillary refill time, and vomiting. This puppy was treated with intravenous normal saline, Rimadyl injection, amoxicillinipotassium clavulanate (5 days), glucose (5% 

### wlv, Lv.), and intramuscular dexamethasone (given on day 8) and recovered by day 10.

An additional 5X puppy (#34880) was observed to be "dull" on day 3, without any other abnormal clinical signs noted at any time point during the study.

23TABLE 3: Vomiting and abnormal feces from puppies treated with 104.5 or 104.05 Placebo 

# ,
Dosage Observation Control IX 3X 5X

Abnormlll feees ": Incidence 0 I I 15 # Affeeted pups 0 I I 5 First / last days Nol applicable Day 5 Day 0 (before 1st treatment) Day 0 (before 2nd treatment) noted I Day 6 Vomiting: Incidenee 0 0 0 7 # Affeeted 0 0 0 4 Days noted Nol applicabk Nol applicable Not applicable Day 0 (before 2nd treatment) I day 2



## , Data compiled from Table 4, p. 52, MRID 48467118. b Includes feces that were liquid, loose, mucoid, with traces ofblood, and/or discolored (green or yellow).

2. Cosmetic effects: On day 0, clumping and a greasy appearance of the hair coat were observed on all animals beginning within one hour of the first application, and other changes such as matting, spiking, and deposits were noted on**1~3** animals in the control, 3X, and SX groups, with a later onset,**3~S** hours after the initial treatment. On day 1, additional deposits were noted on 1-2 animals from each ofthe control, IX, and 3X groups, although the cosmetic effects had already fully resolved in some of the animals in these sanle groups. All control, IX, 3X, and SX animals
were free of cosmetic effects by day 2, 4, 3, or 4, respectively.

3. Mortality: There were no deaths or rnoribWld sacrifices during the study.



### C. BODY WEIGHT AND WEIGHT GAIN: Selected body weight data are given in Table 4. Statistical analysis ofthe absolute body weights indicated that there were no significant group*sex*day or group*day interactions. There were significant (p<O.OS) group*sex and sex*day interactions, and the group main effect was significant (p<O.OO 1). The results of the statistical analysis of body weight were considered (by the study statistician) inconclusive. Comparison ofthe mean absolute body weights ofthe treated male and females to those of controls at each time point did not reveal any**dose~** or treatment-related differences, but the SX animals of both sexes had treatment-related decreases in body weight gain relative to their respective controls during days -1 to 7. Differences in body weight gain during days -7 to -1, were not treatment-related and are likely due to individual difftculties with weaning.



### D. FOOD CONSUMPTION: Selected food consumption data are given in Table S. Three to seven puppies per group consumed the entire ration on most of the days ofthe study. The SX animals had biologically and statistically significantly lower mean food consumption than controls on days I-S, and nine ofthe puppies in this group consumed less than 100 grams of food on at least one day during the period from Day 1 to Day 9 (Table 6). This drop in food consumption correlates with the decreased body weight gain by the animals in this group during days -1 to 7.

24

# , b



# , TABLE 4: Body weight data from puppies treated with 104.5 or 104.05 Placebo (kg) a Parameter! Dosage Study day or interval Control 

# I IX 

# I 3X 

# I 5X

Males Absolute body weight: Day -14 1.63±0.47 1.47±0.30 1.58±0.40 1.87±0.50 Day-7 2.00±0.53 1.85±0.30 2.00±0J8 2.23±0.42 Day-l 2.1O±0.45 2. I7±0.4 I 2J3±OJ3 2.50±0.51 Day7 2A5±0.46 2.55±0.51 2.72±OJ8 2.67±0.72 Day 14 2.67±0.47 2.75±0.53 2.93±OJ5 2.83±0.61 Body weight gain 

# , Days -14 to-7 0.37 0038 0.42 0.36 Days -7 to-l 0.10 0.32 0033 0.27 Days -1 to 7 0035 0.38 0.39 0.17 (-51) c Days 7 to 14 0.22 0.20 0.21 0.16
Femalcs Absolute body weight: Day-14 1.65±O.14 L57±OJ3 1.70±0.13 1.47±0.24 Day -7 2.02±0.17 1.82±OJ4 2.08±0.19 1.78±0.13 Day -1 2.33±O.29 2,02±OJ8 2.37±0.25 1.97±0.12 Day7 2.73:=0.33 2J3±0.41 2.73±0.33 2.15±0.29 Day 14 2.98±0.40 2.63±0.44 2.98±OJ7 2A8±0.27 Body weight gain u: Days -14 to-7 0.37 0.25 0.38 0031 Days-7to-l 0.31 0.20 0.29 0.19 Days -1 to 7 OAO 0031 0036 0.18 (-55) Days7to14 0.25 0.30 0.25 0.33
Data derived from Table 73, p. 189, MRlD 48467118. Values are Mean ± Standard Deviation, with n=6 for all groups. Calculated by reviewer, using group mean values; not analyzed statistically. Numbers in parentheses equal percent different from control; calculated by reviewer.



### 25b TABLE 5: Selected food consumption data (g/day, with sexes combined) from puppies treated with 104.5 or 104.05 Placebo a
Dosage Study day Control IX 3X 5X**Day~I** 354±68 341±89 386±39 321±78 DayO 329±73 326±88 374±51 296±IOO Day I 336±87 280± 1\9 344±72 209±132 u**(~38%)** 0 Day 2 325±68 309±106 343±99 163±147 

###  (~50%)**  Day 3 328±96 309±118 360±69 182±145 u (-45%) Day4 333±94 327:::95 361±67 226±130 

### ****(~32%)** DayS 353±95 361±59 378:!:38 235±145 u**(~33%)** Day6 341±97 338±101 383-'-47 270±146**(~21%)** Day7 366±72 338±76 401±1 316±132**(~14%)** Day8 359:!:73 347±81 397±1l 298±\38**(~17%)** Day9 374±42 359±61 389:!:30 331±115**(~12%)** Day 10 371±53 359±59 390±27 375±63 Day 11 376±39 358±59 401±J 363±73

Data derived from Tables 75, 76, and 79, pp. 191, 192, and**194~196,** MRID 48467118. Values are Mean ± Standard Deviation, with n"'12 for all groups. Numbers in parentheses equal percent different from control; calculated by reviewer. Statistically different (p<O.05) from the control. ** Statistically different (p<O.O I) from the control.

TABLE 6: Number of puppies in each group (sexes combined) consuming less than 100 g of food on that given day

### , Dosage Study day Control IX 3X 5X
Day ·1 0 0 0 0 DayO 0 0 0 0 Day I 0 I 0 2 Day2 0 0 I 7 Day 3 0 I 0 6 Day4 0 0 0 I Day 5 0 0 0 3 Day 6 0 0 0 3 Day 7 0 0 0 I Day8 0 0 0 2 Day9 0 0 0 I Day 10 0 0 0 0 Day II 0 0 0 0



# , Data denved from Table 6 p. 560fMRlD 48467118, With n-12 for all groups.



### 26

### E. BLOOD ANALYSES:

1. Hematology: About two animals per group had nonnocytic normochromic or microcytic hypochromic anemia on day -7. There were no treatment-related effects on erythrocyte parameters, including Heinz body formation. A reported decrease in mean 

### MeV in 5X animals on day 7 relative to controls was not significant at p<O.05 and was of insufficient magnitude to be considered biologically significant.

A statistically significant increase in the mean leukocyte count ofthe 5X animals on day 7 was primarily due to two individual values (from puppies #36094 and #87310) outside the reference ranges. The affected animals were among those that exhibited abnormal clinical signs, suggesting that the abnonnal observations in these particular animals may have been at least prutly due to infection. A statistically significant increase in the mean monocyte count ofthe 5X animals on day 7 was primarily due to one individual value (from #40074) outside the reference range. The affected animal was treated with dexamethazone on day 3, and the monocytosis may have been the result ofthat treatment. Statistically significant group*sex*day, group*sex, and/or group*day interactions or group main effects with significru1t differences at individual time points were noted for some parameters. Comparison ofthe mean values ofthe treated groups to those ofcontrols at each time point did not reveal any biologically or statistically significant differences, or where a statistically significant difference was found it was not considered treatment-related due to the absence of a dose response. A reported increase in mean basophil count in 5X animals on day 7 relative to controls was not significant at p<0.05 and was of insufficient magnitude to be considered biologically significant.

2. Clinical Chemistry: A statistically significant increase in the mean potassium concentration of the 5X group relative on day 7 (5.32±0.53 mmollL vs. 4.72±0.37 mmollL for controls; p<O.OI)
was considered potentially treatment-related but non-adverse, as the group mean and all but one individual value fell within the provided reference range.
There were statistically significant group*sex*day, group*sex, and/or group*day interactions, or group main effects for some parameters, including urea, creatinine, and inorganic phosphate concentrations, but comparison of the mean values ofthe treated groups to those ofcontrols at each time point did not reveal any biologically or statistically significant differences. Mean sodium concentration was reported as decreased in 5X animals on day 1 and increased in 5X animals on day 7, but these differences were significant at p<O.IO.

3. Thyroid function evaluation: Selected results ofthe thyroxin (T4) and thyroid stimulating honnone (TSH) assays are given in Table 7. No clear treatment-related effect on thyroid function
was seen. 

### It must be noted that, for both parameters, the data were quite variable, with high standard deviations in many cases. However, all group mean values for both parameters and all individual TSH concentrations were within the reference ranges (T4: 10.3-39.0 nmollL for males and 12.4-43.3 nmollL for females; TSH: <0.800 ng/mL for males and <0.56 ng/mL for females). Some ofthe individual T4 concentrations were above or below the reference range; however, there
were no correlated increases in TSH for the low values, and no dose- or treatment-related pattern
was evident. A statistically significant increase in T4 concentration in IX animals on day 1 relative to controls was not considered treatment-related due to the absence ofa dose response.



### 27

## "

• TABLE 7: Thyroxin (T4) and thyroid stimulating hormonc (TSH) concentrntions in beagle puppies treated with 104.5

or 104.05 Placebo (with sexes combined) a
Study dny Control IX Dosage 3X 5X

T4 (nmolfL): Day -7 31.5±5.1 3 1.3±8.4 28.7±8.6 32.6±7.6 Day 1 22.4±7.7 30.8±7.0 

### ** 25.9±9.0 2l0±7.6 Day 7 18.5±5.9 19.3±9.1 16.8±7.1 23.7±7.6 Day 14 16.1±6.7 17.5±8.6 13.9±6.1 18.1±7.1 TSH (ng/mL); Day -7 0.l5±0.04 0.15±0.01 0.17±0.06 0.14±0.00 Day 1 0.17±0.06 0.15±0.03 0.16±0.04 0.15±0.01 Day 7 0,15±0.01 0.15±O.OI 0.I6±O.03 0.17±0.06 Day 14 0.17±0.06 0.15±O.O2 0.14±0.OI 0.17±0.06
Data laken from Tables 68 and 70, pp. 184 and 186, MRID 484671 18. Values arc Mcan ± Standard Deviation, with n=12 for all groups, except n= II for T4 analyses of I X group on day 7 and controls on day 14. Statistically different (p<0.05) from the conlrol. ** Statistically diffcrenl (p<O.Ol) from the contro\.



### F. GROSS PATHOLOGY: An animal that died during the acclimation of set 3 was submitted for gross necropsy. The following gross lesions were noted: slight congestion ofthe mucosa ofthe duodenum, jejunum, ileum, and colon; hemorrhages and necrosis ofthe lung tissues; reddish froth in the trachea; hemorrhagic lesions in the bronchial lymph node; and pale appearance ofthe spleen. Based on these findings, the animal was diagnosed with pneumonia.

III.DISCUSSION and CONCLUSIONS

A. INVESTIGATORS' CONCLUSIONS: The study author concluded that topical application of the test substance, 

### 104.05, at IX and 3X the intended dosing volume was generally well tolerated; however, the serious episodes of abnormal clinical signs in two puppies treated. at 5X were considered potentially treatment-related and indicative that topical application ofthe test substance at 5X the intended dosing volume was not well tolerated.



### B. REVIEWER COMMENTS: Guideline OPPTS 870.7200 states that the animals should be free of infectious diseases, which could complicate the interpretation ofthe study results. In this study,
one animal tested positive for coccidia while abnonnal feces consistent with coccidia (i.e. mucoid
or loose with mucus and/or frank blood) were seen in what appeared. to be a dose-related manner. One animal that died during the week prior to treatment had pneumonia, and during the study one 5X animal had serious respiratory disease requiring the administration of oxygen. Baseline blood work revealed that about two animals per group had normocytic nonnochromic or microcytic hypochromic anemia on day -7, and one animal had leukopenia. Blood work done on day 7 suggested that the abnormal observations in two 5x animals with serious abnonnal clinical signs may have been at least partly due to infection.

Effects were seen that were dose-related. There were increased incidences of vomiting and abnonnal feces in 5X animals, and 5X animals ofboth sexes had decreased weight gain during days -1 to 7, along with decreased food consumption during days 1 through 5. Although it is not possible to know to what extent the compromised health status ofthe animals contributed to the expression ofthese effects, special attention must be called to the abnormal neurological signs 

### 28

### seen in this study, which included salivation, ataxia, inability to walk properly, trismus (inability to properly open the mouth), circling, head pressing, seizures, and retropulsion ofthe neck, which must be considered due to exposure to the formulation.

Because of the severe effects observed in the 5X group, an adequate margin of safety was not established and this study is considered unacceptable to support the use of this product on 8 week old puppies at the proposed dose of 1 mL for puppies weighing up to 22.9 Ibs.

C. 

### ADDITIONAL STUDY DEFICIENCIES:

These include the following:

• Some ofthe puppies may have had a compromised health status. One animal that died during the week prior to treatment had pneumonia. Baseline blood work revealed that 1-2 animals per group had normocytic normochromic or microcytic hypochromic anemia on day -7, and one animal had leukopenia. Blood work done on day 7 suggested that the abnormal observations in two 5X animals with serious abnormal clinical signs may have been at least partly due to infection.
• The product was applied from the base ofthe head to the rump area, whereas the proposed label says that the product should be applied at a single site in small dogs and puppies 8 weeks old or older and weighing up to 22.9 lbs.
• All groups were not represented in some ofthe replicates.

IV. REFERENCES: Anonymous (2011) Summary ofcompanion animal safety data for EffitixTM Topical Solution for Dogs (Fipronil 6.01% and Permethrin 44.88% end use product).' Virbac, lere Avenue, 06511 Carros Cedex, France. Study number Virbac 104.05-2, April 10,2011. MRlD 48467]]9. Unpublished.

29

### DATA EVALUATION RECORD
PERMETHRIN; FIPRONIL [EFFITIX''' TOPICAL SOLUTION FOR DOGS / 104.05]

STUDY TYPE: COMPANION ANIMAL SAFETY STUDY- PUPPIES; OPPTS 870.7200 MRID 48487302

Primary Reviewer: Donna L. Fefee. D.V .M.
Secondary Reviewers: Prepared for Registration Division Office ofPesticide Programs U.S. Environmental Protection Agency One Potomac Yard 2777 South Crystal Drive

Arlington, VA 22202
Prepared 

### by Summitec Corporation 9724 Kingston Pike, Suite 602

Knoxville, Tennessee 37922

Task Order No. 3-C-03

Signature: Date:
Virginia A. Dobozy. V.M.D

.. M.P.H. Signature: 

### Date:

Robert H. Ross. Program Manager Signature: Date: 

### Quality Assurance: Angela M. Edmonds. B.S. Signature: 

### Date:

Disclaimer 

# DOMn 0- 

# L· 

# re.-ke I 

# 4E SEP 14 Z911

# ~f/1.~ SEP 1 42011

This review may have been altered subsequent to the contractor's signatures above.EPA Reviewer: Byron T. Backus, Ph.D. Technical Review Branch, Registration Division (7505P)

EPA Secondary Reviewer: Kit Farwell, D.V.M., D.A.B.T. Risk Assessment Branch VII, Health Effects Division (7509P) Signature:

## _G,-,-~~-=;-:=-~=I ci-r:;-(\-,-J-.. Date:
__

### 5.Lj-L!L1..",:I-L,I,-,'-;;Q~" Signature:

# _.-J{,-ct-'-'-~"~-f-"" Date: (0 

# h**r~O{** 

# I Template version 02106 I 

### DATA EVALUATION RECORD I



### STUDY TYPE: Companion Animal Safety Study

- Puppies; OPPTS 870.7200

PC CODES: 109701, 129121 DP BARCODE: 390818

TEST MATERIAL (PURITY): 104.05 [6.71 g/IOO mL Fipronil and 50.26 g/100 mL Permethrin; Batch No. CGA 09007-1 (T3MOIS 5° C)]

SYNONYMS: 

### EffitixTM Topical Solution for Dogs

CITATIONS: Gupta, S. (2010) A 14-day tolerance study in beagle pups when administered 104.05 (6.7% Fipronil and 50% Pennethrin topical solution) topically at IX and 5X the recommended dose. Charles River Laboratories Preclinical Services Ireland Ltd., Canentrilla, Ballina, Co. Mayo, Ireland. Study Number F004109-001, March 12, 2010. MRID 48487302. Unpublished.

SPONSOR: Virbac SA, Pre-clinical and Clinical Unit (VB7), 13""' Rue Lid

- B.P. 27, 06511 Carras Cedex, France.

EXECUTIVE SUMMARY: In a 14-day companion animal safety study (MRID 48487302),104.05 [6.71 g/IOO mL Fipronil and 50.26 g/IOO mL Permethrin; Batch No. CGA 09007-1 (T3MOIS 5° C)]
was applied topically to the skin on the dorsal midline from the base ofthe head to the mid back (this is inconsistent with the proposed label which states the entire applicator contents should be squeezed onto the dog's skin at a single site for small dogs and puppies 8 weeks or older weighing up to 22.9 lbs). Groups of six male and six female 52-56 day old (approximately 8-week-old, weighing from 1,5 to 3.5 kg) beagle puppies were treated at IX (1.0 mLipuppy) or 5X (5.0 mLipuppy) the total recommended dosing volume for the end use product in puppies weighing less 10 kg. "104.05 Placebo" was applied in identical manner to a control group of 6 male and 6 female animals at a dosing volume of 5.0 mLlpuppy. The IX puppies were treated once; the 5X and placebo puppies received five doses of 1.0 mL at approximately 1 hour intervals. Animals were treated on day 0 and observed for 14 days.

One 5X female exhibited profuse salivation on the morning of day 3, exhibited ataxia, generalized tremors, "dullness," and lateral recumbency on days 3-4, and was subsequently euthanized for humane
reasons on day 4. There were no gross or microscopic findings to 

### account for the neurological signs; chronic active inflammation with hemorrhage was present in a localized area of one lung, but the study pathologist did not consider these changes extensive enough to cause clinical signs. The 5X males gained less weight than controls during days -1 to 7 (49% less than controls), and 5X animals of both sexes had biologically and statistically significantly decreased mean food consumption on days 1-3 (25-29% less than controls; p<O.Ol). Transient cosmetic effects such as clumping and a greasy appearance ofthe hair coat, with or without deposits, matting, or spiking were noted within one hour

31

### ofthe first application and resolved by day 5 at all dose levels. There were no treatment-related effects on hematology, clinical chemistry, or coagulation parameters, or serum thyroxin and thyroid stimulating honnone concentrations. Toxicity was evident at the 5X dose level as abnormal neurological clinical signs (ataxia, generalized tremors, and profuse salivation) were observed in one female along with decreased food consumption in both sexes on Days 1 through 4 and decreased body weight gain in males. therefore, an adequate margin of safety has not been demonstrated in 8-week-old puppies.

This companion animal safety study in 8 week old puppies does not demonstrate an adequate margin of safety and is classified as Unacceptable/Guideline. It does not satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in juvenile dogs. It 

### should be noted that this limit test preceded a later full study in puppies (MRID 48467118).

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements
were provided for the study report (MRlD 48487302). Signed and dated GLP and Data Confidentiality statements were provided for the safety summary (MRID 47914234); the GLP Compliance Statement consisted of a declaration that this volume "is not subject to GLP certification" because no study was being submitted.

32

### I. MATERIALS AND METHODS

A. MATERIALS:



### 1. Test material: Dcscri]ltion: Batch #: Purity:
ComJlOund Stability:

CAS#:



### 2. Vehicle control: Description: Batch #: Purity: Compound Stability:

CAS#: 

### 104.05 

### [EndMuse Product 

### EffitixTM Topical Solution for Dogs] Clear, slightly yellow solution eGA 09007-1 (T3M01S 5° C) 6.7 J g/ J00 mL Fipronil and 50,26 gI J00 mL Pennethrin EXpiration dale: December 2009; considered stable until that date, stored in original packaging, at 16_26° C.). Not Provided



### 104.05 Placebo Clear solution NDE 09132 0.02% (w/v) ButylhydroxyanisoJc, 0.01% (w/v) ButylhydroxytoJucnc, and Ethylene diethylene glycol (QSP J00 mL) Expiration date: September 2009; considered stable until that date, stored in original packaging, at 16-26° C.). Not Provided



### 3. Positive control: No positive control was used.

4. Test animals: Species: Breed: Agelweight at study initiation: SourCe: Housing:

Dict:

'Vater: Environmental conditions:

Acclimation period:



### B. STUDY DESIGN: Dog Beagle 52-56 days oldl Males: 1.5-3.5 kg(on day -I); Females: 1.6-3.1 kg (on day-I) Charles River Laboratories Preclinical Services Ireland Ltd., Glcnamoy, Co. Mayo, Ireland Prior to weaning (day -7): puppies were housed with dams in two adjoining pens (each 1.7 m x 1.4 m) with the dividing gate opened, except during daily 2- to 3-hour intervals, during which the dam was separated from the puppies 10 prepare them for weaning; Days -7 through -3: puppies were housed in groups oftwo or three; Days -2 through 14: puppies were housed individually in pens measuring 1.7 m x 1.4 m. Infrared lamps were provided. Pedigree pup tood (Pedigree Masterfoods, Melton Mowbray, Leicester, U.K.), approximately 400 glpup/day Supplemental food (e.g. Welpi® milk replacer) was offered to pups when deemed nceessary. Ad libilllm potable water via automatic drinkers or stainless steel bowls Temperature: Humidity: Air changes: Photoperiod: Fourteen days. 15-19°C. 49-65% Not reported Not reported



### 1. 

### In life dates: Start: July 13,2009; End: October 19, 2009.

332. Animal assignment: Study design is given in Table 1. The study was conducted in nine replicates, as pups ofthe appropriate age became available. On day -1, the animals from each replicate were assigned to groups according to body weight, using a stratified randomized block design. All pups meeting the inclusion criteria were ranked within sex in order of decreasing body weight, with any same-sex pups of identical body weight ranked in order of decreasing microchip number. To the extent possible, blocks of three same-sex pups were formed and then randomly allocated to study groups using random order numbers derived from Fisher and Yates tables. When necessary, an incomplete block would be completed using pups from the subsequent set. Table 2 lists the number ofpups in each set that were assigned to each group. The study was not blinded.

TABLE 1: Study design 

# ,

Test Dosing volume (mL/puppy) Dose (mg/puppy) Dose (mg/kg) v Number assigned Group Fipronil Permethrin Fipronil Pcrmcthrin Males Females
1. Control 5 mL 0 0 0 0 6 6 (5 applications of 1.0 mL of vehicle control) 2. IX I mL 67.1 502.6 19.2-39.5 143.6-295.6 6 6 (I application of 1.0 mL of the test item) 3.5X 5 mL 335.5 2513 101.7- 761.5- 6 7 ' (5 applications of 1.0 mL ofthe test item) 176.6 1323 

## " Dala taken from pp. 23 and 39, MRID 48487302. b



## , Calculated by reviewer, using day -I body weighl ranges of 1.7-3.5 kg and 1.9-3.3 kg for the IX and 5X groups, respectively. An additional animal was assigned Collowing the moriuund sacrifice of one animal in Ihis group.

