EPA Reg. No. 2382-187

1
2

75-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< 
3

"5'"i9i2Oi 1; New Registration; 

s: 894831 4128'2011; New Re{}istrIltiofl,· 
4
5
6

-

s: 896235 5119/2011; New Re!}!s/(;]tion; 

S: 894831 412f:12D11; New Registration" 

~ ~'.~ "'~ w.J t"::-~I;;~"1"-j;'H __ 

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"b ~ -i'? ~ ~ tt::>.. "'''''' ~ w..s:.Jl ... 

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7

Tracking 

Create Res.ubmissicn 

FFS Letters 

Action Code History 

7/(irw 
8

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 __ 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[)~_~ __ ~~Y~§_'!',I? <?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 * * * 
9

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 
10
11
12

- , , ' 

Rejected 

Studies 
13

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 submission 
14

Tracking 

Create ReSubmiasion 

Action ClXle History 

15(n /VOI/ 
15

21-Day Screen Completed by 

Contractor 

21-Day Expires on _----'S-:::..--.!-I C,.:---.:./-!...i_ 

Jacket # z. 3 g 2. - f( / 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: 
16

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 
17

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) 
18

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 of Formula 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 
19

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 If applicable 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 
20

Comments: 

2.S I~ rilt"sSUIl\ 

f"c~je bt..t-\- flu rc.spC'U1!;c.C 

L~ e.e,_J \ l/\ .z /J, 6 ~ "I ,{ ,of> D t-;, (\ '! 

{I\ (loc(Y\De-l-lotj C'>n S/!2-/I! , , 

* N/A - Not Applicable 

Footnotes 

~ 

Cu\ J 

CJ?l~ r'(~Ce1v<:J 

c..-P+c_r ob'h:<;""(..~ 

CD II 

u,y, \ t\ : If d c '\)-c1.- , 

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 
21

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 

h Up:/ /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; 

4 
22

3. 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 
23

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 
24

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: 
25

--

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 of the 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? 

... ~.-'~ 

Is · a Confidential Statement of Formula (EPA Fonn 8570~ 

2 

r 

9) Included in the Submission Package, is it completely 

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

-

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

2 7) Induded in the Submission Package? .-~---------

Is , it Certification wlth Respect to Citation of Data (EPA 

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

-_ .. '.,-----

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

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: 

i 

K 

f --- -.--

t<. ---

f.. 

X 

y:. 
26

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. J n 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, 2011 
27

2 

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 

of the date of this Notice of Registration. 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 of formula (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 the Agency 

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, acceptable positive 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 of each 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: pounds 
28

3 

Primary Route of Exposure: 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 of incidents 

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 of incidents in dogs weighing less than that product weight 

range, nwnber ofincidents in dogs in lower half of weight range, number of incidents in dogs 

in upper half of weight range, and dogs weighing more than the product weight range. 

h. Table showing nwnber of incidents for each dog breed. 

1. Table showing number of incidents 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) of your product under FIFRA 

. section 4. 
29

4 

If EPA 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. 

If you 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 of these conditions. 

A copy of your 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 
30

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 F IT IX TM TOPICAL SOLUTION FOR DOGS 

Alternate brand names: 

(E F F IX TM TOPICAL SOLUTION FOR DOGS) 

(EFFICANIXTM TOPICAL SOLUTION FOR DOGS) 

(EFFIPROTIX TM 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 LBSr 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 I 
31

IF 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 II 
32

FREQUENCY 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: EFFITIX TM 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 
33

{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. 2011 
34

Kills 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 M Topical 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: EFFITlXTPJ 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 
35

[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 t 
36

Effitix PDP with no strikeouts 

Jim Barron 

to: 

Bonaventure Akinlosotu 

11117/201101:11 PM 

Hide Details 

From: "Jim Barron" <jbarron@exponent.com> 

To: Bonaventure AkinlosotuJDC/uSEP AlUS@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 

EXponel1t@, 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 
37

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 
38

,. 

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... 1 III 7/201 1 
39

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, 1011 
40

I 

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 I 
41

FREQUENCY 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 EFFITIXT" 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: EFFITIXT" 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 
42

{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, EfflTIXw ~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 t 
43

Fleas: 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 

EFFITIXT" 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 

• EFFITlXnJ 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 
44

[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 t 
45

Available 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, 2011 
46

tiNITED 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/m2 or mg/cm2 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% if the 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 of6 
47

concentrations, when converted to a weight/weight ratio to calculate the active ingredient concentrations. 

This study is acceptable and claims ofkil1ing fleas within 6 hours of treatment 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 of control 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 of Action. 

I. GLP Study 

2. A laboratory study was conducted to test the efficacy and duration of control 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 of killing 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 of Shampooing and Periodic Water Immersions. 

1. GLP Study 

2. A laboratory study was conducted to to evaluate the efficacy and duration of control 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 of pre-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 of6 
48

substance, 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 of Amblyoma 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 of Ticks (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 

3 
49

on 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 BL T 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 BL T 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 of A. 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. 