TABLE 2: Study design
Sels Test Group I 2 3 4 5
1. Control 21' I M, IF 2 M, I F IF



### -- 2. IX I M,2 F I M, IF 1M 1M 1M
3.5X 2F I M, IF I M,IF I M, IF 1 M, I F 

## " Data compJ\ed by revIewer usmg Table I, p. 38, MRiD 48487302. M '" male; F '" female. 

## "

6 7 8 9
IF 1M 2M


## -- 1M, 2 F IF



### -- --

1M 1M


# -- IF

3. Dose selection rationale: According to the study report, a 1-mL dosing volume is the normal recommended dose for this product for dogs, and presumably for puppies, weighing less than 10 kg. The study author stated that the "multiple" ofthe recommended dose was required by OPPTS 870.7200. The vehicle control substance was also administered at 5 times the normal recommended dosing volume of the product. The exaggerated doses were achieved via five applications ofthe enduse product or the control item (at approximately one hour intervals).

. It should be noted that this limit test preceded a later full study in puppies (MRID 48467118).

34

### 4. 

### Treatment: The control or test material, as appropriate, was applied topically on day 0, using a syringe without a needle. For each application, the tip ofthe syringe was positioned on the dorsal cervical area at the base ofthe pup's head and used to separate the pup's hair so the material could be applied at the skin level, and the contents ofthe syringe were then applied, as evenly as possible, from the base ofthe head to the mid back. Following application, the pup was restrained in an upright position for at least two minutes to prevent run-off ofthe test or control substance. Syringe volumes were visually confinued immediately prior to administration, and each syringe
was checked after administration to ensure that none ofthe contents remained. To achieve the exaggerated 5x doses, the control or test material was applied on five occasions with 1 hour (± 

### 5 minutes) between each application. There was no evidence of run-off

5. 

### Statistics: Descriptive statistics were generated for all endpoints (separately by sex and combined) at each time point.
Body weight and food conswnption, hematology and clinical chemistry parameters, and thyroxin and thyroid stimulating honnone values were analyzed using repeated measures analysis of covariance (RMANCQVA) including treatment, sampling day, sex, and the interaction tenns "treatment by sampling day (group*day)," "treatment by sex" (group*sex), "sex by sampling day" (sex*day), and "treatment by sex by sampling daY" (group*sex*day) as fixed effects. The set (replicate) was also included in the model as a fixed factor but was only retained if significant (p<0.05). The individual animal was identified as the subject in the repeated statement. The covariate was the pretreatment baseline measurement or the average ofthe three pretreatment baseline measurements in the case of body weight.

For each analysis, the appropriate variance-covariance matrix structure was selected from among compound symmetry, heterogeneous compound symmetry, first-order autoregressive, and heterogeneous first-order autoregressive, based on the Akaike Information Criterion.

lfthe group*sex*day interaction was significant (p<0.05), then the statistical analysis was considered inconclusive. Ifthe group*sex*day interaction was not significant, the interactions of group*sex and group*day were evaluated. If group*sex was significant at p<0.05 but group*day
was not significant (p>0.1 0), then the statistical analysis was considered inconclusive. If group*day was significant at p<O.l 0, pair-wise comparisons of each treated group least squares mean was performed against the control group least squares mean at each sampling day, using a two-sided Student's t-test.

When the group*sex, group*day, and group*sex*day interactions were not significant, the "treatment" main effect was evaluated at p<O.l O. If significant, pair-wise comparisons ofeach treated group least squares mean was perfonned against the control group least squares mean, using a two-sided Student's t-test. Ifnot significant, no further analyses were conducted on the variable.

Profile plots were provided for all continuous variables and included baselines (or aritlnnetic
means ofpre-study data) and all data collected from day 1 through the end ofthe study. For each endpoint, the individual data were presented separately for each treatment group (with the sexes



### 35

### combined), and group mean values (for the sexes combined) were presented together, on a single plot.

Potential outliers were verified with the study director, and no outliers were excluded. The following defaults were used for the analyses: creatinine values recorded as "<18" were defaulted to 18; total and direct bilirubin values recorded as "<1.7" were defaulted to 1.7; and thyroid stimulating hormone values recorded as "<0.14" were defaulted to 0.14.

The clinical signs data were not subjected to statistical analysis. The planned statistical analysis of death or sacrifice via logistic regression was not conducted because only one animal was sacrificed.

C. 

### METHODS:

1. Observations:

a. General health observations: Beginning 011 

### day -14 and continuing through day -1, general health observations were recorded once daily. No further details were provided concerning the evaluated parameters or whether the evaluations were cage-side or hands-on.

b. Clinical assessments: All pups were examined by a veterinarian on days -14 and -1. During the study, a veterinarian conducted clinical assessments on all animals prior to the first treatment and at 1 hour (±5 minutes), 2, 3, 4, and 5 hours (±1O minutes), and 6,7, and 8 hours (±30 minutes) after the final treatment on day 0, For the control and 5X animals, clinical assessments were also performed within 10 minutes prior to the second, third, fourth and fifth treatment. During the remainder ofthe study interval (days 1-14), clinical assessments were perfonned by a veterinarian twice daily, once in the morning and once in the afternoon, with at least four hours between assessments. Clinical assessments consisted of observing each animal for at least one minute and recording the presence or absence ofthe following: lethargy, ataxia, recumbency, paralysis, coma, pruritis, hyperactivity, tremors, convulsions, abnormal mydriasis, abnonnal miosis, corneal opacity, dyspnea, tachypnea, coughing, abnonnal salivation, vomiting, abnonnal mucous membranes, ocular discharge, nasal discharge, cardiovascular changes, abnonnal feces, abnonnal urine, abnonnal coat condition, and abnonnalities ofthe application site, For any finding that was present, a brief comment further describing the condition was made at the first point of detection and/or at other points of detection.

2. Body weight: The animals were weighed on days -14, -7, -1, 7, and 14.

3. Food consumption: From day -2 through day 13, each puppy was offered a pre-weighed, approximately 400-g quantity of food, and, on the following day, unconsumed food was removed from the pen and weighed,

4. Clinical Pathology: Each animal had blood collected for hematology, clinical chemistry, and thyroid function evaluation on day -7, day 1 (24 hours ± 

### 2 hours after the first application), and day 7, and blood was collected for thyroid function evaluation on day 14, On days -7, 1, 7, and 14, food was not offered to the animals until after blood sampling was perfonned, but there was no mention ofwitliliolding food and/or water for a specific duration oftime prior to collection, and the venipuncture site also was not reported. The CHECKED (X) parameters were examined. 36

### a. Hematology:

X Hema(oerit (HCT)* 

## x LeukocY(e differential eount* (absolu(e) X Hemoglobin (HGB)* X Mean corpuscular HGB (MCH)* X Leukocyte eoun( (WBC)" 

## x Mean eorpllse. HGB conc.(MCHC)* X Erythrocyte eOllnt (RBC)* X Mean corpusc. volume (MCV)* X Platelet count Retieulocy(e count Blood cio((ing measurements Morphology (if indicated) X (Thromboplastin time)* X Heinz body formation (Clotting time) X (Pro(hrombin time)*



### . * Recommended for companIOn anlmnls safety evaluation based on OPPTS 870.7200


### b Clinical Chemistry'



# . .

ELECTROLYTES OTHER X Caleium* X Albumin" X Chloride* X Creatinine* Magnesium X Urea nitrogen (BUN)" X Fhosphorus* Cholestcrol X Potassium* X Globulins* X Sodium* X Glucose" ENZYMES X To(al bilirubin" X Alkaline phosphatase (ALK)* X Direct bilirubin* Cholinesterase (CitE) Indirect bilirubin Creatine phosphokinase X Total protein (TP)* Laetie acid dehydrogenase (LDH) Triglyeerides X Alanine aminotransferase (ALT/also SGPT)* Sen In! protein electrophoresis X Aspartate aminotransferase (AST/also SGOT)* Albumin/globulin ratio Sorbitol dehydrogenase Gamma glutamyl transferase (GOT) Glutamate dehydrogenase 

### * Rccommended for a companIOn animal safety evaluation based on OPPTS 870.7200.



### c. Thyroid Function: Serum thyroxin and thyroid stimulating hormone assays were done using canine-specific radioactive immW10assays (Siemens), with the results cOW1ted using a gamma counter. The separated serum was stored at between 

### _ISO C and 

### _30 0 

### C W1til shipment on dry ice to the analyzing laboratory (Charles River Laboratories, Central Laboratory Services, Edinburgh, U.K.).



### 5. Urinalysis: Urinalysis is not required for companion animal safety studies and was not done as part of the current stu9y.

6. Sacrifice and Pathology: Terminal sacrifices and gross necropsies were not done and are not required W1der OPPTS 

### 870.7200. One animal was sacrificed moribund during the study and subjected to gross necropsy. The indicated (X) organs or representative samples thereof were collected, preserved in neutral buffered formalin, processed, and examined microscopically.

37X DIGESTIVE SYSTEM X CARDIOVASCJHEMAT. X NEUROLOGIC Tongue 

### X Aorta and carotid arteries 

# + Brain

- -" Salivary glands I-leart Peripheraillcrve (sciatic) 

# T

---

### I~ Esophagus Bone marrow X Spinal cord -co-

- X Stomach (fundic, gastric, pyloric) Lymph nodes Pituitary ",,- 

### IX**~** Duodenum 

# f"- Spleen Eyes X Jejunum

## ~ Thymus GLANDULAR

- X Ileum X Adrenal gland

- X Cecum UROGENITAL X Parathyroid 

## X Colon X Kidneys 

# f"- Thyroid

- Rcctwn

# ~ Urinary bladder



### --**~** Liver 

## r-- Testes OTHER Gall bladder Epididymides Bone (femur)

- Bile duct 

## r--

- Prostate Skeletal muscle



### -- 

### f-- 

# ex- X Pancreas Seminal vesicles Skin (application site and untreated skin) RESPIRATORY X Ovaries C"- Gross lesions and masses (selected) Trachea

## ~ Ulerus 

### f-- X LUltg Vagina 

# e--

- 

### I- 

# e-- Nose



### -- 

### f-- 

## r--

- Pharynx 

### f-- 

## r-- Larynx



### II. RESULTS

A. ACTUAL DOSES ADMINISTERED: The mglkg 

### doses ofthe active ingredients are given in Table L



### B. OBSERVATIONS:

1. 

### Mortality: One 5X female (animal #63312) was euthanized for humane reasons on day 4.

2. Clinical signs of toxicity: No abnonnalities were noted during the "general health observations" conducted between day -14 and day -1. 

### One 5X female (animal #63312) exhibited profuse salivation on the morning of day 3, exhibited ataxia, generalized tremors, "dullness," and lateral recumbency on days 3-4, and may have shown signs ofpain on day 4 (it was unclear from the study report); this animal was subsequently euthanized for humane reasons on day 4.

The only other reported abnonnal clinical signs were abnormal feces, i.e. slightly loose feces, mucoid feces, and/or fresh blood and/or mucus in feces. Three to four animals per group exhibited abnonnal feces on at least one occasion during the study, most commonly prior to the first treatment on day O.



### 3. Local effects at the dose sites: Within one hour ofthe first application, all ofthe animals had clumping and a greasy appearance ofthe hair coat, with or without additional findings such as deposits, matting, or spiking. All control and IX animals were free ofcosmetic effects by day 2, and all 5X animals were free ofcosmetic effects by day 5.

38C. 

### BODY WEIGHT AND WEIGHT GAIN: Body weight data are given in Table 3. Statistical analysis of absolute body weight indicated that there were no significant group*sex*day, 

### group*day, or group*sex interactions, and the group main effect also was not significant. The 5X males gained less weight than controls during days -1 to 7, but a similar difference was not seen in females.



# ,

b



# , TABLE 3: Body weight data from puppies treated with 104.5 or 104.05 Placebo 

## ,

Parameter! Dosage Study day or interval Control IX 5X

Males Absolute body weight: Day -14 1.72±O.15 2.03±O.58 1.85±O.46 Day -7 2.12±O.29 2.50±O.53 2.27±O.50 Day -I 2.38±O.23 2.82±OA9 2.53±O.60 Day 7 2.75±O.14 3.13±OA9 2.72±O.58 Day 14 3.08±O.19 3.38±O.48 2.9&±O.58 Body weight gain tJ: Days -14 to-7 DAD 0.47 0.42 Days-7to-t 0.26 0.32 0.26 Days -1 to 7 0.37 0.31 0.19(_49)c Days 7 to 14 0.33 0.25 0.26
Females Absolute body weight: Day-14 1.60±0.35 1.55±0.21 1.73±0.42 Day -7 1.92±0.45 1.83±0.34 2.09±0.42 Day -1 2.1O±0.48 2.10±0.42 2.39±0.38 Day 7 2.52±0.39 2.37±0.33 2.75±0.40 Day 14 2.75±0.36 2.60±0.33 3.03±0.39 Body weight gain D: Days-14to-7 0.32 0.28 0.36 Days -7 to-l 0.18 0.27 0.30 Days -1 to 7 0.42 0.27 0.36 Days 7 to 14 0.23 0.23 0.28

Data derived from Table 74, p. 207, MRID 48487302. Values arc Mean ± Standard DevIatIOn, wIlh n-6 for all groups, except 0=7

ror 5X lemales on days -14 through -I. Calculated by reviewer using group mean values. Numbers in parentheses equal pereenl diflhenl rrom control; calculated by reviewer.



### D. FOOD CONSUMPTION: Selected food consumption data are given in Table 4. Almost all of the puppies consumed the entire ration on most, or even all, ofthe days of the study. The 5X animals had biologically and statistically significantly lower mean food consumption than controls
on days 1-3. A smaller statistically significant decrease in the IX group on day I served to illustrate a dose response pattern and is considered treatment-related but was insufficient magnitude and duration to be considered biologically significant.

39

# ,

b



### , The food consumption data are of somewhat limited usefulness because the puppies were not fed ad libitum and because, more often than not, most ofthe puppies consumed all ofthe food that
was offered.

TABLE 4: Selected food consumption data from puppies treated with 104.5 or 104.05 Placebo (g/day, with sexes combined) a Dosage Study day Control IX 5X Day -1 332±128 393±24 360±79 Day 0 384±33 354±67 

### * (-8%) u 356±64 Day 1 391±34 336±78 n (-14%) 293±1 \0 

### ** (-25%) Day 2 379±69 382±64 285±143 

### ** (-25%) Day 3 377±69 368±70 269±142 

### ** (-29%) Day 4 379±46 369±69 327±J39 

### ** (-14%) DayS 386",29 370±67 375±46
Data dcrived from Tables 76, 77, and 80, pp. 209, 210, and 212-213, MRlD 48487302, Valucs arc Mean ± Standard Deviation, with n""12 for all groups, exccpt n""13 for 5X group on days -1 through 4. Numbers in parcntltcscs cqual percent different from control; calculated by reviewer. Statistically diffcrent (p<0,05) from the control. ** StatisIically differenl (p<O.O I) from the control.



### E. BLOOD ANALYSES:

1. 

### Hematology and coagulation: There were no treatment-related effects on the evaluated hematology and coagulation parameters, Increased MCV in IX animals on day 1 relative to controls was not considered treatment-related because a dose response was not evident, and because there were no correlated effects on REC, HCT, or HGB, Monocyte counts ofthe IX and 5X groups were lower than those ofcontrols for the study overall, but the mean values for these groups were within the provided reference range at all time points; the apparent difference was related to higher than normal mean values for controls on days I and 7, i.e. mean values that fell outside the provided reference range. Statistical analyses for a number ofparameters were considered (by the study author and statistician) to be inconclusive, but all group means were within the provided reference ranges and no dose response patterns were evident.
2. Clinical Chemistry: There were no treatment-related effects on any ofthe evaluated clinical chemistry parameters. There were statistically significant group*sex*day, group*sex, and/or group*day interactions, or group main effects for some parameters, including aspartate amino transferase activity and chloride, sodium, and albumin concentrations, but comparison ofthe mean values ofthe treated groups to those of controls at each time point did not reveal any biologically
or statistically significant differences,

3. ThYroid function evaluation: Selected results ofthe thyroxin (T4) and thyroid stimulating hormone (TSH) assays are given in Table 5. No clear treatment-related effect on thyroid function
was seen. It 

### must be noted that, for both parameters, the data were quite variable, with high standard deviations. However, all group mean values for both parameters and all individual TSH concentrations were within the reference ranges (T4: 10.3-39.0 nmoliL for males and 12.4-43.3


### 40

## "

b 

### nmollL for females; TSH: <0.800 nglmL for males and <0.56 

### ng/mL for females; MRID 48467118). Some ofthe individual T4 concentrations were above or below the reference range; however, there were no correlated increases in TSH for the low values, and no dose- or treatmentrelated pattern was evident.

TABLE 5: Thyroxin (T4) and thyroid stimulating hormone (TSH) concentrations in beagle puppies treated with 104.5

or 104.05 Placebo (with sexes combined) a Dosage Study day Control IX 

### 'X

T4 (nmoIlL): Day -7 32.4±12.0 28.2"'-75 30.S±7.9 Day 1 23.0±8.9 22.7±4.5 24.4±8.0 Day? 22.3±9.0 20.3±8.3 20.3±5.2 b Day 14 17.7±5.6 17.1±75 \S.I±6.6 TSH (ng/mL): Day-7 O.20±O.O4 O.19±O.O9 O.21±O.O7 Day 1 O.16±O.O3 O.17±O.O4 O.18±O.O6 Day? O.17±O.O5 O.I8±O.06 O.I8±O.06 b Day 14 O.17±O.04 0.15±0.03 0.16±0.02



### - Data taken from Tables 70 and 72, pp. 203 and 20" MRID 48487302. Values arc Mean::!; Standard DevmtlOn, with 0=12 for all groups, except n=\3 lor the 5X group on days.7, I, and 7. Mean includes results from a sample takenli'om the moribund 5X female on day 4.



### F. SACRIFICE AND PATHOLOGY:



### 1. Gross pathology: The following gross lesions were noted in the 5X animal that was sacrificed moribund on day 4: congestion of the duodenal mucosa; focal congestion in the jejunal mucosa; congested and hemorrhagic lungs; congestion ofthe thymus; and enlargement of the liver with a finn consistency. There were no findings that correlated with the observations of ataxia, tremors, profuse salivation, dullness, or recumbency.

2. Microscopic pathology: Chronic active inflammation with hemorrhage was present in a localized
area of one lung as a histopathological correlate to the gross findings in the lungs; however, the pathologist did not consider these changes extensive enough to cause clinical signs. Gram staining
was done and found to be negative for bacteria. There were no findings that correlated with the observations of ataxia, tremors, profuse salivation, dullness, or recumbency.

III.DISCUSSION and CONCLUSIONS

A. INVESTIGATORS' CONCLUSIONS: The study author concluded that 104.05 (a combination of 6.7% 

### w/v fipronil and 50% 

### w/v pennethrin) was well tolerated both locally and systemically when administered topically to beagle pups at IX and 5X the recommended dose.

B. REVIEWER COM:MENTS: 

### In disagreement with the study author, it is the opinion ofthe reviewer that toxicity was evident at the 5X treatment level as decreased food consumption in both
sexes and decreased body weight gain in males over days -1 to 7. The puppies were not fed 

### ad libitum by offering them more food than they were likely to eat, and not feeding 

### ad libitum 41

### decreases the likelihood that body weight data accurately reflect an adverse effect. This may be why a similar effect on body weight gain was not seen in females.

The reviewer also disagrees with the study author's conclusion that "inability to cope physiologically following individual housing post-weaning" was the most likely cause ofthe moribundity ofthe animal that was sacrificed on day 4, and the neurological signs (ataxia, generalized tremors, and salivation) exhibited by this animal are ofparticular concern. In a later companion animal safety study, conducted at the same testing laboratory (MRID 48467118), neurological signs were also seen at the 5X dose. These included ataxia, generalized tremors, and salivation along with additional signs such as inability to walk properly, trismus, circling, seizures, and retropulsion of the neck. Although physiological stress and concurrent or prior respiratory disease may have contributed to the moribundity, considering the MO 

### studies together, it is concluded that the neurological signs seen in the current study were treatment-related, at least in part. It also must be noted that neurological signs are consistent with the known toxicity ofthe active ingredients.
Toxicity was evident at the SX dose level as abnormal neurological clinical signs (ataxia, generalized tremors, and profuse salivation) in one female along with decreased food consumption in both sexes and decreased body weight gain in males; therefore, an adequate margin of safety has not been demonstrated in 8-week-old puppies.

C. STUDY DEFICIENCIES: The following deficiencies were noted:
• The product was applied from the base ofthe head to mid back, whereas the proposed label says that the product should be applied at a single site in small dogs and puppies 8 weeks old
or older and up to 22.9 lbs.
• All groups were not represented in some ofthe replicates. Replicate 5 had no control group, Replicate 8 had only 2 control animals and Replicate 9 had one 5x female.

42

### IV. REFERENCES
Gupta, S. (2011) A 14-day tolerance study in beagle pups when administered 104.05 (6.7% Fipronil and 50% Permethrin topical solution) topically at IX, 3X and 5X the recommended dose. Charles River Laboratories Preclinical Services Ireland Ltd., Carrentrila, Ballina, Co. Mayo, Ireland. Study Number F004110-003. Apri16. 2011. 

### MRlD 48467118. Unpublished.
Anonymous (2011) Summary ofcompanion animal safety data for Effitix

### TM Topical Solution for Dogs (Fipronil 6.01 

### % and Permethrin 44.88% end use product). Virbac, 

### lere Avenue, 06511 Carras Cedex. France. Study number Virbac 104.05-2. April 10,2011. MRID 48467119. Unpublished.

43

### ACUTE TOX ONE-LINERS:

1. DP BARCODE: 390818 2. PC CODES: 10970 I (Pennethrin), 129121 (Fipronil) 3. CURRENT DATE: September27,2011 4. TEST MATERIAL: 104.05 (6.71 g/IOO mL Fipronil and 50.26 g/lOO mL Permethrin; Batch No. eGA 09007· \); described as a clear, slightly yellow solution.

Study/Species/Lab MRID Results Tax. Core Study # IDate Cat. Grade Companion Animal 48467117 There were no treatment-related effects on mortality, 

### NA A Safety / adult beagle body weight or body weight gain, food consumption, dog / Huntingdon Life hematology, clinical chemistry, or coagulation Sciences / Lab Project parameters, or serum thyroxin and thyroid stimulating 10 VRBOOl7 / hormone. Treatment at 5X the recommended February 5, 2010 therapeutic dose resulted in an increased incidence of loose feces within 4 to 8 hours of dosing; three 5X dogs exhibited a total of seven incidences compared to no incidences in controls. It is concluded that the margin of safety in 10- to 20-kg adult beagle dogs administered 104.05 [End-use Product: EffitixTM Topical Solution for Dogs] is at least 5x the recommended dose (2.0 mLld02). Companion Animal 48467118 At 5X there were increased incidences ofvomiting and 

### NA U Safety / 8 week old abnormal feces, Le. feces that were liquid, loose, beagle dog / Charles mucoid, with traces ofblood, and/or discolored (seen in River Laboratories 4-5 5X animals vs. 0 controls). 5X animals ofboth Ireland / Lab Study sexes had decreased weight gain during days -I to 7 No. F004\110406 / (51 % and 55% less than controls for males and females, April 6, 2011 respectively). During days 1-5 ofthe study, the daily food consumption ofthe 5X animals was 32-50% less than that ofcontrols (p<O.OI), and there were 26 occasions (involving nine 5X puppies) in the period from Day 1 to 9 when a 5X pilppy consumed less than 100 g of food in a single day (this occurred only twice in the IX group and once in the 3X group during this period). Two 5X animals also exhibited abnormal neurological signs, including salivation, ataxia, inability to walk properly, trismus (inability to properly open the mouth), walking in a circle to the right, resting head against the wall, generalized tremors, one episode of seizures (clonic convulsions), "dullness," and regular retropulsion ofthe neck in one animal and salivation, ataxia, unsteadiness on hind limbs and gait incoordination due to weakness, and slight generalized tremors in the other animal.

This companion animal safety study with 8 week old puppies does not demonstrate an adequate (5X) margin ofsafety. This study is classified as Unacceptable/ Guideline. It does not satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in juvenile dogs.



### 44Companion Animal 48487302 One 5X female exhibited profuse salivation on the 

### NA U Safety! 8 week old morning ofday 3, exhibited ataxia, generalized tremors, beagle dog / Charles "dullness," and lateral recumbency on days 3-4, and River Laboratories was subsequently euthanized for humane reasons on Ireland / Lab Study day 4. There were no gross or microscopic findings to No. F004\09-00 1/ account for the neurological signs; chronic active March 12,2010 inflammation with hemorrhage was present in a localized area ofone lung, but the study pathologist did not consider these changes extensive enough to cause clinical signs. The 5X males gained less weight than controls during days -1 to 7 (49% less than controls), and 5X animals ofboth sexes had biologically and statistically significantly decreased mean food consumption on days 1-3 (25-29% less than controls; p<O.OI).

It is concluded that toxicity was evident at the 5X dose level as abnormal neurological clinical signs (ataxia, generalized tremors, and profuse salivation)
were observed in one female along with decreased food consumption in both sexes on Days 1 through 4 and decreased body weight gain in males. therefore,
an adequate margin of safety has not been demonstrated in 8-week-old puppies.

This companion animal safety study in 8 week old puppies does not demonstrate an adequate margin of safety and is classified as Unacceptable/Guideline. It does not satisfy the guideline requirement for a companion animal safety study (OPPTS 870.7200) in juvenile dogs.



# . Core Grade Key. A Acceptable, S Supplementary, U Unacceptable, W Waived



### 45

### Effitix Pup Safety Proposal 

# 1"2..-3.3 'Z

- 

# t.ll Jim Barron to: Bonaventure Akinlosotu ll!OS/2011 02:27 PM 

### Cc: 

### Richard Gebken, "Brenton Smith", "Terry McNamara", isabelle.villard.extemal Hide Details 

### From: "Jim Barron" <jbarron@exponent.com>

To: Bonaventure AkinlosotulDC/uSEPAJUS@EPA Page I of3

Ce: Richard GebkenlDC/uSEPAlUS@EPA, "Brenton Smith" 

### <brenton.smith@virbacus.com>, "Terry McNamara" <tmcnamara@exponent.com>, 

### <isabelle.villard. external@virbac.com>



# ------

November 8,2011

Dear Bonaventure,



### Thank you for sending us the Agency's October 13, 2011 review of the companion animal safety studies conducted with Effitix'" Topical Solution For Dogs. Based on the Agency review, the Effitix studies conducted with 8 week old puppies have been classified as Unacceptable/Guideline. Nonetheless, having a puppy claim on the label for this product is very important to Virbac.

Therefore, Virbac is submitting the following proposal based on the supporting justification summarized below:



### • EPA grant a canditianal registratianfar Effltix Tapical Salutian Far Dags with a 10 week minimum age 

### limit and a S 

### Ib minimum weight restrictianl
• As a canditian afregistratian, Virbac will canduct and submit ta EPA, within 1 Jiear af registratian, a new campanian animal safety study with 10 

### week old puppies to 

### confirm praduct**sa&1Y~**

file:/IC:\Documents and Settings\BAkinlos\LocaJ Settings\Temp\notes87944B\-web 1 064.... 11/9/2011

### Page 2 of3



### The rationale for the above proposal is as follo_ws:

• Fipronil alone spot-on products have an 8 week age limit, and have been used for
more than 

### 15 years;

• Permethrin spot-ons have been used for many years, some with even lower minimum age limits; i.e.



### o 4 week age limit(EPA Reg. No. 

### 773

- 73);


### o 7 week age limit for permethrin in combination with imidacloprid (EPA Reg. No. 

### 11556 -132 to 

### 135 and 

### 11556 -141 to 

### 144);


### o 7 week age limit for permethrin in combination with dinotefuran (EPA Reg. No. 

### 83399

- 6).

• In the two Virbac Effitix studies on 

### 8 week old pups, there were 

## no**significan~** 

## gjtects observed in a total of twenty-four 

### 8 week old pups 

## at the IX

## dosing; and;

• There were also 

## no sig!/jiLcant effects observed in the twelve 

### 8 week old pups at the 

### 3X

## dosing.

• Significant adverse effects were only seen with 5 of 

## the 24 

## eight week old rums treated at 5X; 

## no adverse effects were seen at the lower dose levels ot3X

## and IX;


## • Because 

## of the rapid growth**otpup~** 

## moving the age limitation from 8 

## weeks 

## of age to 

## 10 weeks ot age and including a 5 

## Ib minimum weight restriction adds additional**si~niiLcant** 

## safetyfactors to 

## the label.

Thank you for consideration of our proposal. We would be happy to discuss this matter further with the Agency at any time.
Sincerely,



# o jimsig

Jim Barron, Ph. D. Managing Regulatory Consultant 

### EXponent®, 

### Inc. 1000 Centre Green Way Suite 200 Cary, NC 27513

Office Telephone (919) 228-6479 Mobile Telephone (919) 534-6018 Facsimile (919) 228-6501 Email Addressjbarron@exponent.com
CONFIDENTIALITY NOTICE: This electronic transmission (including any files attached hereto) may contain information that is privileged, confidential and protected from disclosure. The information is intended only for the use of the individual or entity named above and is subject to any confidentiality agreements with



### file:IIC:IDocuments and SettingslBAkinioslLocal SettingsITemplnotes87944BI-webI064.... I I19/20 

### II

### Page 3 of3

such party. If the reader of this message is not the intended recipient or any employee or agent responsible for delivering the message to the intended recipient, you are hereby notified that any disclosure, dissemination, copying, distribution, or the taking of any action in reliance on the contents of this confidential information is strictly prohibited. If you have received this communication in error, please destroy it immediately and notify the sender by telephone. Thank you

*********************** ATTACHMENT NOT DELIVERED *******************

This Email message contained an attachment named image001. jpg which may be a computer program. This attached computer program could contain a computer virus which could cause harm to EPA's computers, network, and data. The attachment has been deleted.

This was done to limit into the EPA network. sent from the Internet the distribution of computer viruses introduced EPA is deleting all computer program attachments into the agency via Email.

If the message sender is known and the attachment was legitimate, you should contact the sender and request that they rename the file name extension and resend the Email with the renamed attachment. After receiving the revised Email, containing the renamed attachment, you can rename the file extension to its correct name.

For fUrther information, please contact the EPA Call Center at (866) 411-4EPA (4372). The TOO number is (866) 489-4900.

*********************** ATTACHMENT NOT DELIVERED ***********************

file:IIC:IDocuments 

### and SettingslBAkinloslLocal SettingslTemplnotes87944BI-webl 064.... 1119/2011lNITED STATES ENVIRONMENTAL PROTECTION AGENCY \VASI-IINGTON, D.C 20460



### September 30, 2011

MEMORANDUM OFFICE OF OIDII(",\\. S,\n:TY AC\D POLU :no" l'IH;VEC\TlU:-;

OFFICE OF peSTlClnE I'ROGR,"I$

REGISTfUTlO,'; [)[VISIOC\ (75051')



### Subject: Name ofPesticide Product: EPA Reg. No.lFile Symbol: EFFITEX TOPICAL SOLUTION FOR DOGS 2382-RIT DP Barcode: Decision No.: Action Code: PC Code: DP 390816 448350 R310 109701 (Permethrin: 44.88%) 129121 (Fipronil: 6.01%)

From: Byron T. Backus, Ph.D.l Toxicologist Technical Review Branch Registration Division (7505P)

# (J~-()~ '1 

# 1"" ( 1..-0

# '.~{ " () ,



### To: Bonaventure AkinlosotuiRichard Gebken RM 10

Registrant: Insecticide Branch Registration Division (7505P)

VIRBAC AH, INC.

FORMULA nON FROM LABEL:

Active Ingredient(s): 129121 Fipronil 109701 Permethrin Other Ingredient(s): TOTAL

ACTION REQUESTED: The Risk Manager requests:

# ~~/fk.P**teL:Lcy;u;.j~~**

bywt. 6.01% 44.88% 49.11 % 100.00%

"For your review: MRID Nos. 484671-11 to 15; for an R310, new fipronil/pennethrin containing spot-on for dogs

..."



### 1

### BACKGROUND:

The material received for review includes a set of 5 acute toxicity studies (MRIDs 48467111- 48467115); a request for a waiver for the acute inhalation toxicity study; a proposed label (with the signal word CAUTION), a basic CSF (dated March 21, 2011), 

### a cover letter dated April 28, 2011, and
a data matrix.

COMMENTS AND RECOMMENDATIONS:

1. A 

### contractor (Summitec Corporation) did the primary reviews on the five acute toxicity studies and produced a DER for each study; TRB did secondary reviews on the DERs, making revisions where appropriate.

2. Four (the acute oral, dermal toxicity, prima:?1eye and primary dennal irritation) ofthe acute toxicity studies h,4e been classified as acceptable. In addition, TRB recommends for a waiver for the acute inhalation study data requirement, with the product being assigned to EPA Toxicity Category IV by this exposure route.

3. For the dermal sensitization study (MRID 484671 15) there was no indication that the test material is a dennal sensitizer. However, the provided positive control study was not conducted within six months ofthe current study, and the methods used in the positive control study were not described in adequate detail for the reviewer to be able to detennine whether the two studies were performed in a similar manner.

4. The folIowing is the acute toxicity profile of2382-RIT (EFFITEX TOPICAL SOLUTION FOR DOGS) based on the results ofthe acute toxicity studies, and with designation ofthe test material
as a dennal sensitizer in lieu of an acceptable dennal sensitization study:

Acute oral toxicity 

### III Acceptable MRID 4846711 I Acute dennal toxicity III 

### Acceptable MRlD 48467112 Acute inhalation toxicity IV Waived Primary eye irritation IV Acceptable MRID 48467113 Primary dennal irritation IV Acceptable MRID 48467114 / 

## , 

# /flr Dennal sensitization Positive a 

### Unacceptable MRID 48467115



### aIn lieu of an acceptable study, TRB recommends this product be classified as a sensitizer.

25. Based on the acute toxicity profile above, and taking into consideration the proposed uses specified on the label and infonnation in the CSP, the following would be the precautionary and 

### first aid labeling for EPA File Symbol 2382-RlT (EFFITEX TOPICAL SOLUTION FOR DOGS)
as obtained from the Label Review System:

PRODUCT ID #: 002382-00187

PRODUCT NAME: EFFITEX TOPICAL SOLUTION FOR DOGS

PRECAUTIONARY STATEMENTS SIGNAL WORD: CAUTION
Hazards to Humans and Domestic Animals:

Harmful if absorbed through skin. Harmful if swallowed. AVOid contact with skin, eyes or clothing. Wash thoroughly with soap and water after handling and before eating, drinking, chewing gum, using tobacco or using the toilet. Wear**long~sleeved** shirt and long pants, socks, shoes, and gloves. Remove and wash contaminated clothing before reuse. Prolonged or frequently repeated skin contact may cause allergic reactions in some individuals.

First Aid:

If on skin:**~Take** off contaminated clothing.**~Rinse** skin immediately with plenty of water for 15-20 minutes.**~CaU** a poison control center or doctor for treatment advice.

If swallowed:**~Call** a pOison control center or doctor immediately for treatment advice.**~Have** person sip a glass of water if able to swallow.**~Do** not induce vomiting unless told to by a poison control center or doctor.**~Do** not give anything to an unconscious person.
NOTE TO PHYSICIAN: Note to PMjCRMjRegistrant: The proposed label should contain a "Note to Physician". The following statements are suggested types of information that may be included, if applicable:**~** technical information on symptomatology;**~** use of supportive treatments to maintain life functions;**~** medicine that will counteract the specific physiological effects of the pesticide;**~** company telephone number to specific medical personnel who can provide specialized medical advice.

Have the product container or label with you when calling a poison control center or doctor or going for treatment. You may also contact**1-800-xxx~xxxx** for emergency medical treatment information.



### 6. The CSF (dated March 21, 20Il) for EPA File Symbol 2382-RlT should also be reviewed and accepted by the TRB Chemistry Team.



### 3

### DATA EVALUATION RECORD
PERMETHRIN; FIPRONIL {PROJECT 104.05]

STUDY TYPE: ACUTE ORAL TOXICITY

- RAT {OPPTS 870.1100; OECD 423] ACUTE DERMAL TOXICITY

- RAT {OPPTS 870.1200; OECD 402] ACUTE INHALATION TOXICITY

- RAT {OPPTS 870.1300; OECD 403] ACUTE EYE IRRITATION

- RABBIT {OPPTS 870.2400; OECD 405] ACUTE DERMAL IRRITATION

- RABBIT {OPPTS 870.2500; OECD 404] DERMAL SENSITIZATION

- GUINEA PIG {OPPTS 870.2600; OECD 406] MRID: 48467111,48467112,48467113,48467114, and 48467115

Primary Reviewer: Donna 

### L. Fefee. D.V.M. 

### Secondary Reviewers: Prepared for Registration Division Office ofPesticide Programs U.S. Environmental Protection Agency One Potomac Yard 

### 2777 

### South Crystal Drive

Arlington, 

### VA 22202
Prepared by Summitec Corporation 

### 9724 Kingston Pike, Suite 

### 602

Knoxville, Tennessee 37922

Task Order No. 3-B-42



### Signature: Date:

Thomas C. Marshall. Ph.D

.. D.A.B.T. Signature: Date:

Robert H. Ross, M.S., Program Manager


### Quality Assurance: Jennifer Goldberg, B.S. Signature: Date:



### Disclaimer 

## AUG] 

## ? lOll

AUG] 

## '1 lOll

This review may have been altered subsequent to the contractor's signatures above. 

# /4£:

### Reviewer: Byron T. Backus, Ph.D. Date: September 30, 2011 Risk Manager (EPA): 10

STUDY TYPE: Acute Oral Toxicity

- Rat; OPPTS 870.1100; OECD 423

TEST MATERIAL: Project 104.05; 6.75% (w/v) Fiproni!, 49.8% (w/v) Permethrin; Batch No.: NDE 08301-1; Clear, slightly yellow solution; Density: 1.1125 g/mL; Expiration Date: May 1, 2009; stored at room temperature; expected to be stable for the duration oftesting.

CITATION: Rached, E. (2009) Project 104.05: acute oral toxicity study in rats. Study Number C24620. Unpublished study prepared by Harlan Laboratories Ltd., Fullinsdorf, Switzerland. May 15, 2009. 58 p. MRID 48467111.

SPONSOR: Virbac SA, lere Avenue 2065 M - LID, BP 27, 06511 Carros Cedex, France.

EXECUTIVE SUMMARY: In a modified acute toxic class method oral toxicity study (MRID 48467111), five groups ofthree fasted, female HanRcc: WIST(SPF) rats were given single oral gavage doses ofundiluted Project 104.05 [6.75% (w/v) Fipronil, 49.8% (w/v) Permethrin; Batch #NDE 0830 I-I] at dose levels of2000 mg/kg bw (2 groups, steps 1 and 2), 300 mg/kg bw (2 groups, steps 3 and 4), or 500 mg/kg bw (1 group, step 5). The first four "steps" were in accordance with OECD 423. The animals were treated on day 1 and observed for up to 14 days. The animals were 11 weeks old, weighed**170.3~214.8** 

### g, and were supplied by Harlan Laboratories Ltd., Laboratory Animal Services (Fullinsdorf, Switzerland).

The three "step 1"**2000~mglkg** 

### animals were found dead between days 4 and 6, and one "step 2" 2000-mglkg animal was found dead on day 6. All "step 1" 2000-mg/kg animals had rumed fur on day I, at**3~5** 

### hours**post~dosing,** 

### and did not exhibit any subsequent abnormal clinical signs prior to being found dead on day 4, 5, or 6. All "step 2" 2000-mg/kg animals had rumed fur, beginning 2 hours after dosing and persisting through death (on day 6) for one animal or through day 12 for the survivors. Additional signs in the "step 2" animals included sedation on days 5 through**6~7** 

### (all 3 animals), reddish, serous nasal discharge in both survivors on day 7, and aggression and vocalization in both survivors between days 6 and 9. No abnormal clinical signs were seen in any ofthe animals dosed at 300 or 500 mglkg bw. Almost all ofthe animals gained weight during both weeks ofthe study; the exception was one**2000~mglkg** 

### survivor that lost weight during the first week but had a cumulative body weight gain over the entire study interval. Abnormal gross necropsy findings were noted in two**2000~mglkg** 

### animals. These included dark red discoloration ofthe lungs, gaseous distension ofthe stomach, reddish or yellowish discoloration ofthe stomach, small intestines, and
cecum (all noted in both ofthese animals), and reddish discoloration ofthe colon and rectum (in 

### one animal).

LD50 in females> 500 

### mglkg bw; 

### < 2000 mg/kg

Based on the acute oral LDso 

### > 500 mg/kg, Project 104.05 is in EPA Toxicity Category III by this exposure route.

This acute oral study is classified as Acceptable. 

### It satisfies the guideline requirement for an acute oral study (OPPTS 870.1100; OECD 423) in the rat.



### 5COMPLIANCE: Signed and dated GLP, Quality Assurance, and [No] Data Confidentiality statements were provided.

RESULTS and DISCUSSION: Individual animals were dosed as follows:

Group / Step Animal Number Dose Level (mg/kg) Short-Term Long-Term Outcome Outcome I S 0 I 2 2000 S 0 3 S 0 4 S S 2 5 2000 S S 6 S 0 7 S S 3 8 300 S S 9 S S 10 S S 4 II 300 S S 12 S S 13 S S 5 14 SOD S S 15 S S S - SurvIval, D Death

In the absence of mortality or persistent clinical signs oftoxicity, the second group was dosed 48 hours after the second group. Due to the delayed deaths at the initial dose level, subsequent groups were dosed at at least 4-day intervals. The first four "steps" were in accordance with OECD 423; the fifth group ofthree animals was dosed at 500 mg/kg bw with the stated intention of gaining additional information about the approximate LD50 ofthe test materiaL

Statistics: Statistical analysis and detennination of an exact LDso value were not done and are not required under OPPTS 870,1100 or OECD 423.

A. Mortality: Four ofthe six animals dosed at 2000 mg/kg bw were found dead (on days 4-6),



### B. Clinical observations: The three "step 1" 2000-mglkg animals had ruffled fur on day 1, at 3-5 hours post-dosing, and did not exhibit any subsequent abnormal clinical signs prior to being found dead on day 4, 5, or 6, The three "step 2" 2000-mg/kg animals had ruffled fur, beginning 2 hours after dosing and persisting through death (on day 6) for one animal or through day 12 for the survivors, Additional signs in the "step 2" animals included sedation on days 5 through 6-7 (all 3 animals), reddish, serous nasal discharge in both survivors on day 7, and aggression and vocalization in both survivors between days 6 and 9. No abnormal clinical signs were seen 

### in any ofthe animals dosed at 300 or 500 mg/kg bw. Almost all ofthe animals gained weight during both weeks ofthe study; the exception was one 2000-mg/kg survivor that lost weight during the fIrst week but had a cumulative body weight gain over the entire study interval.

C. Gross Necropsv: Abnonnal findings were noted in two ofthe decedent, "step 1" 2000-mg/kg animals. These included dark red discoloration ofthe lW1gs, gaseous distension ofthe stOl;nach, reddish or yellowish discoloration ofthe stomach, small intestines, and cecum (all noted in both of these animals), and reddish discoloration ofthe colon and rectum (in one animal), 6

### D. Reviewer's Conclusions: It is concluded that in the absence ofmortality and symptoms in the three rats dosed at 500 mg/kg the oral 

### LD50 can be set at >500 mg/kg. The deaths of 4/6 

### rats dosed at 2000 mglkg indicates the 

### LD50 < 

### 2000 mg/kg. We can use these findings to assign Project 104.05 to EPA Toxicity Category III by this exposure route.

E. 

### Deficiencies: None.



### 7

### Reviewer: Bvron T. Backus, Ph.D. Date: September 30, 2011 Risk Manager (EPA): 10

STUDY TYPE: Acute Dermal Toxicity

- Rat; OPPTS 870.1200; OECD 402

TEST MATERIAL: Project 104.05; 6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch No.: NDE 08301-1; Clear, slightly yellow solution; Density: 1.1125 g/mL; 

### Expiration Date: May I, 2009; stored at room temperature; expected to be stable for the duration of testing.

CITATION: Rached, E. (2009) Project 104.05: acute dermal toxicity study in rats. Study Number C24631. Unpublished study prepared by Harlan Laboratories Ltd., Ftillinsdorf, Switzerland. March 20,2009. 53 p. MRID 48467112.

SPONSOR: Virbac SA, I ere Avenue 2065 M - LID, BP 27, 06511 Canos Cedex, Frmlce.

EXECUTIVE SUMMARY: In an acute dermal toxicity study (MRID 48467112), a group offive male and five female HanRcc:WIST (SPF) rats was dermally exposed for 24 hours to W1diluted Project 104.05 [6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch #NDE 08301-IJ at a dose of 

### 2000 mglkg (=1.80 mLlkg) bw. The doses were applied to clipped application sites on the dorsal trunk**(~IO%** 

### ofthe body surface area) and covered by a semi-occlusive dressing wrapped around the trunk and secured with an elastic adhesive bandage. The day of application was considered to be day I, and the animals were observed for 14 days. The animals were supplied by Harlan Laboratories Ltd., Laboratory Animal Services (Flillinsdorf, Switzerland); males were 9 weeks old and weighed 250.5-265.6 g, and females were II weeks old mld weighed 186.6-195.0 g.
There were no deaths or abnormal gross necropsy findings. There were no abnormal systemic clinical signs in males, and all males gained weight during both weeks ofthe study. All five females exhibited splayed hind legs between days 2 and 5, and three females exhibited sedation and ventral recumbency on day 2. Two females gained weight during both weeks ofthe study; the remaining three females lost weight during the first week but had net body weight gain over the cumulative study interval. Erythema was noted on the dose sites of all animals ofboth sexes on day 2, and one male and one female also had erythema on the dose site on days 6-11. Additional findings on the dose sites included scales and/or crusts, which were noted on three males and four females, with onset on day 6 and resolution prior to day 15 in most cases.

LDso Males > 2000 mg/kg 

### bw LDso Females > 2000 mglkg 

### bw LDso Combined> 2000 mglkg 

### bw

Based on the acute dermal LDso for males, females, and the combined sexes, Project 104.05 is in EPA Toxicity Category III,

This acute dermal study is classified Acceptable. It does satisfy the guideline requirement for an acute dermal study (OPPTS 870.1200; OECD 402) in the rat.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and [No

## JData Confidentiality statements were provided.



### 8

### RESULTS and DISCUSSION:

Mortality/Number Tested Dose (mg/kg bw) Males Females Combined 2000 0/5 

## I 0/5 OlIO



### Statistics: Statistical analysis and determination of an exact LD50 value were not done and are not required under OPPTS 870.1200 or OECD 402.

A. Mortality: There were no deaths.

B. Clinical observations: There were no abnonnal systemic clinical signs in males. All five females exhibited splayed hind legs between days 2 and 5, and three females exhibited sedation and ventral recumbency on day 2. Erythema was noted on the dose sites of all animals ofboth sexeS 

### on day 2, and one male and one female also had erythema on the dose site on days**6~11.** 

### Additional findings on the dose site included scales and/or crusts, which were noted on three males and four females, with onset on day 6 and resolution prior to day 15 in most cases. All males and two females gained weight during both weeks ofthe study; the remaining three females lost weight during the first week but had net body weight gain over the cumulative study intervaL

C. Gross Necropsy: There were no abnonnal findings.

D. Reviewer's Conclusions: In agreement with the study author, the acute dennal 

### LD50 for males, females, and the combined sexes is greater than 2000 mg/kg bw. This places the test material in EPA Toxicity Category Ill.



### E. Deficiencies: None.

9

### Reviewer: Byron T. Backus, Ph.D. Date: September 30, 2011 Risk Manager (EPA): 10

STUDY TYPE: Acute Inhalation Toxicity

- Rat; OPPTS 870.1300; OECD 403

TEST MATERIAL: EffitixTM Topical Solution for Dogs; 6.01% Fipronil, 44.08% Permethrin; Enduse product for spot-on use in dogs.

CITATION: Parks, C. (2011) EffitixTM Topical Solution for Dogs (EPA File Symbol 2382-TBA);
new product application; waiver request. Study number: not applicable. Unpublished study prepared by Virbac Animal Health, Fort Worth, Texas. April 28, 2011. MRID 48467100.

SPONSOR: Virbac SA,lere Avenue 2065 M - LID, BP 27, 06511 Carros Cedex, France.

EXECUTIVE SUMMARY: Virbac Animal Health requests a waiver from the requirement to conduct an Acute Inhalation Toxicity study (OPPTS 870.1300). The waiver request is based on the following:
I) The measured vapour pressures ofboth active ingredients are extremely low. For fipronil it is 2.8 x 10-9 

### mm Hg at 25° C, and for permethrin it is 2.18 x 10-8 

### mm Hg at 25° C. 

### The active ingredients are not expected to vaporize from the skin following application, and, thus, will not be available for inhalation. 2) The potential human inhalation exposure to the product is expected to be negligible because only very small amounts ofproduct are applied per application. Application volume depends
on the weight ofthe animal, and the maximum volume to be applied to a single pet at one time is 6.0 mL. The 6.0 mL application volume is recommended only for use on dogs that weigh more than 89 pounds. According to the author, "Therefore, according to the proposed label, a great deal of anticipated product use will occur at much lower volumes on smaller dogs." 3) The method of applying the liquid product directly to the pet creates no particulates, aerosols,
or other respirable matter.

In considering this request, the reviewer agrees that non-volatile products, which cannot be readily aerosolized, and which are not heated or diluted to an inhalable state during application are likely waiver candidates. In addition, the Agency has routinely waived the data inhalation study requirement for spot-on products, based on the relatively small quantity ofproduct used and its application directly to the pet.

TRE recommends that the waiver request be granted. The product can be assigned to EPA Toxicity Category IV by this exposure route,

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements
were not 

### provided.

10

### Reviewer: Byron T. Backus, Ph.D. Date: September 30, 2011 Risk Manager (EPA): 10

STUDY TYPE: Primary Eye Irritation

- Rabbit; OPPIS 870.2400; OECD 405

TEST MATERIAL: Project 104.05; 6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch No.: NDE 08301-1; Clear, slightly yellow solution; Density: 1.1125 glmL; Expiration Date: May 1, 2009; stored at room temperature; expected to be stable for the duration oftesting.

CITA nON: Rached, E. (2009) Project 104.05: primary eye irritation study in rabbits. Study Number C24653. Unpublished study prepared by Harlan Laboratories Ltd., Filllinsdorf, Switzerland. April 30, 2009. 57 p. MRlD 48467113.

SPONSOR: Virbac SA, 1ere Avenue 2065 M - LID, BP 27, 06511 Carros Cedex, France.

EXECUTIVE SUMMARY: In a primary eye irritation study (MRID 48467113), 0.1 mL 

### of undiluted Project 104.05 [6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch #NDE 08301-1] was instilled into the conjunctival sac ofthe unanesthetized left eye of one male and two female New Zealand albino rabbits, and the upper and lower lids were held shut for approximately one second. Eyes were scored for ocular irritation according to the Draize method at 1,24,48, and 72 homs and at 7 days after instillation. The untreated right eye ofeach animal served as a control. The animals were 17 weeks old (male: 2.48 kg; females: 2.69-2.89 kg) and were supplied by Harlan Laboratories B.V. (Horst, the Netherlands).

There were no observations ofcorneal opacity or iritis. One hour after instillation ofthe test material, all three treated eyes had conjunctival redness, chemosis, and discharge (scores=l, 1-2, and 1-2, respectively). Conjunctival redness persisted in all three eyes through 72 hours after instillation, and chemosis persisted in one treated eye through 24 homs after instillation. The sclerae of all three treated eyes were slightly reddened at 1 hom and remained reddened in one animal through 48 hours after instillation. No "positive" findings were seen at or after 24 hours, and all eyes were clear of ocular irritation at 7 days. No abnormal systemic clinical signs were recorded. The maximum mean total score (MMTS) was 7.33, recorded one hour after instillation.

In this study, the formulation is mildly irritating. Based on the absence of "positive" findings at
or after 24 hours, Project 104.05 is classified as EPA Toxicity Category IV for primary eye irritation.

This study is classified as Acceptable. It does satisfy the guideline requirement for a primary eye irritation study (OPPIS 870.2400; OECD 405) in the rabbit.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and [No] Data Confidentiality statements were provided.

II

### RESULTS and DISCUSSION:

Number "positivc"/numbcr tested Observations Hours Days 1 24 48 72 7 Corneal Opacity 0/3 0/3 0/3 0/3 013 Iritis 0/3 0/3 0/3 0/3 0/3 Conjunctivae: Redness 

# . 0/3 0/3 0/3 0/3 0/3 Chemosis 

# . 1/3 0/3 0/3 0/3 0/3 Discharge** 1/3 0/3 0/3 0/3 0/3 Severity of Irritation: 7.33 2.67 2.00 2.00 0.00

Mean Total Score 

### " . . Score of2 or more reqUIred to be considered posItive.

# .. Not considered a positive irritation effecl; however, scores of2 or greaIer are noted here for completeness.



### A. Observations: There were no observations ofcorneal opacity or iritis. One hour after instillation ofthe test material, all three treated eyes had conjunctival redness, chemosis, and discharge (scores=l, 1-2, and 1-2, respectively). Conjunctival redness persisted in all three eyes through 72 hours after instillation, and chemosis persisted in one treated eye through 24 hours after instillation. The sclerae of all three treated eyes were slightly reddened at 1 hour and remained reddened in one animal through 48 hours after instillation. No "positive" findings were seen at or after 24 hours, and all eyes were clear of ocular irritation at 7 days. No abnormal systemic clinical signs were recorded.

B. Results: The maximum mean total score (MMTS) was 7.33, recorded one hour after instillation.

C. Reviewer's conclusions: The test material is mildly irritating to the eye and (in disagreement with the study author who indicated a Toxicity Category III classification was appropriate) is classified as EPA Toxicity Category IV for primary eye irritation.

D. Deficiencies: None.

12

### Reviewer: Bvron T. Backus, Ph.D. Date: September 30, 2011 Risk Manager (EPA): 10

STUDY TYPE: Primary Dermal Irritation

- Rabbit; OPPTS 870.2500; OECD 404

TEST MATERIAL: Project 104.05; 6.75% (w/v) Fipronil, 49.8% (w/v) Permethrin; Batch No.: NDE 08301-1; Clear, slightly yellow solution; Density: 1.1125 g/mL; Expiration Date: May 1, 

### 2009; stored at room temperature; expected to be stable for the duration oftesting.

CITATION: Rached, E. (2009) Project 104.05: primary skin irritation study in rabbits (4-hour semiocclusive application). Study Number C24642. Unpublished study prepared by Harlan Laboratories Ltd., Flillinsdorf, Switzerland. April 30,2009. 50 p. MRlD 48467114.

SPONSOR: Virbac SA, lere Avenue 2065 M - LID, BP 27, 06511 Carros Cedex, France.

EXECUTIVE SUMMARY: In a primary dermal irritation study (MRlD 48467114), one male and two female New Zealand albino rabbits were dennally exposed to 0.5 mL ofundiluted Project 104.05 [6.75% (w/v) Fipronil, 49.8% (w/v) Permethrin; Batch #NDE 08301-1] for 4 hours. The doses were applied to intact, clipped application sites on the left flank using a 6.25 cm2 

### surgical gauze patch that
was held in contact with the skin by an adhesive hypoallergenic semi-occlusive dressing and DennaPlast® restrainer bandage wrapped around the abdomen. The animals were observed for skin reactions at 1,24,48, and 72 hours after patch removal, and any irritation at the dose sites was scored according to Draize. The animals were 15-16 weeks old (male: 2.71 kg; females: 2.44-2.78 kg) and
were supplied by Harlan Laboratories B.V. (Horst, the Netherlands).

There were no observations ofedema. Very slight erythema (score=l) was noted on all three sites one hour after patch removal with resolution within 24 hours ofpatch removal. No abnonnal systemic clinical signs were reported.



### In this study, the Primary Irritation Index (PH) is 0.25, and the formulation is a slight irritant. Project 104.05 is classified as EPA Toxicity Category IV for primary dermal irritation.

This study is classified as Acceptable. 

### It does satisfy the guideline requirement for a primary skin irritation study (OPPTS 870.2500; OECD 404) in the rabbit.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and [No] Data Confidentiality statements were provided.

RESULTS and DISCUSSION:

INDIVIDUAL SKJN IRRITATION SCORES [ERYTHEMAfEDEMA! Hours after atch removal Animal No. Sex 0.5- t 24 48 72 81 M I/O 0/0 0/0 0/0 82 F I/O 0/0 0/0 0/0 83 F I/o 0/0 0/0 0/0 Severity of Irritation

- Mean Score 1.00/0.00 0.00/0.00 0.00/0.00 0.00/0.00



### 13

### A. Observations: There were no observations of edema. Very slight erythema (score= 1) was noted
on all three sites one hour after patch removal with resolution within 24 hours ofpatch removal. No abnonnal systemic clinical signs were reported.



### B. Results: The PH is 0.25.

C. 

### Reviewer's Conclusions: The test material is a slight irritant and is classified as EPA Toxicity Category IV.

D. Deficiencies: None.

14

### Reviewer: Byron T. Backus. Ph.D. Date: September 30, 20 II Risk Manager (EPA): 10

STUDY TYPE: Dermal Sensitization

- Guinea Pig; OPPTS 870.2600; OECD 406

TEST MATERIAL: Project 104.05; 6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch No.: NDE 0830 I-I; Clear, slightly yellow solution; Density: 1.1125 g/mL; Expiration Date: May I, 2009; stored at room temperature; expected to be stable for the duration oftesting.

CITATION: Arcelin, G. (2009) Project 104.05: contact hypersensitivity in albino guinea pigs, Buehler test. Study Number C24664. Unpublished study prepared by Harlan Laboratories Ltd., FOllinsdorf, Switzerland. March 20, 2009. 72 p. MRID 48467115.

SPONSOR: Virbac SA, I ere Avenue 2065 M - LID, BP 27, 06511 Carras Cedex, France.

EXECUTIVE SUMMARY: In a dermal sensitization study (MRID 484671 15), twenty young adult, male, CRL:(HA)BR Dunkin Hartley albino guinea pigs were tested with W1diluted Project 104.05 

### [6.75% (w/v) 

### Fipronil, 49.8% (w/v) 

### Permethrin; Batch #NDE 08301-1] using the Buehler method. A separate naiVe control group often males was treated at challenge only. The animals were 5-7 weeks old, weighed 350-449 g, and were supplied by Charles River Deutschland GmbH (Kisslegg, Germany).

No positive dermal reactions were seen following challenge with the undiluted test material. No abnormal systemic clinical signs were reported, and all ofthe animals gained weight over the course ofthe study.

Based on this study! it cannot be determined whether Project 104.05 is a dermal sensitizer.

This study is classified as Unacceptable. It does not satisfy the guideline requirement for a primary dermal sensitization study (OPPTS 870.2600; OECD 406) in the Guinea pig. The study may be upgraded pending receipt of an adequately reported positive control study, conducted within the appropriate time frame, provided the results are appropriate.

COMPLIANCE: Signed and dated GLP, Quality Assurance, and [No] Data Confidentiality statements were provided.

I. 

### PROCEDURE

A. Induction: The animals were clipped prior to each treatment. For each ofthree successive weekly inductions, 0.5 mL ofthe W1diluted test material was applied to the left shoulder of each animal using
an occlusive 25 mm Hill Top Chamber® and secured in place with adhesive tape wrappings for six hours. Reactions were scored 24 hours post application.



### B. Challenge: Twenty-eight days after the first induction, the test animals were challenged with 0.5 mL ofthe W1diluted test material (the highest non-irritating concentration according to preliminary testing), applied to naive sites on the left flank of each animal for 6 hours using the same procedure. Reactions were scored 24 and 48 hours post application.

15

### C. Naive Controls: At challenge, a separate "naive" group often previously untreated animals was also treated with 0.5 mL ofthe undiluted test material. Reactions were scored 24 and 48 hours post application.

II. RESULTS and DISCUSSION:

A. Reactions and duration: No irritation was noted on any ofthe application sites ofthe treated animals following any ofthe induction or challenge doses. Following challenge, no erythema was noted on any ofthe naIve controls at either time point.

B. Positive control: The study report included the results from a positive control study with alphaHexylcinnamaldehyde CRCC Study #B86027), completed on May 5, 2008, which is not within six months ofthe in-life dates (January 14 to February 19, 2009) ofthe current study. It cannot be detennined whether the induction and challenge procedures used 

### in both studies were similar. One clear difference between the two studies is that two different challenge doses were used in the positive control study.



### C. Reviewer's Conclusions: In agreement with the study author, under the conditions ofthis study, the test material is 

### not a dennal sensitizer. However, due to the below-mentioned deficiencies related to the positive control study, the current study is classified as unacceptable and does not satisfy the guideline requirement. The study may be upgraded pending receipt of an adequately reported positive control study, conducted within the appropriate time frame, provided the results are appropriate.

D. Deficiencies: The provided positive control study was not conducted within six months of the current study, and the methods used in the positive control study were not described in adequate detail for the reviewer to be able to detennine whether the two studies were perfonned in a similar manner.



### 16

### ACUTE TOX ONE-LINERS:

1. DP BARCODE: 390816 2. PCCODE: 109701,129121 3. CURRENT DATE: Auoust 1\,2011 4. TEST MATERIALS: 

### • Project 104.05 [6.75% (w/v) Fipronil, 49.8% (w/v) Pennethrin; Batch #NDE**08301~** 1] 

## • EffitixTM Topical Solution for Dogs; 6.01 % Fipronil, 44.08% Pennethrin; End-use product for spot-on use in dogs Study/Species/Lab MRlD Results Study # IDate Acute oral toxicity / rat 48467111 LDso in Females> 500 mglkg, < 2000 Harlan Laboratories Ltd. mglkg Study #C24620 / May 15,2009 Acute dennal toxicity / rat 48467112 LDso Males > 2000 mg/kg Harlan Laboratories Ltd. LDso Females: > 2000 mg/kg Study #C24631 / March 20, 2009 LDso Combined > 2000 mg/kg Acute inhalation toxicity / rat N/a Waived Yirbac Animal Health No Study # I April 28, 2011 Primary eye irritation I rabbit 48467113 Mildly irritating; Harlan Laboratories Ltd. MMTS=7.33, at one hour; no positive Study #C24653 I April 30,2009 effects present at or after 24 hours. Primary dennal irritation Irabbit 48467114 Slight irritant; PH 0.25; Harlan Laboratories Ltd. All sites clear of irritation at 24 hours. Study #C24642 I April 30, 2009 Dennal Sensitization Iguinea pig 48467115 No indication ofdennal sensitization, Harlan Laboratories Ltd. but positive control study not within 6 Study #C24664 I March 20, 2009 months ofthis study.



# . Core Grade Key. A Acceptable, S Supplementary, U Unacceptable, W WaIved N/a = Not applicable



### 17 Tox. Core Cat. Grade

III A

1lI A

IV W

IV A

IV A



# -- U

### June 21, 2011



### Bonaventure Akinlosotu, PM Team 10 Office ofPesticide Programs (7504P) 

### U.S. Environmental Protection Agency Document Processing Desk Room S-4900, One Potomac Yard 2777 South Crystal Drive Arlington, VA 22202

Subject: Efftix® Topical Solution for Dogs (EPA Reg. No 2382-RlT); Revised Proposed Labeling. 

### Dear Dr. Akinlosotu, Virbac Animal Health (Virbac AH, Inc. P. O. Box 162059, Ft. Worfb, Texas, Company 

### Number 2382), made the submission mentioned above on April 28, 

### 2011. Although not confimled in writing, we understand the unofficial PRIA date ofthis 

### action is November 19, 2011, Please confinn this for us as soon as possible for our records. We see that the submitted 

### studies are in NPIRS, but we also still have not received a confinnatory PR-86-5 compliance statement from the front end.



### During the course ofthe 

### beginning phases of label printing and production, Virbac has located some minor errors and word changes in the original submitted label that it wishes to 

### be refelected on the final stamped label. Therefore please find five copies ofproposed labeling that
we request be utilized in the label review process ofthis 

### submission. For security, please shred for us the original labels carrying the date ofApril 28, 2011.



### Sincerely,

Craig Parks, MS, DVM Vice President, Research & Development Virbac Animal Health, Inc.



### 3200 Meacham Blvd .• Fort Worth, TX 76137 Telephone: (817) 831-5030. (800) 338-3659. Fax (817) 831-8327

# Virbac's Master Label
Date 21JUN11 Version US-S EPA Reg. No. 2382·RIT Flpronil+?ermethrin Topical Solution for Dogs Optional text appears in brackets. 

# EFFITIXTM TOPICAL SOLUTION FOR DOGS Alternate brand names: 

# (EFFIXTM TOPICAL SOLUTION FOR DOGS) 

# (EFFICANIXTM TOPICAL SOLUTION FOR DOGS) 

# (EFFIPROTIXTM TOPICAL SOLUTION FOR DOGS)
FOR USE ONLY ON DOGS AND PUPPIES 8 WEEKS OLD OR OLDER (WEIGHING UP TO 22.9 LBS, WEIGHING 23 TO 44.9 LBS, WEIGHING 45 TO 88.9 LBS, WEIGHING 89 TO 132 LBS) ACTIVE INGREDIENTS: FiproniL

.. Permethrin*

.. OTHER INGREDIENTS:

. TOTAL: ."
• cis/trans ratio: maximum 55% (±) cis and minimum 45% (±) trans

HAZARDS TO HUMANS KEEP OUT OF REACH OF CHILDREN 

### CAUTION READ ENTIRE LABEL BEFORE EACH USE

PRECAUTIONARY STATEMENTS HAZARDS TO HUMANS AND DOMESTIC ANIMALS ....... 6.01%

..... 44.88%

. .... 49.11% 100.00%

Harmful if swallowed. Causes eye irlitation. Avoid conlaci with skin, eyes, or clothing. Wash hands thoroughly with soap and waler after handling and before eating, dlinking, chewing gum, using tobacco, or using the toilet. HAZARDS TO DOMESTIC ANIMALS For external use on dogs ONLY.

DO NOT USE ON CATS -IF INGESTED BY CAT THAT ACTIVELY GROOMS A RECENTlYTREATED'DDG, THIS PRODUCT MAY HAVE SERIOUS HARMFUL EFFECTS. IFTHIS OCCURS, CONTACT YOUR VETERINARIAN IMMEDIATELY.

Do not use on puppies under 8 weeks of age. Individual sensitivities, while rare, may occur after using ANY pesticJde product. Dogs may experience some temporary irritation at the site of product application. If signs of sensitivity occur, balhe your pet with mild soap or shampoo and linse with large amounts of water. If signs of sensitivity occur and persist, contact a veterinarian immediately. If your dog has an unusual reaction to the initial application, consult a veterinarian before repeating application. Certain medications can interact with pesticides. Consult a veterinarian before using on medicated, debilitated, aged, pregnant or nursing dogs, or animals known to be**sens~ive** to pesticide products.

EPA Reg. No. 2382·RIT JXl.gc I of 7**~** Draft label versiolJ 9 June 212011FIRST AID

, IF SWALLOWED: 

### • Catt a poison control center or doctor immediately for treatment advice. 

# · Have person sip a glass ofwaler if able to swattow. 

# · Do not induce vomiting unless told to do so by a poison control center or doctor.


### • Donol ive anything to an unconscious person. IFIN EYES: 

### • Hold eye open and rinse slowly and gentty with water for 15-20 minules.


### • Remove contact lenses, if presenl, after the first 5 minutes, then continue rinsing eye. 

### • Catt a ooison contrOl center or doclor for treatment advice. IF ON SKIN OR 

### • Take off contaminated clothing. CLOTHING: Rinse skin immediately with plenty of water for 15"20 minutes. 

### • 

# · Catt a poison control center or doctor for trealment advice. Have product container or label with you when calling a poison control center or doctor, or going for treatment You may also contact the Hotline number 1-800-338-3659 for human or vetertnary health concerns, emergency medical treatment Information or pesttclde Incidents.

DIRECTIONS FOR USE It is a**viola~on** of Federal law to use this product in any manner inconsistent with its labetting. Do nol attow children to apply product. TO PREVENT HARM TO YOU AND YOUR DOG, READ ENTIRE LABEL AND DIRECTIONS BEFORE EACH USE. FOLLOW ALL DIRECTIONS AND PRECAUTIONARY STATEMENTS CAREFULLY. FOR EXTERNAL USE ON DOGS ONLY. DO NOT USE ON CATS OR RABBITS. DO NOT USE ON OTHER ANIMALS. DO NOT USE ON CATS. FOR EXTERNAL USE ON DOGS ONLY. Do not use on puppies under 8 weeks of age. Do not split tubes between dogs. Do not use multiple tubes on one dog. Weigh your dog to be sure you are applying the right dose formulated for the weight of your dog. Overdosing your dog can result in serious illness. Do not bathe your dog within the first 24 hours after the product has been applied. If your dog is exhibiting Signs of andlor is being treated for skin problems,lalk to your veterinarian before applying any topical flea and tick control product. Do not apply more often than once a (per) month (every 30 days).

For use in DOGS and PUPPIES (8 weeks old or older). To repel and kilt fleas, ticks, and mosquitoes; to kill lice and mijes; 10 repel and prevent blood feeding by sandflies and biting flies. Apply monthly according to directions.
APPLICATION DIRECTIONS

1. Remove one applicator from packaging. Hold applicator upright and remove cap. 2. Invert cap and place other end back onto applicator tip. Push cap down to break seat. Remove cap prior to treatment application. 3. Part dog's ha'lr untit skin is visible. Place applicator tip directly against exposed skin. 3a. For small dogs and puppies 8 weeks old or older and up to 22.91b$- Deposit entire contents by squeezing Ihe entire applicator conlents onto dog"s skin. at a single sHe, between the Shoulder blades as shown in diagram 3a. 3b. For medium dogs 23-44.9 lbs or largo dogs 45-88.9 Ibs- Apply the product evenly to three spots on the don'S oack starting between the shoulder blades and continuing on to the second and third spols as shown in diagrom 3b, squeezing the applicator until empty. 3c. For extra large dogs 89·132 Ibs- Apply the product evenly to four spots on the dog's back, starting between'<he shoulder blades and continuing on to the second, third and fourth spots as shown in diagram 3c. squeezing the applicator untit empt¥,: Ensure that EFFITIX \ Topical Solution for Dogs is not applied superficially on dog's hair.

# o~

# ~**,,~ \~**  

# °t ! .--... ,

# ~~:,?:~~1 \ 

# H
)1

### ~- 

# 1")"**~** ," 

# V V

.**~** ;**llIlo::l~lMpro..""l~y.:tlI** lltg'.,..ormOlJ'JI 3,



### I EPA Reg. No. 2382-RIT _page 2 of 7 - Dral"t label version 9 June 21 2011 3b**Dor<lIMt\!poj"\I~1'" d'i'<Ii'''~''\\**  3,FREQUENCY OF APPLICATION Research has shown that flea, tick, (sucking, biting and cheWing) lice and**m~e** Infestations, can be completety controlled With monthty applications of EFFtTIXTM Topical Solution for Dogs Biting files and mosqUitoes are (at so) repelled by EFFITIXTM Toplcat Solution for Dogs.

Fteas: EFFITIXTM Topical Solution for Dogs can start killing adutt fleas within 6 hours and lasts for up to three months. Appty monthty if your dog has fleas that may cause fiea allergy dermatitis (FAD), or if re-infestation is tikety. Ticks: EFFITtXTM Topical Sotution for Dogs can kill ticks for at teast a month. Apply monthty where tick control is consistently needed. Lice: EFFITIXTM Topicat Solution for Dogs can kitl SUCking. biting and chewing tice for a month or longer. Apply monthty where lice control is consistently needed. Mites: When applied monthty, EFFITIXTM Topical Sotution for Dogs kills mites. BIting flies and Mosquitoes: When apptied monthly, EFFITIXTM Topicat Solution for Dogs (prevents blood feeding by) (and) (kills) (and) (repets) biting flies and mosquitoes for up to 4 weeks (a (one] month). Kills mosquitoes for up to four weeks (a [one] month).

Notes: wait at teast 30 days before re-apptication of EFFITIXlM Topicat Sotution for Dogs. Avoid contact with treated area until dry.

STORAGE AND DtSPOSAL Do not contaminate water, food, or feed by storage and disposal. STORAGE: Store unused product in original container only, out of reach of children and animats. PESTICIDE /CONTAINER DISPOSAL: If empty: Nonrefillable. Do not reuse or refitl this container. Offer for recycling, if available. If partially filled: Call your tocat sotid waste agency for disposal instructions. Never ptace unused product down any indoor or outdoor drain. LIMITED WARRANTY AND DISCLAtMER VIRBAC warrants this product only if il is used, stored and handled in accordance with the label instructions. The buyers and users are solely responsible for all risks of use and handling of this product when such use and handling are conlrary to or differ from the labet instructions. To the extent permitted by applicable law, any damages arising from a breach of this warranty shall be limijed to direct damages only and shall not inctude any type of consequential damages.

How supplied: For easy and convenient application, EFFITIXTM Topical Solution for Dogs is avaitabte in Sizes for small dogs and puppies 8 weeks old or otder and up to 22.9 Ibs (0.034 fI oz)/(1.0 mL). medium dogs 23-44.9 Ibs (0.068 fI oz)/(2.0 mL). taTge dogs 4S-88.9Ibs (0. t35 fI oz)/(4.0 mL). and extra large dogs 89-1321bs (0.203 fI oz)/(6.0 mL). Net Contents: 1 (3,6 or 36) single-dose applicator(s) per package containing 1mL (2mL. 4mL or 6mL)/ 0.034 fI oz (0.068 fI oz. 0.135 fI oz. 0.203 fI oz) (of solution).
(Detachable) catendar (monthly application) reminder stickers (with illustration of dog or puppy)

EPA Reg. No. 2382-RIT EPA Est. No. 2382-FRA-1

VIRBAC AH, INC. PO BOX 162059 FORT WORTH TX 76161 1-800-338-3659

Made in France EFFITIXTM is a trademark of Virbac SA QUestions or comments? Calt: 1-800-338-3659 

### {Text for Front Panel, Back Panel, Inside Flap and Side Panel}

See package insert(s) for directions for use and frequency of application See package insert for directions for use and storage and disposal See package insert for frequency of application and storage and disposal Open resealable label for directions for use Open resealabte tabet for directions for use and storage and disposal See back panel for additional prec.autionary statements See package insert(s) for frequency of application See enclosed insert(s) for directions for use and storage and disposat See enclosed insert(s) for directions for use Lift here to open (LIFT HERE TO OPEN) For Use on Dogs ONLY Use ONLY on dogs See inside fiap for directions for use 

### {Text for Foil of Blister package} Virbac EFFtTtXTMTopical Solution For Dogs


### I EPA Reg No. 2382-RtT ,page 3 of 7 - Draft tabet version 9 June 2 t 20t tOnly for use on dogs up to 22.91bs (23-44,9Ibs, 45-88.9Ibs. 89-t32Ibs}/0.034 n oz (0.068 n oz. 0.135 n oz, 0.203 n oz) (1.0 mL, 2.0 mL, 4.0 mL, 6.0mL) Contains fipronil (S.01 %) and permethrin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUTION See full label for addilional directions EPA Reg. No. 2382-XXX DO NOT USE ON CATS CAT PROHIBITION ICON 

### {Text for Applicator Tube} Virbac EFFITlXll.I Topical Solution For Dogs Only for use on dogs up to 22.91bs (2344.9Ibs, 45-88.9Ibs, 89-132Ibs) 0.034 n oz (0.068 fl oz, 0.135 fl OZ, 0.203 n oz) [/1.0 mL (2,0 mL, 4.0 mL, S.OmL)[ Contains fipronil (S.01%) and permelhrin (44.88%) KEEP OUT OF REACH OF CHILDREN CAUTION See full label for additional directions DO NOT USE ON CATS EPA Reg. No, 2382-XXX CAT PROHIBITION ICON

• Illustration of flea life cycle Illustration of tick life cycle Illustration of mosquito life cycle

• Illustration of mite life cycle IIlustraUon of louse life cycle

• Illustration of nea
• IIluslration oftick
• Illustration of mosquito Illustration of mite Illustration of louse

• Picture or illustration of a dog (or puppy)
• Picture or illustration of the Virbac logo

• Picture or illustration of the primary package (applicator tubes) 

### MARKETING CLAIMS

[Multiple infostations] For convenient, quick-acting, long-lasting, effective control of neas, ticks, mosquitoes, lice and mites.
• (When) Applied topically on a monthly basis, EFFITIXThi Topical Solution for Dogs repels and kills neas, ticks and mosquitoes, kills (biting, chewing and sucking) lice and mites, and repels and inhibits blood feeding by biling nies and mosquitoes.
• (When) Applied topically on a monthly basis, EFFITIXTM Topical Solution for Dogs repels and kills fleas, ticks and**mosqu~oes,** kills (biting, chewing and sucking) lice and mites, and repels and inhibits blood feeding by biting flies, sandflies and mosquitoes. For easy and convenient application. EEFITIXrM Topical Solution for Dogs is available in sizes tor small dogs and' puppies 8 weeks old or older and up to 22.9 Ibs (0.034 n oz)(1.0 mL), medium dogs 23-44.9 Ibs (0.OS8 n oz) (2.0mL), lerre 00']5 45-88.9Ibs (0,135 n oz) (4.0 mL), and extra large d09S 89-1321bs (0.203 n oz) (6.0 mL). EFFtTlXThI Topical Solution for Dogs contains the aClive ingredients fipronil and permethrin, whi('.h (,0'11'('1 infestations caused**~** fleas, ticks, lice, and mites; repel against biting flies, and repel and kill mosquitoes. , • EFFITIX Topical Solulion for Dogs contains the active ingredients fipronil and permethrin, which conlrol infesta:ior,s caused by neas, ticks, lice. and**m~es;** repel against biting flies, and sandflies, and repel and kill in<Ji-quIII,es.

• Kills neas, ticks, lice, mites and mosquitoes, repels biting flies and mosquitoes
• Repels and kills fleas and ticks Repels fleas, ticks, biting flies and mosquitoes Repels neas. ticks, biting flies, sandflies and mosquitoes Kills, repels and detaches ticks
• Kills lice and mites
• Forthe control and prevention ofnea [and lice] infeslations

• ResearCh has Shown that nea, tick, (sucking, biting and chewing) lice and mite infeslations, can be completely co.llrolled with monthly applications of EFFITIXll.I Topical Solution for Dogs. Biting flies and mosquitoes are (also) repelled by EFFITIXll.I Topical Solulion for Dogs.

• Controls highly [initating[ [annoyingl [neal bites
• Effective monthly application against neas, ticks and mosquitoes
• Kills fleas, ticks and mosquitoes for one month Monthly application is recommended for control and prevention of fleas, ticks and mosquitoes 

### I EPA Reg. No. 2382-RIT JXlgc 4 of 7 - Draft label version 9 JUlie 2 I 20t I

### • •

• • •

{Fleas1 

### •

•

• • •

•

• • • • •

• • • • • •

•

• • [TIcks]



### •

• Long lasting flea, tick and mosquito control for your pet EFFITIXlM Topical SOlution for Dogs is indicaled for the prevention and contrOl of fleas, ticks, biting flies, mosquitoes, and lice on dogs 8 weeks of age and older Helps to relieve your dog's pain (diSComfort) by controlling flea, tick, mite and lice infestations Kills the vectors that may transmit Lyme disease, Rocky Mountain spotted fever. ehrlichiosis, hepatozoonosis and heartwonn disease. Kills fleas, ticks, mosquitoes, lice, and mites Kit!s and repels fleas, ticks, and mosquitoes. (Also) kit!s tice and**m~es.**

Fleas: EFFITIXTM Topical Sotution for Dogs can kill adult fleas in 6 hours for up to three months. Apply monlhly if your dog has fleas that may cause flea allergy dermatitis (FAD), or if reinfestation is likely. Kills newly emerged adult fleas prior to egg laying Kit!s fleas (within 6 hours) that may transmit bartonellosis, (tularemia) (and tapewonn) Kit!s fleas (wilhin 6 hours) that may transmit diseases, including bartonellosis, (tularemia) (and tapeworm infestations) Kills fleas (wilhin 6 hours) that may transmit diseases, including bartonellOSiS and tularemia Rap'ld kill of fleas is important in the prevention of olsease transmiSSion by (these) paras·rtes Acts to kill fleas that may**transm~** disease, such as bartonellosis and tularemia Kills fleas that may serve as an intermediate host for tapewonns (Dipylidium caninum) Kills fleas that may serve as an intennediate host for cysticercoids of tapeworms Kills fleas that may serve as hosts for life cycle intennediates of tapewonns Kills (adult) fleas (within 6 hours) that may cause Flea Allergy**Dennal~is** (FAD) (or) (f1ea·bite anemia) Fleas do not have to bite to die EFFITIXlM Topical Solution for Dogs rapidly kills fleas that may cause FAD (Flea Allergy Dermatitis) The successive feeding activity of fleas on dogs may elicit a hypersensitivity skin disorder known as Flea Allergy Dermatitis (FAD)**EFFITIXn~** Topical Solution for Dogs kit!s fleas and may reduce the incidence of Flea Allergy**Dennat~is** (FAD) Effective monthly application against fleas Effective monthly conlrol of fleas Kills adult fleas for up to one month (4 weeks) Kills fleas Easy to apply, (effective) control of (for) fleas that lasts up to 1 month (4 weeks) EFFITIXlM Topical Solution for Dogs kills fleas on your dog Once a month topical flea control for dogs 8 weeks of age or older EFFITIXlM Topical Solution for Dogs is indicated for the prevention and control of fleas on dogs 8 weeks of age and older One application prevents further flea infestations for up to (4 weeks) (a [one] month) Monthly treatment (all year) is recommended for control and prevention of fleas Regular (monthly) use breaks the flea life cycle Provides ongoing proteclion against fleas and the diseases they may transmit for one month Stops existing flea infestations by rapidly killing adult fleas Kills fleas before they lay eggs Stops existing flea infestations by killing adult fleas Prevents [Stops] re-infestations by killing adult fleas (before they lay eggs) Effectively breaks the flea life cycle Treatment with EFFITIXTM rapidly kills fleas which may cause flea allergic dennatitis [FAD] or fiea bite**hypersens~iv~y** Controls flea problems Provides flea protection Use flea r\frevention[ [protection[year-round EFFITIX Topical Solution for DogS controls flea infestation that may lead to painful skin irritation and bacterial infection

Ticks: EFFITIXTM Topical Solution for Dogs can kit! ticks for at least a [one] month. Apply monthly where tick ct:1trol is consistently needed. Kills and repels at! stages of Brown dog ticks, American dog licks, Lone Star ticks, and Deerticks (that may trans,T"t Lyme disease, Rocky Mounlaln Spotted Fever, babesiosis, ehrtichiosis and anaplasmosis) Kills licks including Deer ticks (that may transmit Lyme disease), American dog ticks (that may ,trfl,)siTJi( Rocky Moun'ain Spoiled Fever), Brown dog ticks (that may transmit ehrlichiosis), and Lone Star ticks (thai may**Tan~:nit** hepatozoonosis) for up to one month (4 weeks)

. Kills ticks including Deer ticks (that may transmit Lyme disease), American dog ticks (that may ,r"r,$,n,t i<;ocky**~Iouma,n** Spotted Fever), and Brown dog tickS (that may**transm~** ehrlichiosis) for up to one month (4 weeks). Kit!s Brown dog ticks (Rhipicephalus spp), American dog ticks (Dennacenforvariabilis), Deer tirk" rlv('des spp)/md Lone Starticks (Amblyomma ameriCanum) for up to one month (4 weeks). Kills Amblyomma americanum (Lone Star ticks) for 4 weeks (for up to one month). Effective monthly application against ticks [Mosquitoes, sandflies and biting fIIes1

• Kills**mosqu~oes** Kills mosquitoes for up to 28 days (four weeks) (a (one] month) Repels and inhibits blood feeding by biting flies and mosquitoes


### I EPA Reg. No. 2382-RIT .page 5 of 7 - Draft label vClSion 9 June 2t 20] tRepels and inhibits blood feeding by biting fiies, sandfiies and mosquitoes Biting flies and mosquitoes: When applied monthly, EFFITIXTM Topical Solution for Dogs prevents blood feeding (repels) for up to 4 weeks (a lone] month)
• Biting flies, sandflies and mosquitoes: When applied monlhly, EFFITIXTM Topical Solution for Dogs prevents blood feeding (repels) for up to 4 weeks (a [one] month) Repels and kills mosquitoes for up to four (4) weeks Prevents blood feeding by mosquitoes Repels and prevents blood-feeding by biting flies

• Repels and prevents blood-feeding by sandfiies Repels and kills mosquitoes often before they have a chance to take a blood meal [(Prevents blood-feeding by) (Kills and repels)] mosquitoes Repels**b~ing** flies Repets sandflies
• Repels and inhibits blood"feeding by biting flies
• Repels and inhibits blood-feeding by sandfiies
• Repels [(annoying)(bolhersome)(nuisance)] biting flies
• Inhibits [(annoying)(bothersome )(nuisance)] biting flies
• Repels [(annoying)(bothersome)(nuisance)J sandflies Inhibits [(annoying)(bothersome )(nuisance)] sandflies

• [(Prevents)(inhibits)] blood-feeding by biting flies
• [(Prevents)(inhibits)] blood-feeding by sandflies
• Kills**mosqu~oes** that may carry heartworm disease Repels and kills mosquitos (Culex spp, Ochlerota/usspp, Aedes spp) which may vector heartworm (Dirofilaria immilis) for one month [Lice and Mites] Lice: EFFITIXTM Topical Solution for Dogs can kill sucking, biting and chewing lice for a [one] month or longer. Apply monthly where lice control is consistently needed.
• Mites: When applied monthly, EFFITIXn.! Topical Solution for Dogs kills mites.

•**M~es** (Chey/etie//a yasgun): When applied monthly, EFFITIXTM Topicat Solution for Dogs kills Chey/e/iel/a yasguri mites.
• When applied monthly, EFFITlXTM Topical Solution for Dogs aids in the control of sarcoptic mange**(m~e),** and Cheyletiella yasguri mite infestations Kills mites (that may cause sarcoptic mange) Aids in (the) control of sarcoptic mange mite infestation Kills chewing, biUng and sucking tice Controts existing chewing/biting/sucking (chewing. biting and sucking) lice infestations Kills [(biting) (chewing)] lice For control and prevention of](biting) (chewing)] lice (infestations) Stops existing ((biting) (chewing) (sucking)] lice infestations Prevents and controls ](biting) (chewing)(suckingJ[ lice (infestations)

• Provides effective controt of](biting) (chewing) (sucking)] lice (infestations)
• Kills ](biting) (chewing)(sucking)]lice and prevenls further infestations
• For control and prevention of (infestations with) [(biting) (chewing) (suckinglllice [Others] • 1 (3, 6, 36) applicator(s) (tube[s]) 1.0 mL (2.0 mL, 4.0 mL, 6.0 mL) 1 (3, 6, 36) appl"lcator(s) (tube[s]) 0,034 fl oz (0.068 fl oz, O. t35 fi oz, 0.203 fl oz) 1 (3, 6, 36) applicator(s) (tube[s]) 0.034 fl oz [1.0 mL] (0.068 fi oz ]2.0 mL), 0.135 fl oz [4.0 mL], 0.203 fi oz [6.0 mL]) 1 (3. 6, 36) applicator(s) (tube]s]) (each) containing 0.034 fi oz [1 ,0 mL] (0.068 fl oz ]2.0 mL), O. t35 fl oz [4.0 mLt 0.203 fi OZ ]6,0 mL]) t (3, 6, 36) applicator(s) (tube[s]) 1 (3,6,36) monthly dose(s) (application]s]) 1 (3,6,36) applicator(s) (tube]sj) 1 (3, 6, 36) month(ly) dose(s) (apptication(s)

• DO NOT USE ON CATS
• (For dogs and puppies) 8 weeks (of age) or older May be used on puppies from 8 weeks of age This product is only for use on dogs up to 22.9 Ibs (weighing 23 to 44.9Ibs, weighing 45 to 88.9Ibs, weighing 89 ,0 132 Ibs)

• Up to 22.91bs (weighing 23 to 44.9 Ibs, weighing 45 to 88,91bs, weighing 89 to t321OO)
• Easy and convenient application (applications)
• Remains effective for a (one) month (4 weeks) Stops existing infestations and prevents establishment of new infestations Reinfestation 01 fleas, ticks and mosquitoes, (biting, chewing and sucking) lice and mites, and biting**'~i,",s** is prevd,lf!d tor a (one) month or longer Convenient topicat \leatment for dogs Quick onset of**activ~y** Persistent efficacy through 30 days Prevents (re-)infestation for one month Once monlhly application
• Quick drying, non-greasy
• (Convenient) (to use) Easy (to apply) spot-on (topical) application
• Fragrance (odor) free 

### I EPA Reg. No. 2382-RIT _page 6 of 7 - Draft label veBion 9 June 2 I 201 INO noticeable odors Single application lasts 4 weeks (one month)**{3~** days) Easy to use applicator makes treatment simple (trouble free, smooth) and comfortable for your pet Convenient, easy to apply topical solution

• Convenient, easy to apply and fragrance free topical solution
• Starts working by (on) contact
• (In) child-resistant packaging

• Convenient (to use). easy to apply (topical solution)
• EFFITIXTM Topical Solution for Dogs remains effective after bathing, shampooing, water immersion, or sunlight exposure.
• Walerproof (remains effective after bathing and swimming) for up to four weeks (a month) (one month) Remains effective after exposure to sunlight
• Remains effective even after bathing, water immersion, or exposure to rain or sunlight Remains effective even after bathing (and swimming) Remains effective after exposure to rain and/or sunlight Still works after bathing, swimming or exposure to sunlight

• Maintains residual efficacy after bathing and swimming
• Remains effective after bathing (and swimming) [(for a month) (for one month) (for up to four weeks)]
• For dogs that enjoy the outdoors For indoor and outdoor dogs

• Convenient topical treatment for dogs who enjoy the outdoors
• Formulated for dogs that love the outdoors
• For dogs that enjoy the oUldoors Available from licensed veterinarians Sold by veterinarians Velerinarian recommended



### I EPA Reg. No. 2382-RIT _page 7 of 7 - Dml1lubel ve!5ion 9 June 21 2011UNITED STATES**E~vIRONMENTAL** PROTECTION AGENCY WASHINGTON, D.C. 20460 1

OFFICE OF CH01IClIL !lllF£'l"i MID POLLUTIoll PREVENTIOlI



### CHILD-RESISTANT PACKAGING REVIEW Technical Review Branch

IN 06/16/2011 

### OUT 08/05/2011

# ~/~ RD, TRB, Reviewed by Rosalind L. Gross 08/05/2011



### EPA Reg, No, or File Symbol 2382-RIT

DP Barcode..JD"'P"'3"'9"'0"'8"'1""9

____ _ Decision 

### # 448350 EPA

## Petitio-n-=0!:r~E"'UC!:.P~N70-,---
Date Division Received 04/28/2011 

### Type Product(s) Insecticide (flea product)

Data Accession No(s), MRID numbers 48467130, 48467131, 48467132, 48467133,46467134,48467135,48467136,48467137, 48467138,46467139,48467140,48467141,48467142, 48467143,48467144,48467145

Product MgrJChemical Review 

### Mgr/Contact Person RM 10 Bonaventure Akinlosotu Division "R",D,-

__ Product Name(s) Effitix Topical Solution for Dogs Company Name(s) Virbac AH, Inc,

Submission Purpose Review of CRP studies to determine if they are adequate to support CRP certification for this product in 4 fill levels in 3 tube sizes in 4 retail sizes (1, 3, 6, 36 tubeslretail package)

Active Ingredient(s), PC code, & % Fipronil 6,01 

### % Permethrin 44,88%

### 2



### Summary of Findings

In conclusion all the requirements for CRP have been met for EPA Reg. No. 2382-RIT as a 1, 3, 6, and 36 tube package with a lml fill level in a lml tube, a 2ml fill level in a 3ml tube, a 4ml fill level in a Sml tube, and a 6ml fill level in a 6ml tube. The directions on opening the package given to consumers must be identical to those given to the seniors during testing for the tubes (see package section for exact language). All 4 fill levels in 3 tube sizes (1ml tube with 1 ml placebo. 3ml tube with 2ml placebo, 6ml tube with 4ml placebo. 6ml tube with 6ml placebo) in 4 retail sizes (1, 3. 6. 36 tubes/retail package) meet the CRE requirements in 16 CFR 1700.20 and SAUE effectiveness specifications in 16 CFR 1700.15(b)(2)(i) when tested in accordance with 16 CFR 1700.20. For the details of each study refer to the attached summary chart (selfcertreviewsummarycht2382-187.doc).

The CRP certification submitted April 28, 2011 for EPA Registration No. 2382-RIT is acceptable. The April 13, 2011 master label (pin punched April 28, 2011) for EPA Registration No. 2382-RIT has the CRP directions used in SAUE testing on page 2. Note the package insert and all locations where directions for use refer to the CRP being opened must have the same directions as used in the SAUE testing as per MRID 48467130 1710-072 as discussed in the package section. Afterthe text for applicator tube on page 4 a "picture or illustration of the primary package (applicator tubes)" is mentioned. This is not allowed unless the tube picture is part , of artwork in the directions as used in the SAUE testing (MRID 484671301710-072 in the package section). The CRP directions in all locations on the final stamped label must be identical to those used in SAUE testing.
Should any human experience/epidemiological evidence indicate a problem once the product is in the marketplace, the Agency reserves the right to reexamine this data comprehensively and to question the child resistance of the package involved. Package
The package is a white plastic tube with a white closure containing a pin. The closure (19.0 mm x 8.25 mm) is a rexam polyoxymethylene closure with a pin and a rexam PP liner. The tube has a neck (cannula), which is sealed. The closure fits onto the tube neck. The pin is recessed from the top of the closure. The closure pulls off the tube and is inverted and pushed down for the pin to puncture the tube neck. The closure is then removed to release the product. The tube is the child-resistant feature. The tube comes in 3 different sizes with 4 fill levels of water as a placebo (1 ml tube with 1 ml placebo, 3ml tube with 2ml placebo, 6ml tube with 4ml placebo, 6ml tube with 6m! placebo). The tube comes in packages of 1 tube, 3 tubes, 6 tubes, or 36 tubes.

### The writing on the tube is in black ink. The tube has no instructions for opening the package. The instruction given to Seniors during CRP testing were in the addendum of the Senior Adult Use Effectiveness (SAUE) studies directing the Seniors to "Please open one tube according to directions 1 

### & 2 on this paper.

......." and the Seniors were provided the package insert and directed to the following instructions (from MRID48467130. 1710-072):

Toxicitv
The toxicity of the product is based only on the toxicity of Fipronil. The toxic or harmful amount of Fipronil for an 11.4 kg child is 2.5mg/kg 

### times 11.4kg. which equals 28.5mg. Access to a toxic or harmful amt 

## = 28.5mg 

## = 28.5mg divided by 

### [1114mg/ml x 0.0601 Fipronilj 

## = 0.43 ml for EPA REG 

### # 2382-RIT Effitix Topical Solution for Dogs.

Failure

For the purposes of CRP testing a child failure is access to 1 unit. Access to 1 unit is more than 28.5mg of Fipronil for all sizes greater than 0.43 ml. A unit failure is opening the tube or any partial or complete access to the placebo (water). A Senior Adult Use Effectiveness failure is failure to access the tube contents in the prescribed test time of 5 minutes for the first package or 1 minute for the second package. not accessing the tube contents in the correct manner in the prescribed test time of 5 minutes for the first package or 1 minute for the second package. Analysis of Data and Conclusion 3



### The eRP certification submitted April 28, 2011 for EPA Registration No. 2382-RIT is acceptable. The April 13, 2011 master label (pin punched April 28, 2011) for EPA Registration No. 2382-RIT has the CRP directions used in SAUE testing

### 4



### on page 2. Note the package insert and all locations where directions for use refer to the CRP being opened must have the same directions as used in the SAUE testing as per MRID 48467130 1710-072 as discussed in the package section. After the text for applicator tube on page 4 a "picture or illustration of the primary package (applicator tubes)" is mentioned. This is not allowed unless the tube picture is part of artwork in the directions as used in the SAUE testing (MRID 484671301710-072 in the package section). The CRP directions in all locations on the final stamped label must be identical to those used in SAUE testing.

The CRP written reports included summaries of the test data. A computer analysis and complete review of the 16 Child-Resistant Effectiveness (CRE) and 16 SAUE studies were not done. We used the summaries of the test data in the written reports, the April 28, 2011 CRP certification, and the April 13, 2011 master label (pin punched April 28, 2011) for EPA Registration No. 2382-RIT to evaluate the 4 fill levels in 3 tube sizes in 4 retail sizes. The results of these studies indicate that all 4 fill levels in 3 tube sizes (1ml tube with 1 ml placebo, 3ml tube with 2ml placebo, 6ml tube with 4ml placebo, 6ml tube with 6ml placebo) in 4 retail sizes (1, 3, 6, 36 tubeslretail package) meet the CRE requirements in 16 CFR 1700.20 and SAUE effectiveness specifications in 16 CFR 1700. 15(b)(2)(i) when tested in accordance with 16 CFR 1700.20. For the details of each study refer to the attached summary chart (selfcertreviewsummarycht2382-187 .doc).

In conclusion all the requirements for CRP have been met for EPA Reg. No. 2382-RIT as a 1, 3, 6, and 36 tube package with a 1ml fill level in a 1ml tube, a 2ml fill level in a 3ml tube, a 4ml fill level in a 6ml tube, and a 8ml fill level in a 8ml tube. The directions on opening the package given to consumers must be identical to those given to the seniors during testing for the tubes (see package section for exact language).
Should any human experience/epidemiological evidence indicate a problem once the product is in the marketplace, the Agency reserves the right to reexamine this data comprehensively and to question the child resistance of the package involved.CRPdatasummarychtEPAREG#2382-RITEffitixTopicalSolutionforDogsCompanyNameVirbacAH,Inc.Chemical-Fipronil6.01%Permethrin44.88%August3,2011ASeniorAdultUseEffectivenessfailureisfailuretoaccessthetubecontentsintheprescribedtesttimeof5minutesforthefirstpackageor1minuteforthesecondpackage,notaccessingthetubecontentsinthecorrectmannerintheprescribedtesttimeof5minutesforthefirstpackageor1minuteforthesecondpackage.Achildfailureisaccessto1unit.Accessto1unitismorethan28.5mgofFipronilforallsizesgreaterthan0.43ml."unitfailureisopeningthetubeoranypartialorcompleteaccesstotheplacebo(water).Accesstoatoxicorharmfulamt=28.5mg=28.5mgdividedby[ll14mg/mlx0.0601Fipronilj=0.426ml=0.43mlforFipronil&PermethrinDogProductEPAREG#2382-RIT%AI-Fipronil6.01%Permethrin44.88%Note:1.Thetubeisthechild-resistantfeature.2.Thetubesarefilledinmi.:2EPAMRIDamtamtPKGDescription#PkgesCRESAUEConclusionREG#placebo placeboIncludemlperChild#childtestIprodIprodPkgGetatFI.Oz.ml(ml#unitlpkg,childBegin(29.6ml=fail=#units,Test=1fL02)0.0338color,tox/harm=ft.oz.)#units2382-484671300.0341mla1mlsizetube1tube50childtest100%Meet16CFR1700.20eRECriteria-yesRIT1710-072with1ml- 1childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671340.0682mla3mlsizetube1tube50childtest100%Meet16CFR1700.20CRECriteriayesRIT1710-076with2ml5childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status4/28/2011acceptableallrequirementsforCRPper16CFR1700.202382-484671380.1354mla 6mlsizetube1tube50childtest100%Meet16CFR1700.20CRECriteriayesRIT1710-080with4ml1childSAUEMeet16CFR1700.20SAUECriteriayes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-------------JEPAMRIDamtamtPKGDescription#PkgesCRESAUEConclusionREG#placeboplaceboIncludemlperChild#childtestIprod/prodPkgGetatFI.Oz.ml(ml#unitJpkg,childBegin(29.6ml=fail=#units,Test=1fl.oz)0.0338color,tox/harm=fl.oz.)#units2382-484671420.2036mla6mlsizetube1tube50childtest100%Meet16CFR1700.20eRECriteriayesRIT1710-084with6ml- 1childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelISlimitedtoSAUEtestpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671310.0341mla 1mlsizetube3tube50chHdtest98%Meet16CFR1700.20CRECriteria-yesRIT1710-073with1ml-nochHdSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671350.0682mla 3mlsizetube3tube100child98%Meet16CFR1700.20CRECriteria-yesRIT1710-077with2mltest- 9childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes.._.....---_....-4EPAMRIDamtamtPKGDescription#PkgesCRESAUE ConclusionREG#placebo placeboIncludemlperChild#childtestIprodIprodPkgGetatFI.Oz.ml(ml#unitlpkg,childBegin(29.6ml=fail=#units,Test=1fl.oz)0.0338color,tax/harm::::fl.oz.)#units2382-484671390.1354mla6mlsizetube3tube50childtest100%Meet16CFR1700.20eRECriteria-yesRIT1710-081with4ml- 4childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671430.2036mla6mlsizetube3tube50childtest98%Meet16CFR1700.20CRECriteria·yesRIT1710-085with6ml• 1childSAUEMeet16CFR1700.20SAUECriteria·yes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR170020-yes2382-484671320.0341mla 1mlsizetube6tubes50childtest95%Meet16CFR1700.20CRECriteria·yesRIT1710-074with1ml• 1childSAUEMeet16CFR1700.20SAUECriteria·yes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status·4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes-5EPAMRIDamt amtPKGDescription#PkgesCRESAUEConclusionREG#placeboplaceboIncludemlperChild#childtestIprodIprodPkgGetatFI.Oz.ml(ml#unitJpkg,childBegin(29.6ml=fail=#units,Test=1fl.oz)0.0338color,tox/harm=fl.oz.)#units2382-484671360.0682mla3mlsizetube6tubes50childtest99%Meet16CFR1700.20eRECriteria-yesRIT1710-078with2ml- 4childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671400.1354mla 6mlsizetube6tubes50childtest99%Meet16CFR1700.20CRECriteria-yesRIT1710-082with4ml- 1childSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671440.2036mla 6mlsizetube6tubes50childtest98%Meet16CFR170020CRECriteria-yesRIT1710-086with6ml-nochildSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstructLabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes6EPAMRIDamt amtPKGDescription#PkgesCRESAUEConclusionREG#placebo placeboIncludemlperChild#childtestIprod/prodPkgGetatFl.Oz.ml(ml#unitlpkg,childBegin(29.6ml=fail=#units,Test=1fl.oz)0.0338color,tax/harm=ft.oz.)#units2382-484671330.034lmla1mlsizetube3650childtest98%Meet16CFR1700.20eRECriteria-yesRIT1710-075with1mltubes- 1childSAUEMeet16CFR1700.20SAUECriteriayes(placebo/product)failurepass4/13/2011masterlabel(pinpunched4/28/2011)onp 2sequentialmatchesSAUEtestpkginstruct.Notep4aftertubetest16CFRtextnotallowedpictureofapplicatortubeasnotpart1700.20ofSAUEtestpkginstruct.LabelislimitedtoSAUEtestpkginstruct.CRPCertdate&status-4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671370.0682mla3mlsizetube3650childtest99%Meet16CFR1700.20eRECriteria-yesRIT1710-079with2mltubes4childSAUEMeet16CFR1700.20SAUECriteriayes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status4/28/2011acceptableallrequirementsforCRPper16CFR1700.20-yes2382-484671410.1354mla 6mlsizetube3650childtest100%Meet16CFR1700.20CRECriteriayesRIT1710-083with4mltubes2childSAUEMeet16CFR1700.20SAUECriteriayes(placebo/product)failures4/13/2011masterlabel(pinpunched4/28/2011)onp 2passmatchesSAUEtestpkgInstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotparttest16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-412812011acceptableallrequirementsforCRPper16CFR1700.20-yes------'jEPAMRIDami amiPKGDescription#PkgesCRESAUEConclusionREG#placebo placeboIncludemlperChild#childtestIprodIprodPkgGetatFI.Oz.ml(ml#unit/pkg,childBegin(29.6ml=fail=#units,Test=1fl.oz)0.0338color,tax/harm=fl.oz.)#units2382-484671450.2036mla6mlsizetube3650childtest100%Meet16CFR1700.20eRECriteria-yesRIT1710-087with6mltubes-nochildSAUEMeet16CFR1700.20SAUECriteria-yes(placebo/product)failures**4/13/2011**masterlabel(pinpunched**4/28/2011)**onp 2passmatchesSAUEtestpkginstruct.Notep4aftertubesequentialtextnotallowedpictureofapplicatortubeasnotpartlesl16CFRofSAUEtestpkginstruct.LabelislimitedtoSAUE1700.20testpkginstruct.CRPCertdate&status-**4/28/2011**acceptableallrequ'lrementsforCRPper16CFR1700.20-yesRichard Gebken, PM 10 Office of Pesticide 

### Programs (7504P) 

### U.S. Environmental Protection Agency Document Processing Desk (REGFEE) Room S-4900, One Potomac Yard 2777 South Crystal Drive Arlington, VA 22202 Subject: EFFITJXTh'Topical Solution for Dogs (EPA File Symbol 2382· TBA); 

### New Product Application.
Dear Mr. Gebken,

Virbac Animal Health (Virbac AH, Inc. P. O. Box 162059, FI. Worth, TX 76137, 

### (Company Number 2382) is hereby submitting an application to 

### register the spot-on pesticide 

### product EFFIT.J.X:TM Topical Solution for Dogs. This product contains the active ingredients fipronil at 6.01% w/w, and pennethrin at 

### 44.88% w/w 

### and is intended to 

### control fleas, 

### ticks. mosquitoes, and other pests in 

### dogs only. Permethrin itselfis registered alone and in 

### combination with other active ingredients in


### numerous end use products for spot-on insecticide use in 

### dogs. There are also permetluin alone spot on products registered for dogs that contain up to 65% active ingredient w/w. As indicated on Form 8570·34, Virbac is 

### using the selective method to 

### address applicable data requirements for this application pursuant to 40 CPR 152.90. Pursuant to 40 CFR 152.93, 

### Virhac has issued Offer to 

### Pay letters to 

### the submitters of

### data cited in Virbac's application 

### that
were originally submitted within the past 15 years. Below is 

### a list ofthe 

### components included with this 

### application:
1. Cover Letter; 2. Transmittal Document; 3. Application for Pesticide Form**8570~1** for Effitix tM Topical Solution For Dogs;

. 4. Confidential Statement ofFormula for Effitix"" Topical Solution for Dogs· 2 Copies; 5. nata Matrix Fotnl 8570·4 for Effitix'" Topical Solution for Dogs; 6. Cerdfication ofData Citation Form 8570·34 For EffitixTM TopiCal Solution For 

### Dog;;; : : , ' 7. Proposed Label

- Use Directions for EffitixtM: Topical Solution for**Dog~** 

### - 

## '5 copies; - , 8. 3 copies ofbound PR 86·5 compliant study reports supporting registrati\>n; , 9. Waiver Request for Acute Inhalation Study (attached to Cover Letter); 10. Letter ofSelf -certification ofCbiId·Resistant Packaging. 

### 11. Data Matrix listing 

### submitted and cited 

### data in support oftbe unregistered

3200 Meacham Blvd. • Fort Worth, TX 76137 Telephone: (817) 831·5030. (800)**338~3~~9'** Fax (817) 831·8327
,(, , 485107·00Fipronil TGAI source previously approved for use in manufacturing the registered 

### products 2382-185 and 2382-186.

12. Copy ofPRlA 

### Check for category 

### R-31O ($4807).

Child-Resistant Packaging Testing & 

### Data


### EFFITIJCTM Topical Solution for Dogs and 

### will be marketed in single dose unit applicators that 

### are designed to be Child Resistant. Included with this submission are reports supporting CRP certification ofall proposed presentations ofthe product applicator that are found on the proposed product label. In addition to the written reports, a CD containing raw 

### data required under 

### PR 97-9 has been included 

### with this application.
PRIA Considerations

After reviewing the Agency's PRlA category interpretations, we believe that the R-310 

### PRlA category and a 

### 6 month review period is appropriate for this product. Consequently, please find a copy of one previously submitted check 

### in the amount of$4807 to cover the 

### PRIA fee.

Should you have any questions about this application package, please do not hesitate 

### to contact me via telephone at 682-647-3576 or via e-mail at craig.parks@virbacus.com. Sincerely,

Craig Parks, MS, DVM Vice President, Research & Development Virbac Animal Health, Inc.

,(, ,



### 3200 Meacham Blvd.• Fort Worth, 

### TX 76137 Telephone: (817) 831-5030 • (800) 338-3559, Fax (817) 831-8327

### Virbac Effitix 4128/2011


### TRANSMITTAL DOCUMENT

NAME AND ADDRESS OF SUBMITTER:
Virbac, lnc. (EPA Company Number 2382) P.O. Box 162059 Fort Worth, TX 76161



### REGULATORY ACTION SUPPORTED BY TillS PACKAGE:

TIlls submission is 

### an application to register an end use product named EFFITIXTM Topical Solution for Dogs. EFFITIXTM Topical Solution for Dogs contains the active ingredients Fipronil and Pennethrin and is intended to be used as a spot-on product for dogs.


### SUBMITTAL DATE: April 28, 2011

J

Group A Product Chemistry 1620,
48487101 Sp,,,iiic Chemistry for EFFITIXTM Topical



### 48487102

48487103

Group B Product Chemistry

48487104 ,<, ,

48487108, 

### OPPTS 48487107



## '.DensitylRelative Density (C2471O)

Acute Toxicity

TargetAnimalSafety

Companion animal safety (F 104-05-60012)

"A 14 day tolerance study in beagle pups when administered 104.05 (6.7% Fipronil and 50% 'Permethrin topical solution) topically at IX and 5X the

Companion animal safety (F 104-05·60013)

"104.05: Target Animal Safety Study By Dennal

Product Performance (F 104-05-60024)

"A 14 day tolerance study 

### in beagle pups when administered 104.05 (6.7% Fipronil and 5()'l/o Permethrin topical solution) topically at IX, 3X and 5X

Companion animal safety 

### 48487108
48487301

48487110

48487111
48487112

48487113
48487114

48487115

48487302

48487117

48487118

,., ,



### 48487119



### 2

### Studv~ 

## > No. 21**IOPn~** Companion Animal Safety 

### 48487120 TSH. Validation ofan Immunoassay Method for the Measurement ofTSH in Canine Serum.

Product Performance (Efficacy)

22 OPPTS 810.3300

# ~485107~ Product Perfonnance (F 104·05·60014) "Efficacy study against fleas (Ctenocephalides Felis) on

### ~setoi .. 23 Product Performance (F 104·05·6001 S) 

### 48487122 "104.05: Efficacy study against

## ~'in 24 (F 104.05·60016) Product Performance 

### 48487123 "104.05: Efficacy study against Dermancentor in 25 vc< 

### Product Performance (F 104-OS.o0017) "Efficacy study against the brown dog 

### tick 

### 48487124 (Rhipicephalus sanguineus) and the cat flea (Ctenocephalides Felis) on dogs: effects of shampooing I ;nd . c water

. 26 

## I,::, (F 104-05·60018) Product Performance

"The duration of efficacy ofa single application of 

### 48487125 104.05 (6.7% Fipronil and 50% Permethrin topical solution compared to a no treatment control against artificially induced infestation oHicks (amblyoma

### ~ londo", 

### 27


# ." " Product Performance (F I04.oS-60019)

- -"

, " , "The duration ofefficacy ofa single application of 

### 48487128: 104.05 (6.7% Fipronil and SOO/n Pennethrin topical solution compared to a no treatment control against ":J, induced infestation afticks (ixodes

, rina.

3Product Performance (F 104-05-60022)

''Determination ofefficacy of a combination ofFipronil and Pennethrin in topical solution against Mosquitoes

Product Performance (F 104-Q5-60023) "Repenence study of 104.05 against ticks (Dennancentor variabilus and Rhipicephalus

Child Resistant Packaging

water, 1 applicator tube test as a Poison Prevention

water, 3 applicator tubes test as a Poison Prevention 

### for

water, 6 applicator tubes test as a Poison Prevention

water, 36 applicator tubes test as a Poison

water, 1 applicator tube test as a Poison Prevention

water, 3 applicator tubes test as a Poison Prevention

water, 6 

### 48487127

48487128

48487128

48487130

48487131

48487132

48417133

48487134

48487138

48487138

# ~~~~I--~:"< water, 36 applicator tubes test as a Poison Prevention 

### 48487137 Virbac

water, I applicator tube test as a Poison Prevention 

### 48487138

### · ,

Volume 

### Study Title MRIDNo. 

### 40 

### Evaluation ofthe 6m1 Applicator Tube with 

### 4.OmI water, 

### 3 applicator tubes test as a Poison Prevention 

### 48487138 Packao;e 

### for Virbac 

### SA (1710-81) 41 Evaluation ofthe 6m1 Applicator Tube with 4.0ml water, 6 applicator tubes test as a Poison Prevention 

### 48487140 Package 

### for Virbac 

### SA 0710-82) 42 Evaluation ofthe 6ml Applicator Tube with 4.0ml water, 

### 36 applicator tubes test as a Poison Prevention 

### 48487141 Package 

### for Virbac 

### SA (1710-083) 43 Evaluation of the 6 ml Applicator Tube with 6.0ml water, 1 applicator tube test as a Poison Prevention 

### 48487142 Package 

### for Virbac 

### SA (171 0-084) 44 Evaluation ofthe 6 ml Applicator Tube with 6.0ml water, 

### 3 

### applicator tubes test as a Poison Prevention 

### 48487143 Package 

### for Virbac 

### SA 0710-085) 45 Evaluation of the 6 ml Applicator Tube 

### with 6.Oml water, 6 applicator tubes test as a Poison Prevention 

### 48487144 Package Virbac 

### SA 0710-086) 

### 46 Evaluation ofthe 6 ml Applicator Tube with 

### 6.0ml water, 

### 36 applicator tubes test as a Poison 

### 48487146 Prevention Package 

### for Virbac 

### SA (!

### 710-08'71

,', 

### ,
,{ 

# . ,{, 

### ,

'" 

### ,

5UNITED STATES ENVIRONMENTAL PROTEC lION AGENCY WASHINGTON, D.C. 20460



### NIKITAMAPP VIRBAC AH, INC. VIRBAC AH, INC. 13001 ST. CHARLES ROCK ROAD BRIDGETON, MO 63044- May 31, 2011

Report ofAnalysis for Compliance with PR Notice 86
R 

### 5 OFFICEOl' PREVENTION, PESTICIDES AND TOXIC SUBSTANCES



### Thank you for your submittal of 19
R 

### MAY-ll. Our staffhas completed a preliminary analysis of the material. The results are provided as follows:

Your data submittal was found to be partially in compliance with the standards for submission of data contained in PR Notice 86-5, with the exceptions noted below. A copy of your transmittal bibliography is enclosed, annotated 

### with the Master Record ID's (MRIDs) assigned to each document accepted. Please use these numbers in all future references to these documents.

If deficiencies were found which apply to individual accepted studies, they are listed below following the applicable MRID. Any document which has been assigned a MRID has been accepted under PR Notice 86-5. 

### Ifany comments related to a MRID appear on this report, they are provided for your information and reference when preparing future submissions. Some individual documents were not acceptable, and all copies are being returned to you for correction for the reasons indicated below.

These rejected studies have been assigned separate identification numbers which are annotated on both the enclosed bibliography and the rejected document labels.

The rejected studies and their deficiencies are described below.

Rejected Study [03]: 

## * You must include one ofthe two acceptable statements of data confidentiality claims under FIFRA sectionlO(d)(l)(A), (B), or (C) as the second element in each study. The language oftwo alternative forms ofthe Statement ofData Confidentiality Claims, shown in Attachment 3 ofPR Notice 86-5, cannot be altered. See pages 8 and 13 of the Notice. 

## * A statement of compliance or non-compliance with the Good Laboratory Practices Standards contained in 40CFRl60 is required for all studies (except rangefinding studies and supplements to previously submittedstudies) submitted to EPA. This statement must appearas page 3 of all studies, and must be signed and dated by the study sponsor, the study submitter, andUNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

NIKITAMAPP VlRBAC AH, INC. VlRBAC AH, INC. 13001 ST. CHARLES ROCK ROAD BRIDGETON, MO 63044· May 12, 2011

Report of Analysis for Compliance 

### with PR Notice 86-5 OFACEQF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

Thank you for your submittal of 28-APR-ll. OUf staff has completed a preliminary analysis of the material. The results are provided as follows:

Your data submittal was found to be partially in compliance with the standards for submission of data contained in PR Notice 86-5, with the exceptions noted below. A copy of your transmittal bibliography is enclosed, annotated with the Master Record Il)'s (MRIDs) assigned to each document accepted. Please use these numbers in all future references to these documents.

If deficiencies were found which apply to individual accepted studies, they are listed below following the applicable MRID. Any document which has been assigned a MRID has been accepted under PR Notice 86-5. If any comments related to a MRID appear on this report, they are provided for your information and reference when preparing future submissions. Some individual documents were not acceptable, and all copies are being returned to you for correction for the reasons indicated below.

These rejected studies have been assigned separate identification numbers which are annotated on both the enclosed bibliography and the rejected document labels.

The rejected studies and their deficiencies are described below.
Rejected Study [09J: 

# * The following page(s) in this study is/are illegibledue to the poor quality of the photocopying: 20. 21. 23, 24.
Rejected Study [16J: 

## * The following page(s) in this study is/are illegibledue to the poor quality of the photocopying: 59.
Rejected Study [21J: 

## * Judging from the pagination of the study, page 35 was omitted from the submitted copy.UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### April 29, 2011



### opp 

### Decision Number: D-448350 EPA File Symbol or Registration Number: 2382-RIT Product Name: EFFITIX TROPICAL SOLUTION FOR DOGS EPA Receipt Date: 28-Apr-20 I 1 EPA Company Number: 2382 Company Name: VIRBAC AH, INC.

NIKITA MAPP VIRBAC AH, INC. 13001 ST. CHARLES ROCK ROAD BRIDGETON, MO 63044- OFF!CEOF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES



### SUBJECT: Receipt of Registration Application Subject to Registration Service Fee

Dear Registrant:

The Office ofPesticide Programs has received your application and certification of payment. If 

### you submitted data with this application, the results ofthe PRN-86-5 screen 

### will be communicated separately. During the administrative screen, the Office ofPesticide Programs has detennined that this Action is subject to a Pesticide Registration Service Fee as defined in the Pesticide Registration Improvement Act.

The Action has been identified as Action Code: R3l 

# a

NEW PRODUCT;NON-F AST TRACK (INCLUDES REVIEWS OF PRODUCT CHEMISTRY;ACUTE TOXICITY;PUBLIC HEALTH PEST EFFICACY);

No additional payment is due at this time.

If you have any questions, please contact the Pesticide Registration Service Fee Ombudsman at (703) 308-9362.
Sincerely,

# ~~**Fron7n~ ocessin~~Sta·**  ... I,orma on Tech7 & 

### Resources Management DIVIsIOn 

# / t

, L

### TRANSMITTAL DOCUMENT



### Submission to US EPA Document Processing Desk

Document Processing Desk Office ofPesticide Programs U.S. Environmental Protection Agency Room S-4900, One Potomac Yard 2777 South Crystal Drive Arlington, Va. 22202-4501

NAME AND 

### ADDRESS OF SUBMITTER:

Virbac AH (EPA Company Number 2382) P.O. Box 162059 Fort Worth, TX 76161

SUBMITTAL DATE: April 28, 2011

REGULATORY ACTION SUPPORTED BY TillS SUBMISSION:


### Submission ofnew product application for EFFITIXTM Topical Solution for Dogs.

Confinuation ofreceipt by US EPA Document Processing Desk

SEPA Document Processmg Desk 

# 0'-( &G/JOI/ Datell'ime 1

## R 310

End Use (EP) or Manufacturing Use (MP) product or Technical Grade of the Active Ingredient (TGAI). Must submit Group A and B pro;:luei;chemistry data for each proposed product unless it's a 100% identical (repack): YES or 

### (NO ) (circle one) 

## "-7

EP Data MPData Guideline Group A: Product Chemistry Data SubmiHed SubmiHed TGAI No. Study Title Yes No Yes No Yes No 

### 830.1550 Product Identity & Composition 

### v Description of materials used to 

### 830.1600 produce the product 

## v 830.1650 Description of formulation process v" 

### 830.1670 Discussion on the formation of impurities 

## v 830.1700 Preliminary analysis './ 

### 830.1750 Certified limits 

### (158.345) v' 

### 830.1800 Enforcement analytical method ./

EP Data MPData Guideline Group 

### B: Product Chemistry Data Study

### f.§!,!Q!~~L~,!Q!~~L~T~G~A~1

# r----1 Yes

Stability to normal and elevated



### 5

il

= 

### data not required



### 1

# R 310

New products must either: 1) supply the product specific acute toxicity 6 pack data (listed below),
or 

### 2) provide a bridging rationale document, The bridging document directs opp to use a currently 

### registered set of 6 acute toxicity data and label; instead of submitting product specific data,

Data 

### Guideline Acute toxicity (6 pack) submitted Cited No. Study Title Yes No Yes No 870,1100 Acute Oral (LD50)
870.1200 Acute Dermal (LD50) .... 

### 870.1300 Acute Inhalation (LC50) 

## v
870.2400 Acute Eve Irritation
870.2500 Acute 

### Dermal Irritation**~//** 

### 870,2600 Dermal Sensitization /**-v~**

Efficacy
- which guideline is used depends on the proposed label use


### Data Guideline 

### submitted Cited No, Study Title Yes 

### No Yes 

### No Comments 810.3100 So'll Treatments for Imported Fire Ants Livestock Poultry, Fur and Wool-Bearing 

### 810.3200 Animal Treatments 

### Treatments to Control Pests of Humans and 

## / 810,3300 Pets Mosquito, Black Fly, and Biting Midge 810.3400 (Sand Flv) Treatments
810.3500 

### Premises Treatments
810.3600 structural Treatments Methods for Efficacy Testing of Termite 810.3800 Baits



### 2

### April 25, 2011

U.S. Bank Government Lockbox 979074 1005 Convention Plaza SL-MO-C2-GL St. Louis, MO 63197

RE: Checks for 2011 PRIA Fees; Virbac AH, Inc. (EPA Co. Number 2382)

Dear Sir Of 

### Madam:

Please find enclosed a check numbered 

### 01008652 made out to the Environmental Protection Agency (EPA) in the 

### amoW1t 0[$4,807.00. This check fulfills the financial obligations in support of an animal health pesticide, to be registered under the company Virbac AH, Inc. (EPA Company Number 2382). Also attached for reference are copies of the EPA Fonn 8570-1 with infonnation on the registration ofthe nvo products with EPA.

Should you have any questions about this application package, please do not hesitate to contact me via telephone at 682-647-3576 or via e-mail at craig.parks@virbaclls.com.
Sincerely, 

# C-;JL

Craig Parks, MS, DVM Vice President, Research & Development Virbac Animal Health, Inc.,',



# •



# •

•

# V,rbac

ANIMAL HEALTH

April 28, 2011

Richard Gebken, PM 10 Office ofPesticide Programs (7504P) 

### U.S. Environmental Protection Agency Document Processing Desk (RBGFEE) Room S-4900, One Potomac Yard 2777 South Crystal Drive Arlington, VA 22202 Subject: EFFITJXTh' Topical Solution for Dogs (EPA File Symbol 2382-TBA); 

### New Product Application. Dear 

### Mr. Gebken,

Virbac Animal Health (Yirbac AH, Inc. P. O. Box 162059, Ft. Worth, TX 76137, (Company Number 2382) is hereby submitting an application to register the spot-on pesticide product EFFITJXTh' Topical Solution for Dogs. This product contains the active ingredients fipronil at 6.01 % w/w, and pennethrin at 

### 44.88% 

### w/w and is intended to control fleas, ticks, mosquitoes, and other pests 

### in dogs only. Pennetbrin itselfis registered alone and in combination with other active ingredients 

### in
numerous end use products for spot-on insecticide use 

### in dogs. There are also pennethrin alone spot on products registered for dogs that contain up to 65% active ingredient w/w. As indicated on Pann 8570-34, Virbac is using the selective method to address applicable data requirements for this application pursuant to 40 CFR 152.90. Pursuant to 40 CFR 152.93, Virbac has issued Offer to Pay letters to the submitters of data cited in Virbac's application that
were originally submitted within the past 15 years. Below is a list ofthe components included with this application:

1. Cover Letter; 2. Transmittal Document; 3. Application for Pesticide Fonn 8570-1 for EffitixTM Topical Solution For Dogs; , 4. Confidential Statement ofFonnula for EffitixTM Topical Solution for Dogs - 2 Copies; 5. Data Matrix Form 

### 8570A for EffitixTM Topical Solution for Dogs; 6. Certification ofData Citation Form 8570-34 For EffitixTM Topical Solution For Dogs; 7. Proposed Label

- Use Directions for EffitixTM Topical Solution for**Dog~** - '5 copies; 8. 3 copies ofbound PR 86-5 compliant study reports supporting registratibn; 9. Waiver Request for Acute Inhalation Study (attached to Cover Letter); 10. Letter of Self-certification of Child-Resistant Packaging. 11. Data Matrix listing submitted and cited data in support of the unregistered

3200 Meacham Blvd.• Fort Worth, TX 76137 Telephone: (817) 831-5030. (800)**338'>6~9.** Fax (817) 831-8327 484873-00

### Fipronil TGAI source previously approved for use 

### in manufacturing the registered products 2382-185 and 2382-186.

12. Copy ofPRIA Check for category R-310 ($4807).

Child-Resistant Packaging Testing & 

### Data
EFFITD(TM Topical Solution for Dogs and will be marketed 

### in single dose unit applicators that are designed to be Child Resistant. Included with this submission are reports supporting CRP certification of all proposed presentations ofthe product applicator that are found on the proposed product label. In addition to the written reports, a CD containing raw data required under PR 97-9 has been included with this application.

PRIA Considerations

After reviewing the Agency's PRIA category interpretations, we believe that the R-310 PRIA category and a 6 month review period is appropriate for this product. Consequently, please find a copy of one previously submitted check in the amount of $4807 to cover the PRIA fee.

Should you have any questions about this application package, please do not hesitate to contact me via telephone at 682-647-3576 or via e-mail at craig.parks@virbacus.com. Sincerely,

Craig Parks, MS, DVM Vice President, Research & Development Virbac Animal Health, Inc.



### 3200 Meacham Blvd.• Fort Worth, TX 76137 Telephone: (817) 831-5030. (800) 338-3559, Fax (817) 831-8327Virbac Effitix 

### 4/28/2011


### TRANSMITTAL DOCUMENT

NAME AND ADDRESS OF SUBMITTER:
Virbac, Inc. (EPA Company Number 2382) P.O. Box 162059 Fort Worth, TX 76161

REGULATORY ACTION SUPPORTED BY TillS PACKAGE:

This submission is an application to register an end use product named EFFITIXTM Topical Solution for Dogs. EFFITIX1M Topical Solution for Dogs contains the active ingredients Fipronil and Pennethrin and is intended to be used as a spot-on product for dogs.



### SUBMITTAL DATE: April 28, 2011

Volume 

### Study_Title MRIDNo. I Administrative Materials

EFFITIXTM Topical Solution for Dogs Group A Product Chemistry
2 

### OPPTS 830.1550, 830.1600, 830. 1620,830. 1650, 830.1670,830.1750 

### 48487101 Product Specific Chemistry for EFFITD(1M Topical Solution for Dogs 3 

### OPPTS 830.1700 

### 48487102 Prelimin?:J:Y Analysis (C9654l) 4 

### OPPTS 830.1800 

### 48487103 Enforcement Analytical Method (C96552) Group B Product Chemistry

5 

### OPPTS 830.6302, 830.6303, 830.6304 

### 48487104 Color, Physical State, Odor (C32753) 6 

### OPPTS 830.6314 

### 48487105' Oxidationireduction reactions (C2472I) 7 

### OPPTS 830.6315 

### 48487108. Flash point (C24732)



# - 8 

### OPPTS 830.6317 

### 48487107 Storage stability (C24697)

IVolume Studv Title 

### MRIDNo. 9 OPPTS 830.7000**48~Oa-...,** pH (C24743) lO OPPTS 830.7100 rra4.§13O'1./ Viscosity (C24708) !1 OPPTS 830.7300 DensitylRelative Density (C247lO) 

### 48487110

Acute Toxicity

12 OPPTS 870.1100 Acute oral toxicity (C24620) 

### 48487111 13 OPPTS 870.1200 

### 48487112 Acute dermal**toxi~ity_** _(C24631) 14 OPPTS 870.2400 

### 48487113 Primary eye irritation (C2Mi42) .QLf(pSj 15 OPPTS 870.2500 Primary dermal irritation (C2465cfi OlYbyG, 

### 48487114 16 OPPTS 870.2600 Dermal sensitization (C24664) 

### 48487115
TargetAnimal Safety

17 OPPTS 870.7200

# ~? Companion animal safety (F lO4·05·60012)

"A 14 day tolerance study in beagle pups when administered 104.05 (6.7% Fipronil and 50% Permethrin topical solution) topically at IX and 5X the recommended dose" 18 OPPTS 870.7200 Companion animal safety (F 104·05·60013) 

### 48487117 "104.05: Target Animal Safety Study By Dennal Administration to Beagle Dogs" 19 OPPTS 810.7200 Product PerfOlmance (F lO4·05-60024)

"A 14 day tolerance study in beagle pups when 

### 48467118
administered 104.05 (6.7% Fipronil and 50% Pennethrin topical solution) topically 

### at IX, 3X and 5X the recommended dose" 20 OPPTS 870.7200 Companion animal safety 

### 48487119 Target Animal Safety study summary



# -

2Volume Study Title 

### MRIDNo. 21 OPPTS 870.7200 Companion Animal Safety 

### 48487120 TSH. Validation ofan Immunoassay Method for the Measurement ofTSH in Canine Serum.

Product Performance (Efficacy)

22 OPPTS 810.3300

# C:::~ Product Perfonnance (F 104-05-60014)
"Efficacy study against fleas (Ctenocephalides Felis) on dogs: Onset ofaction" 23 OPPTS 810.3300 Product Perfonnance (F 104-05-60015) 

### 48487122 "104.05: Efficacy study against Rhipicephalus sanguineus in dogs**~** duration of action" 24 OPPTS 810.3300 Product Perfonnance (F 104-05-60016) 

### 48467123 "104.05: Efficacy study against Dennancentor variabilus in dogs**~** duration of action" 25 OPPTS 810.3300 Product Perfonnance (F 104-05-60017) "Efficacy study against the brown dog tick 

### 48487124 (Rhipicephalus sanguineus) and the cat flea (Ctenocephalides Felis) on dogs: effects of shampooing and periodic water immersions 26 OPPTS 810.3300 Product Perfonnance (F 104-05-60018)

"The duration of efficacy of a single application of 

### 48487125 104.05 (6.7% Fipronil and 50% Pennethrin topical solution compared to a no treatment control against artificially induced infestation ofticles (amblyoma americanum) on dogs



# ---- 27 OPPTS 810.3300 Product Perfonnance (F 104-05-60019)

"The duration of efficacy of a single application of 

### 48487128: 104.05 (6.7% Fipronil and 50% Pennethrin topical solution compared to a no treatment control against artificially induced infestation of ticks (ixodes scapularis) on dogs

328 OPPTS

30

31

32

34

35

39 Product Performance (F 104-05-60022)

"Detennination ofefficacy ofa combination of Fipronil and Pennethrin in topical solution against Mosquitoes

Product Performance (F 104-05-60023)
''Repellence study of 104.05 against ticks (Dennancentor variabilus and Rhipicephalus
on under conditions"

Product Performance

Child Resistant Packaging

1m! 

### water, 

### 1 applicator tube test as a Poison Prevention

water, 

### 3 

### SA ofthe Iml Tube with 1.0 ml water, 

### 6 applicator tubes test as a Poison Prevention for Virbac SA



### water, 36 

### applicator tubes test as a Poison 

### Prevention SA 71

water, 

### 1 applicator tube test as a Poison Prevention



### water, 

### 3 for Virbac SA

tubes test as a Poison Prevention 

### SA Evaluation the 3ml Tube with 2.0ml water, 6 applicator tubes test as a Poison Prevention

ofthe 3ml Applicator Tube with 2.0mI water, 36 applicator tubes test as a Poison Prevention

water, 1 applicator tube test as a Poison Prevention 

### 48487127

48487128

48487129

48487130

48487131

48487132

48487133

48487134

48487135

48487138

48487137

48487138

4

### Volume Studv Title MRIDNo. 40 Evaluation ofthe 6ml Applicator Tube with 4.0ml water, 3 applicator tubes test as a Poison Prevention 

### 48487139 Package for Virbac SA (1710-81) 41 Evaluation ofthe 6ml Applicator Tube with 4.Oml water, 6 applicator tubes test as a Poison Prevention 

### 48487140 Package for Virbac SA (1710-82) 42 Evaluation ofthe 6ml Applicator Tube with 4.0ml water, 36 applicator tubes test as a Poison Prevention 

### 48487141 Package for Virbac SA (1710-083) 43 Evaluation ofthe 6 ml Applicator Tube with 6.0ml water, I applicator tube test as a Poison Prevention 

### 48487142 Package for Virbac SA (1710-084) 44 Evaluation ofthe 6 ml Applicator Tube with 6.0ml water, 3 applicator tubes test as a Poison Prevention 

### 48487143 Package for Virbac SA (1710-085) 45 Evaluation of the 6 ml Applicator Tube with 6.0ml water, 6 applicator tubes test as a Poison Prevention 

### 48487144 Package Virbac SA (1710-086) 46 Evaluation ofthe 6 ml Applicator Tube with 6.0ml water, 36 applicator tubes test as a Poison 

### 48487145 Prevention Package for Virbac SA (1710-087)



### 5Unl1ed S1ates 

# &EPA Environmental Protection Agency Amendment Other

i AH, Inc P.O. Box 162059 Fort Worth, TX 76161

Check if this is a new address

Amendment- Explain below 

# o Resubmission in response to Agency leller dated

____ _ 

# o Notification

- Explain below

ii 3. Proposed i I

(b)(i), my product is similar or identical in composition and I 10: EPA Reg No.
Product Name



# D D i response to Agency leller da1ed:;-

_______ _ "Me Too" Application

Olher

- Explain below

Application for registration. PRIA Category R310. Please refer to attached letter.



# Ye, Ye, Ye,
No No No 

# pee I

. per Paper Restricted

be submrtted Unit Packaging wgl. container Package wgt container Other (Specify) 0.5 

# i
Label Container

Craig Parks, MS, DVM 1,3,6,36 II

## 6i~:ei;;~~:;:' 

# of Re,oocch ,,'

i Cer1ification 682-647-3576

t certify that the statements I have made on this form and all attachments thereto are true, accurate and complete. I acknowledge that I false or misleading statcmcnl may be punishablc by fine or impris(lnment or

Vice President of Research and Development, Virbac AH, Inc. I 

# i

(St?fT'rl"d)Fe ,lproved. OMB No. 2070'{)060. Approval cxpires 5-31-98 Unilcd SlaJCS 

# aEPA Ettvironmental Protection Agency Washington, DC 20460 

## Formulator's Exemption Statement (40 CFR 15'.85) Applicant's Name and Address EPA File Symbol/Registration Number Virbac Allimal Health 2382-NEW P. O. Box 162059 Product Name Ft. Worth, TX 76137 EFFlTlXHl Datc of Confidential Statement of Formula (EPA Form**8570~4)** March 21, 2011 As an authorizcd rcprcscntative ofthc applicant for registration ofthe product idcntificd above, I certify that:
(I) This product contains the following active ingredient(s):pcrmcthrin

(2) Ofthcsc, each active ingredient listed in paragraph (4) is prescnt solely as the result ofthe use ofthat activc ingrcdicnt in the manufacturing, formulation or repackaging anothcr product which contains that active ingredient which is registcred under FIFRA Scction 3, is purchased by us from another producer, and is labeled for at least each use for which my product is proposed to bc labeled.
(3) Indicatc by checking (A) or (8) below which paragraph applics: 

# ITI (A) An accurate Confidential Statement of Fonnula (EPA FORM**8570~4)** for the above identificd 11foduct is attached to this statement. That fommla statemcnt indicatcs, by company name, registration number, and product name, the source ofthc active ingredient(s) listed in paragraph (I) 

### OR 

# D (B) The Confidential Statement of Formula (CSF) (EPA Form 8750-4) referenced abovc and on filc with the EllA is completc, current, and accurate and contains thc information required Oll thc current CSF (4) Thc following activc ine:redicnts in this product qualify for thc fommlator's exemption
Source

Active In 'redient Product Name

Pcnncthrin



# d-;i.L Name and Title Vice President, Research & Dcvclopment Signature



### - - EPA Fonn 8570 27 (Re\. 8 95)

*U.S. Gro: 1995-388-820/20413 Registration Number

Date April 28, 20 II



# -- .. \\hne EPA copy**y~llOW·** Applicant copyForm Approved OMB**NO.l070~0060 ".....'~** 

### ... UNITED STATES ENVIRONMENTAL PROTECTtON AGENCY 

## ( "'1 401 M STREET, S.W. 

# 5 WASHINGTON, D.C. 20460 PapelWork Reduction Act Notice: The public reporting burden for this collection of information is estimated to average 1.25 hours per response for registration and 0.25 hours per response for reregistration and special review activities, including time for reading the instructions and completing the necessary forms. Send comments regarding burden estimate or any other aspect of this collection of information, including suggestions for reducing the burden to: Director, QPPE tnformation Management Division (2137), U.S. Environmental Protection Agency, 40t M Street, SW., Washington, DC 20460. Do not send the completed form to this address.
Certification with Respect to Citation of Data Applicant's/Registrant's Name, Address, and Telephone Number EPA Registration Number/Fite Symbol Virbac AH, Inc.! PO Box 162059 Fort Worth TX 761371 telephone**682~647w3576 2382~NEW**  Active Ingredient(s) and/or representative test compound(s) Fipronil, permethrin Date April 28, 2011

General Use Pattern(s) (list all those claimed for this product using 40 CFR Part 158) Product Name indoor residential EFFtTIX n. Topical Solution for Dogs

NOTE: If your product is a 100% repackaging of another purchased EPA-registered product labeled for all the same uses on your tabel, you do not need to submit this form. You must submit the Formulators Exemption Statement (EPA Form 8570-27) 

# D I am responding to a Data-Call-tn Notice, and have included with this form a list of companies sent offers of compensation (the Data Matrix form should be used for this purpose).

SECTION t: METHOD OF DATA SUPPORT (Check one method only) 

# D I am using the cite-all method of support, and have included with 

# 0 I am using the selective method of support (or de-all option this form a list of companies sent offers of compensation (the Data under the selective method), and have included with this form Matrix form should be used for this purpose) a completed list of data requirements (the Data Matrix form must be used).
SECTION It: GENERAL OFFER TO PAY [Required if using the cite-all method, or when using the cite-all option under the setective method to satisfy one or more data requirements[ 

# n I hereby offer and agree to pay compensation, to other persons, with regard to the approval of this application, to the extent required by FIFRA

SECTtON lit: CERTtFtCATtON
I certify that this application for registration, this form for reregistration or this Data-Call-In response is supported by all data submitted or cited in the application for registration, the form for reregistration, or the Data-Call-In response. In addrtion, if the cite-all option or cite-all option under the selective method is indicated in Section 1, this application is supported by all data in the Agency's files that (1) concern the properties or effects of this product or an identical or substantially similar product, or one or more of the ingredients in this product: and (2) is a type of data that would be required to be submitted under the data requirements 'm effect on the date of approval of this apprlcation 'If the application sought the initial registration of a product of identical or similar composition and uses. I certify that for each exclusive use study cited in support of this registration or reregistration, that I am the original data submitter or that I have obtained the written permission of the original data submitted to cite that study.
I certify that for each study cited in support of this registration or reregistration that is not an exclusive use study, either: (a) I am the original data submitter; (b) I have obtained the permission of the original data submitter to use the study in support of this application; (c) all periods of eligibility for compensation have expired for the study; (d) the study is in the public literature; or (e) I have notified in writing the company that submitted the study and have offered (i) to pay compensation to the extent required by sections 3(c)(t)(F) and/or 3(c)(2)(8) of FIFRA; and (ii) to commence negotiations to determine the amount and terms of compensation, if any, to be paid for the use of the study.
I certify that in all instances where an offer of compensation is required, copies of all offers to pay compensation and evidence of their delivery in accordance with sections 3(c)(1 )(F) and/or 3(c)(2)(8) of FIFRA are available and will be submitted to the Agency upon request. Should I fail to produce such evidence to the Agency upon request, I understand that the Agency may initiate action to deny, cancel or suspend the registration of 1'1)' product in conformity with FIFRA.
I certify that the statements I have made on this fonn and aU attachments to it are true, accurate, and**complet~.** t acknowledge that any knowingtyfatse or misteading statement may be punishable by fine or imprisonment of both under appllcabto I<.>w.



## - Signature Date Typed or Printed Name and Title Craig Parks 

# L;t.L April 28, 2011 Vice President, R&D Virbac Animal Health, Inc.

. 

# - . ,. . EPA Form 8570-.,4 (9 97) Ekeirollic and Paper \CrsIOIlS a\31lable. Subnul only Paper \crslOn.

### Apri128,2011

Richard Gebken, PM 10 Office ofPesticide Programs (7504P) U.S. Environmental Protection Agency Document Processing Desk Room S-4900, One Potomac Yard 2777 South Crystal Drive Arlington, VA 22202
Subject: Child Resistant Packaging Certification EFFITIXTM Topical Solution for Dogs; EPA Reg. No. 2382-NEW 

## r211 Dear Mr. Gebken:

I certify that the packaging used for the following product meets the standards of40 CFR 157.32, including the revised standards in 16 CFR 1700.15(b), when tested by 

### the revised testing procedures in 16 CFR 1700.20, as published in 60 FR 37710 (July 21,1995). (...Ir


### o EFFITIXTM Topical Solution for Dogs (EPA Reg. No. 2382-NEW).

Virbac Animal Health (Virbac AH, Inc. P. O. Box 162059, Ft. Worth, TX, 76137; (Company Number 2382) is submitting this child resistant packaging certification to support the pending
new product application filed on the above date for EFFITIX "-"Topical Solution for Dogs (EPA Reg. No. 2382-NEW).

Should you have any questions about this letter, please do not hesitate to contact me via telephone at**682~647-3576** 

### or via e-mail at craig.parks@virbacus.com.
Sincerely, 

# &.tU

Craig Parks, MS, DVM Vice President, Research & 

### Development Virbac Animal Health, Inc.

### Waiver Request Registrant: Virbac Animal Health, Inc. Acute Inhalation Study (OPPTS 

### 830.1300). 6.01 % Fipronil/44.08% Permethrin EUP For Spot On Use In Dogs Brandname: Effitix TM 

### Topical Solution for Dogs.

The Effitix Topical Solution for Dogs product is composed of 6.01 % w/w ofthe active ingredient Fipronil and 44.88% w/w of the active ingredient permethrin. This product is packaged in single use non-refillable applicators that are intended for one time only spot-on applications to 

### dogs. The potential human inhalation exposure to this product is expected to be neglible. Only very small amounts ofproduct are applied per application, depending the weight of the animal. Based on packaging considerations described in the proposed product labeling, the maximum volume of Effitix Topical Solution that can be administered at one time to a pet using the largest available applicator size is approximately 6.0 ml. This application volume represents the worst case because it is the dose that is recommended only for use on dogs weighing more than 89 pounds. Therefore, according to the proposed label, a great deal of anticipated product use will
occur at much lower volumes on smaller dogs. Furthermore, the measured vapor pressure of both of the active ingredients fipronil and permethrin are extremely low (2.8 x 10. 9 

### mm Hg at 25°C and 2.18 x 10·8 mm Hg at 25°C, respectively) indicating that both active ingredients are essentially nonvolatile and are therefore not expected to vaporize from the skin of the treated animal following application. The active ingredients will therefore not be available for inhalation after application according to label directions. Finally, the method of applying the liquid product directly to 

### the pet creates no particulates, aerosols, or other respirable matter. Therefore, based on the criteria provided by the Agency in 

### 40 CFR 158.500, footnote 4 under the 

### Toxicology Data Requirements, a waiver ofthe acute inhalation study for these products is appropriate.

3200 Meacham Blvd.• Fort Worth, TX 76137 Telephone: (817) 831-5030. (800) 338·3£55'. Fax (817) 831-8327UNITEDSTATESENVIRONMENTALPROTECTIONAGENCYs!z401MStreet,S.W..,;"'Mno,..\beinstructionandsandIperresponse..'oed,anyotheraspectofthisII; ;·.:.:'.:otheburdentoDinx,:lor;OPPEInfonnalion,JI)U.S.EnvironmentalProtectionAgency,401MStreet,S,W.,'.DC20460.0,""",d"dd";'.DATAMATRIXf.,li,,,,N,,",.Pro,"o,'?'."':;76161EFFITIXTMTOPICALSOLUTIONFORDOGS;,,",d'N,w'AH.100.>or,U,cdN,w.Yb"AH,boIOWN,Pro""Now.b"AH.100.IOWN830.1650Now.b"AH.boIOWN830.1670i,ofN,wb"AH,100.IOW830.1750Limit>N,w.bocAH.loolOW830.1800Now..bocAH,100.lOW,830Seci"Go'cpCol'"Now.yi.b"Al••100OWN1St",Now,AI•100.d",Now,I83'[,,,IYJ,I83',N,wYJ·!83'·:830,631I,A[VN,Dale;L;iLCraigParksApril]3,VicePresident,Research&Development2011'eA', ,,""0".UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY&401MStreet,S.W.,. g. n.is'.iiisand,perresponseiand,iiforreadingtheinstructionandcompletingthenecessarySendCOlIllllcntsregardingtheburdenestimateoranyotheraspectofthis". iI"::':n1beburdentoDirector:OPPEInfunnationManagementDivision(2137)u.s.Environmental ProtectionAgency,401MStreet,S.W.,"DC20460,'Do001,rnd,<h'"ddre:;"DATAMATRlX'IsName&AddressPro'"ot,EFFITIXTMTOPICALSOLUTIONFORDOGS,IyN,m,IMRIDNomb",StatusNotee",upNow,100,)WNVol10;,lnoit:;;New,I,;,AH,lno,NRI"xkitvINowY',b"AH,lno,OWNINowY',booAH,lnolaWNIi'lox;oilyW,;y,"y',b"AH,100,,AH,;lno,,,100OWNYoll6,.:!.JLCrnigParksVicePresident,Resenrch&Development2011--1";,;,u'.'CO"•.m....'UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WA"lUN.D.C.,A"N,tk".i,ii'iaverngcperresponsefOf,1responseitheinstroctionandcompletingthenecessaryfonns.SendcommentsregardingestimateoranyotheraspectofthisDirector:OPPEInfomlationManagementDivision(2137)u.s.EnvironmentalProtectionAgency,401MStreet,S.W.,DATAMA'uuxi Il'fAddressEFFITlXTMTOPICALSOLUTIONFORDOGS>.3300>.3300Ie,FermAppro....dOM!)Ne.2071)-()(I60y."d"rot,dot,8)0.33008)0.1300811300818181818811.330""rUNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WA:IN,D.C..,horo,'""f'''dh''''hI.t •d',"".1orreamgtemstructJOnancompclmgIburdentoDirector:OPPEInfonnationn;DATAMA'lKlXPmd,,,IPmd,,,IPmd,oJIPmd,oJIPmd,,,I'md,"'mdoc''mdI,otPmdI,ot,-43)2'43)2)tperresponsetanyotheraspectofthis.)U.S.ProtectionAgency,401MStreet,S.W.,,4,fEFFmxTMTOPICALSOLUTIONFORDOGS'110L10L\YPAY00",Apn13,2011Fom>ApprovedOMBNo.%G7{1.0m;OUNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WASHINGTOND.C.20460PaperworkReductionActNotice:Thepublicreportingburdenforthiscollectionofinfonnationisestimatedtoaverage0.25hoursperresponseforregistrntionactivitiesand0.25hoursperresponseforreregistrationandspecialreviewactivities,includingtimeforreadingtheinstructionandcompletingthenecessaryforms.Sendcommcntsregardingtheburdenestimateoranyotheraspectofthiscollectionofinfonnation,includingsuggestionsforreducingtheburdentoDirector:OPPEInfonnationManagementDivision(2137)U.S.EnvironmentalProtectionAgency,401MStreet,S.W.,Washington,DC20460.Donotsendthefonntothisaddress.DATAMATRIXDate:Aiii132011EPAR.No.lFilcSmhol2382-newPage50fllApplicant's/Registrnnt'sName&AddressProduct:VirbacAH,IncPOBox162059EFFrnXn<TOPICALSOLUTIONFOROOGSFortWorthTX76161"ient:FiromlPenncthrinGuidelineReferenceNumberGuidelineStudNameMRIDNumberSubmitterStatusNoteEfficacyandsafetydata-Floroni!810.3300ProductPcnormanceEffica-flea44942106McrialPAY810.3300ProductPerformanceEffica-flca45618501McrialPAY810.3300ProductPerformanceEfficac-flea45620502MerialPAY810.3300ProduclPerformanceEfficac-flea45620503MerialPAY810.3300ProductPerformanceEfficac_flea45628104MerialPAY810.3300ProductPerformanceEfficaev-flea45628105MerialPAY810.3300ProduclPerformanceEfficacy-flea45866901MerialPAY810.3300ProductPerformanceEfficacy-tick43577712MerialOLD810.3300ProduciPcrformanceEfficacy-tick43121114MerialOLD810.3300ProductPcnormanccEfficacy-tick43121115MerialOLD810.3300ProduciPcnormanccEfficacy-tick43121117McrialOLD810.3300ProductPcnormanccEfficacy-tick43121122McrialOLD810.3300ProductPerformance-EfficaC'jBathing43121118MerialOLDSignatureNameandTitle"'"CraigParksApril13,VicePresident,Research&Development2011,,EPAfonn85i{l.35(99i)EI«1",n,e""draper=to..Availioble.Suonlyaper\er'lOn.AOf!'lnl<rnal,"C.u,.py"'UNITEDSTATESENVIRONMENTALPROTECTIONAGENCYrp,:;;;;;;;:;-rp,:;;;;;;;:;-rp,;;;;;;;-rp,;;;;;;;-rp,;;;;;;;-p;;;;;;;;->,;;;;;;;->,;;;;;;;-'ro'""i'co'"d1Pcod"ct;401MStreet,S.W.response.SendcommentsregardingestimateoranyotheraspectofthisDirector:DATAMAI.,.,(2137)U.S.EnvironmentalProtectionAgency,401MStreet,S.W.,Prod""EFFITIXTMTOPICALSOLUTIONFORDOGSPAYPAYPAYPAYPAYPAYPAYPAYPAYPAYDateIrAddressVitbacAH,IncPOBox162059UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY,tv,tv,tv,tv'tv401MStreet,S.W.;'tUN.D.C.IiiandcompletingDire<:lor:QPPEInfonnatioilDATAMATRIX141 41413391408.5_hou.rs.i'. .hoursperresponse.SendIi'anyotheraspectofthisi )U.S.EnvironmentalProtc;,:tionAgency,401MStreet,S.W.,IProd,cr,EFFITIXTMTOPICALSOLUTIONFORDOGS1ort'I10rtzI1OLDLDOLDOLDOLDOLDOLD1PAY..!.c.",,·13-06ID,toApril13,i,011,UNITEDSTATESENVmONMENTALPROTECTIONAGENCY401MStreet,S.W.VN,D.C.20460,A"Noli,,,'11I,perresponse1.forreadingtheinstructionandcompleting:-1anyotheraspectofthis",.I'Iburden(0Direclor:OPPEInfonnalionManagemCl\tOJ,i )U.S.EnvironmentalProtectionAgency,401MStreet,S.w.,DC20460,'0;,"""d,,Mi,sName&Addressem,"",;EFFmXTMTOPICALSOLUTIONFORDOGS,",IS"",D,,.·81Pmd,,,1,·11081Prod"",.1,to1081Pmd,,",.1,1010VicePresident,Research&Devdoprncnt2011'",, , , ,",MO',FonnAppr'Ove<lOMB11'0.2070-0060UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WASHINGTOND.C.20460PapcrworkReduetionActNotice:Thepublicreportingburdenforthiscol1ectionofinfonnatioilisestimatedtoavernge0.25hoursperresponseforregistrntionactivitiesand0.25hoursperresponseforreregistrntionandspecialreviewactivities,includingtimeforreadingtheinstructionandcompletingthenecessmyfonns.Sendcommentsregardingtheburdenestimateoranyotheraspectofthiscollectionofinfonnation,includingsuggestionsforreducingtheburdentoDirector:OPPEInfonnationManagementDivision(2137)U.S.EnvironmentalProtectionAgency,401MStreet,S.W.,WashingtonDC20460.Donotsendtbcfonntothisaddress.DATAMATRIXDate:AIii132011EPAR.No.lFileSbol2382-newPage90fllAITlicant'siRegistrnnt'sNalne&AddressProduct:VirbacAH,IncPOBox162059EFFlTIXTMTOPICALSOLUTIONFORDOGSFortWorthTX76161Ingredient:FironilPennetbrinGuidelineReferenceNumberGuidelineStudNameMRIDNumberSubmitterStatusNoteChildResistantPackae:lng40CFR157EvalualionofthcImlApplicalorTubewithl.0mlwater,INewSubmissionVirbacAH,Inc.OWNapplicatortubetestasaPoisonPrcvenlionPackageforVirbacSA40CFR157EvaluationoftheImlApplicatorTubewith1.0mlwater,3NewSubmissionVirbacAH,IncOWNapplicatortubestestasaPoisonPreventionPackageforVirbacSA40CFR157EvaluationoflheImlApplicatorTubewilh1.0mlwater,6NewSubmissionVirbacAH,Inc.OWNapplicatortubesleslasaPoisonPreventionPackageforVirbacSA40CFR157EvaluationoftheImlApplicalorTubewithl.OmIwater,36NewSubmissionVirbacAH,IncOWNapplicatortubestestasaPoisonPrevenlionPackageforVirbac40CFR157Evalualionofthe3mlApplicatorTubewith2.OmIwater,INewSubmissionVirbacAH,Inc.OWNapplicalortubetcstasaPoisonPreventionPackagefurVirbacSA40CFR157Evaluationofthc3mlApplicatorTubewith2.0mlwater,3NewSubmissionVirbacAH,IncOWNapplicalortubeslestasaPoisonPreventionPackageforVirbacSA40CFR157Evaluationofthe3mlApplicatorTubewith2.0mlwater,6NewSubmissionVirbacAH,Inc.OWNapplicatortubesteslasaPoisonPreventionPackageforVirbacSASignatureNameandTideCmigParksApril13,VicePresident,Researcb&Development-20li. .,EPAFonn8570351997)a.worneondPOp<rVerno""AvailiW"SUOmIIonly""per"""mlLFonnAppr'OvcdOlllBNo.2071)-0(l6(lUNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WASHINGTOND.C.20460PaperworkReductionAetNotice:TIlepublicreportingburdenfortluscollectionofinfonuationisestimatedtoavcmge0.25hoursperresponseforregistmtionactivitiesand0.25hoursperresponseforreregistrntionandspecialreviewactivities,includingtimeforreadingtheinstructionandcompletingthenecessaryforms.SClldcommentsregardingtheburdenestimatcoranyotheraspectofthiscoi1ectionofinforruation,includingsuggestionsforreducingtheburdentoDirector:OPPEInfonuationManagemcntDivision(2137)U.S.EnvironmentalProtectionAgency,401MStreet,S.W.,Washington,OC20460.Donotsendthefonutothisaddress.DATAMATRlXDate:Ari113,20IIEPARe.No.lFileSmhol2382-ncwPagetooft tApplicant'sJRegistmnt'sName&AddressProduct;VirnacAH,IncPO80);162059EFFITIXTMTOPICALSOLUTIONFORDOGSFortWorthTX76161illient;Fironil,PennethrinGuideline GuidelineStudyNameMRIDNumberSubmitterStatusNotcReferenceNumber40CFR157Evaluationofthe3mlApplicatorTubewith2.0mlwater,36NewSubmissionVirbacAH,Inc.OWNapplicatortubeslesJasaPoisonPreventionPackageforVirbacSA40CFR157Evaluationofthe6mlApplicaJorTubewith4.0mlwaler,INewSubmissionVirbacAH,IncOWNapplicatortubetestasaPoisonPreventionPackageforVirbacSA40CFR157Evaluationofthe6mlApplicatorTubewith4.OmIwaler,3NewSubmissionVirbacAH,InC.OWNapplicatortubestestasaPoiSOnPrevenlionPackageforVirbacSA40CFR157EvaluaJionofthe6mlApplicatorTubewith4.0mlwater,6NewSubmissionVirbacAH,IncOWNapplicatortubestestasaPoisonPrevenlionPackageforVirbacSA40CFR157Evaluationofthe6mlApplicatorTubewilh4.0mlwater,36NewSubmissionVirbacAH,Inc.OWNapplicatortubesleslasaPoisonPreventionPackageforVirbacSA40CFR157EvaluationofIhe6mlApplicalorTubcwith6.0mlwater,INewSubmissionVirbacAH,IncOWNVol43applicatortubetestasaPoisonPreventionPackageforVirbacSASignatureNamcandTitleD?tcCraigParksApn]13,VicePresidcnt,Research&Development'201;.---;""InJ..;.;C;;;;;-form8,703>t997)Eb:tmrucandPaperVcrslO""Availablo.SubmIonlyl'apervers,on.,"U.p)f"onnAppnlvedOMBNo.UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WASHINGTON,D.C.20460PapcrworkReduetionActNotice:TIlepublicreportingburdenforthiscollectionofinfoooationisestimatedtoaverage0.25houffiperresponseforregistrationactivitiesand0.25hOUffipcrresponseforreregistrationandspecialreviewactivities,includingtimeforreadingtheinstructionandcompletingthenecessaryfooos.Sendcommentsregardingthcburdenestimateoranyotheraspectofthiscollectionofinfonnation,includingsuggestionsforreducingtheburdentoDirector:OPPEInfoooationManagementDivision(2137)U.S.EnvironmentalProtectionAgency,40I MStrect,S.W.,Washington,DC20460.Donotsendthefonntothisaddress.DATAMATRIXDate:Aril132011EPARe.No.lFileSmbol2382-newPage!!of!1Applieant'slRcgistrant'sName&AddressProduct:VirbaeAH,IncPOBox.162059EFFITlXTMTOPICALSOLUTIONFORDOGSFortWorthTX76161mient:Fironi!,PeooethrinGuidclineReferenceGuidelineStudyNameMRIDNumberSubmitterStatusNoteNumber40CFR157Evaluationoflhe6mlAppliealorTubewith6.0mlwater,3NewsubmissionVirbaeAH,Inc.OWNapplicatortubesleslasaPoisonPreventionPackagcforVirbaeSA40CFR157Evalualionofthe6mlApplicatorTubewith6.0mlwater,6NewsubmissionVirbaeAH,IncOWNapplicatorlubestestasaPoisonPrevenlionPackageVirbaeSA40CFR157Evalualionofthe6mlApplicatorTubewith6.0mlwater,36NewsubmissionVirbacAH,Inc.OWNapplicatortubestestasaPoisonPrevenlionPackageforVirbacSASignatureNameandTitleDateCraigParksApril13,VicePresident,Research&Development2011.v;EMFOM85703S1997)Electro,"c:mdPaper....0..Av.,l.bkSubmilonlFa•"yperCfSt<>•,.,"Inlernalu,.c.1,ho'I"ti_,:...DoIF-D6",IaburdentoDirector:OPPE1tDivision(2137)U.S.Agency,40JMStreet,S.W.,,11Phy,''']S,""IOdo<1IYr.SJorageDATAMATRIX],VirbacVNVNOWNOWNOWNNROWN.CorporateProductInnovationDireclorI2o-ii--S,),--,,",UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY:&401MStreet,S.W.""W'"i,.•",dO.25:,7r'tl::;i. .,i'theinstructionandcompletingthenecessaryfonllS.:"0,;'"",,';'d;;;;d;:rntoDim:lor:OPPElnronnationManagementDivision{2137}U.S.,1 M"""':s,w"DATA'1'1IV.b,"SA,LIDi•So,",INO"iNIAI830.6319i,b"NIAiSolidVi,b"0WN!,voltog,Vi,b"NIAWoivod!pHVi,b"OWNiIiVi,b"'WN,Vi,b",WN-Vi,b"'WN1Vi,,.,OWNVi,b"OWNJean-pascalMarcI25,..CorporateProductInnovationDirector2011", ,"Note:830.6317and830.6320:PerAgencypolicy,storagestabilityandcorrosioncharacleristicsdataarcnotrequiredtobesubmittedunlessspecificallyreql.:cJt,:!J!:I:;theA .;cr.cy.'/irbachasinitiatedthesestudiesandwillsubmitthefinalreportsifrequiredwhenthestudiesarecompleted.Iiil70.11668\-8UNITEDSTATESENVIRONMENTALPROTECTIONAGENCYWf401MiilItiDim.:tor;OPPEInfonnation,,IDDATAMATRTX43279706AcUtO0(o,icityiIIi, itoRatsbyAcuteOrali,SubmilI,...it"i .ilI?ursperresponse.Send,I nestimateoranyotlteraspectofthisu.s.EnvironmentalProtectionAgency,401MStreet,S.W.,BASF"*1J!N,mo!,'Title.lean-PascalMarcCorporateProductInnovationDirector""",,"OLDIOLIOLIOL...--•.D"oApri12S,2011FormAppro..dOMIINo.107o.00WUNITEDSTATESENVIRONMENTALPROTECTIONAGENCY:&401MStreet,S.W.WASHINGTOND.C.20460PaperworkReductionActNotice:Thepublicreportingburdenforthiscollectionofinfonnationisestimatedtoaverage0.25lioun;pcrresponscforregistrntionactivitiesand0.25hoursperresponseforreregistrationandspecialrevicwactivities,includingtimeforreadingthcinstructionandcompletingthenecessaryfonns.Scndcommentsregardiugthcburdenestimateoranyotheraspectoftliiscollectionofiufonnation,includingsuggestionsforreducingtheburdentilDirector:OPPEInfonnationManagemcntDivision(2137)U.S.EnvironmentalProtectionAgency,401MStrcc1,S.W.,Washington,OC20460.Donotsendthcfonntothisaddress.DATAMATRIXDateAri125,2011EPAReNo.lFileSmbolPage4of6Applicant'sJRegistrnnt'sName&AddressProduct:Fipronil TechnicalVirbacSAIcreavenuc2065M •LIDF-06516Carros,FranceI"icnl:FinilGuidclineRcferenceNumberGuidelincStudyNameMRIDNumberSubmitterStatusNote40CFR158.340DataRequirements(Continued84·2Structuralchromosomalaberration42918680BASFOLD84·2Structuralchromosomalaberration42918653BASFOLD84·2Othergenotoxiceffects42918651;42918653BASFOLD4350170385·1/870.7485Generalmetabolism42918655BASFOLD85·1/870.7485Generalmelabolism43253701BASFPAY85-1/870.7485Generalmetaboltsm43737308BASFOLD85-1/870.7485Generalmetabolism42918654BASFOLD85-1/870.7485GeneralmetaboHsm42977904BASFOLD85-1/870.7485Generalmetabolism43253701BASFOLD85-2/870.7600Dennalpenetration43737308BASFPAY85-7/870.7600ImmunotoxicityDATAGAPGAP"Seebelow40CFR158.490WildlifeandAquaticOrganismsDataRequirementsOLD71-1/850.2100AvianoralLD50mallardorbobwhite42918617BASF01..,[,,42918616,72·1/850.1075FreshwaterfishLC50rainbowor42918624;42918673;BASFOLDIbluegHi42918674;42977902bib',43279703;43291718OL'DiSignatureNameandTitle"""I"c.Jean·PascalMarcApril25,CorporateProductInnovationDirector201I:,,EPAFonn&570·)5(9·97EI""lroni<.ndPaperV....;o'"A..it"ble.SubmitonlyPaperv=ion.".Intern.1U••Copy. I•LID,.Fei1·1,IIII,I".I,..UNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.r'"i.''',·..;)ij,n,.lJN,D.C•.,born:,rocI'",...,,=,oO.2S...'."d0.25e. cforreadingtheinstructionandcompletingtbenecessaryfoons.SendcorrunentsregardingtheburdenestimateoranyotherthisII,".plieburdcntoDirector.OPPEinformationManagementDivision(2137)U.S.EnvironmcntaiProtectionAgency,401MStreet,S.W.,DATAMA,!!!!X.",do",48iOI·m!,,"....;on.Prod,,"Fipro,iI',BASFIBASFIBASFIASFBASFJean*PascalMarcCorporateProductInnovationDirectorOLDOLDPAY.D.DOLDOLDOLDOLOLD.!2011i20460..DoIe.,,F-06S16'-LIDUNITEDSTATESENVIRONMENTALPROTECTIONAGENCY401MStreet,S.W.WA."V",D.C..,Ii<.rrr;InfonnationI)u.s.EnvironmentalDATAMATRIXA<utoL?!"a)"IOLDNIAINIA.,ma,aa},42918669BASF,(Soot)-FiDroni!jtorexposurestudies44433303M,ri,IOLDPAYPAY'THI'.Jean-PascalMarc:lUllProduclInnovationDirector*Pursuantto40CfR152.96(c),VirbacherebycertifiesthatVirbachasnobasistobelievethatthisrequirementisnotIIdatagapand,further,thatVirbachassentbycertifiedmaillilallNmpanies011theeurrentEPADataSubmittersListforfipronilII.lctlcrrequestingthatthecompanyidentify,wHhin60daysofrcecipt,anyvalidstudythatwouldflllfilltltisdataO:J.ce60-dayperiodexpires,VirbaewillupdatetheAgencyastotheinformation,Ifany,Virbaereceivesinresponsetothis"dalagnp"[eUer.