Page40f6 
50

i. 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 of 60 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) What pests and site/pest combinations mllst be removed ji·01ll the label? 

Any and all claims against sandflies 

Any claims of control of fleas 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 of this claim is deferred to the product 

5 
51

manager). 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 of these 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 if your dog" ," 

"Effective monthly application against fleas" 

"Effective monthly control of fleas" 

"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 
52

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 
53

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 of Action. 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 26th , 

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 
54

PROPOSED LABEL 

MARKETING CLAIMS: 

PRODUCT APPLICATION RA TE(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 of the 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 of individua1 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 of two animals each and within each block were 

randomly allocated to Group 1 (control) or Group 2. Laboratory breed strain (Clin Vet - 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 
55

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 of each treatment group, Percent efficacy was 

calculated as follows: 

Efficacy (%) ~ 100 x (Gm, - Gm,) / Gm" where: 

Gme = Geometric mean number of live 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. 

T a e bl 1 M . ean Fl ea C oun t . SID th e C t 1 on ro an dT rea t e dG roups. 

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 a bl e 2 P . 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 
56

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 of the 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 of the active 

ingredients in the test product were not verified or supported by a Certificate of Analysis. The 

use of the 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 of the 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 if the registrant can verify that the concentrations of the 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 of the 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 
57

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 
58

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 26th, 

1997 by decision of the 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 

2 
59

PROPOSED 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: elin Vet 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 
60

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 of the 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 of live 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 of Day +37 when it was 87.3%. 

T a hI el. 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 2.3b 

+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 
61

Tab e 2. Percent Efficac'\ Base d G on eometnc 'M eans 0 fP ro d uct 104 . 05 A' \.R:amst T' Ie 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 of the 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 of the 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 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 
62

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 14 
63

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 

484671-23. 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 

2 
64

PROPOSED 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 RA TE(S): Not 

provided. 

.. can kill ticks for at least a month. 

STUDY REVIEW 

Purpose: To test the duration of action of 1 04.05 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 
65

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 of the 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 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. 

T a bl e 1 M . ean T' Ie kC oun t' s III th e C t 1 on ro an dT rea t e dG roups 

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 
66

T a hI e 2 P . ereen tEffi Jeae B d G ase on come t' rIC M eans 0 fP ro d uc tl0405A . ~eams . tT" Ie ks 

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 of the 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 of the 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 of the 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 
67

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 

Date: 

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

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 14 
68

DATA EV ALUA 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 261h, 

1997 by decision of the 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 

2 
69

PROPOSED LABEL 

MARKETING CLAIMS: 

PRODUCT APPLICATION RA TE(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 of the 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 of four 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 
70

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 of the 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 ANOV A 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 ANOV A 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 
71

'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 of the 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 of the study author. OCSPP Test Guideline 810.3300 states 

that the product should "Provide 90% reduction in pest infestation through a killing action when 

5 
72

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 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 of the 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 
73

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 
74

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 

FORMULA TlON 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 
75

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 RA TEeS): Not 

provided . 

.. can kill ticks for at least a month 

STUDY REVIEW 

Purpose: To detennine the duration of efficacy of a single application of formulation 104.05 

against infestations of ticks (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 of Analysis 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 of Day ~5 tick count, within each sex. The first two female dogs were assigned 

to one of the wo 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 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 
76

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 of the 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: 

4 
77

1. 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 morningj 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. 

5 
78

5. 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 
79

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 dogsl 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 
80

Reviewer's Conclusions 

The results support the conclusions of the 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 
81

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 
82

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 

[ENV IMC/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 
83

PROPOSED LABEL 

MARKETING CLAIMS: 

provided . 

.. can kill ticks for at least a month. 

STUDY REVIEW 

Purpose: To determine the duration of efficacy of a single application of formulation 104.05 

against infestations of ticks (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 of two 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 of Analysis 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 of Day -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 of Day -5 tick count, within each sex. The first two female dogs were assigned to 

one of the 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 of 0.1 mLlkg. 

3 
84

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 of each tick were recorded at each assessment time. 

Data analysis: Efficacy calculations were based on geometric means, and specifically on the 

geometric means of the 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 (if the 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 ANOV A for Study Days 1, 2, 30, 37, 44, and 51. 

For Study days 9,16, and 23, comparisons were on the basis of the 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 
85

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 xo es scapu Z'Tks 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 of body 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 
86

Reviewer's Conclusions 

The results support the conclusions of the 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 
87

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 
88

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 of the European Parliament and Council of the 

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 
89

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 of Analysis 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 of the 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 of the 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 
90

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 of blood fed mosquitoes from the treated group to the geometric mean of 

the number of blood fed mosquitoes from the control group: 

Anti-feeding Efficacy (%) ~ 100 x [(FC - FT)/FC], where: 

FC = geometric mean of the number of blood fed mosquitoes from the control group 

FT = geometric mean number of blood fed mosquitoes from the treated group 

The killing efficacy was determined by comparing the mortality of mosquitoes 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: 

4 
91

The 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 I PAC6 

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 of 40 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 of exposure, 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 
92

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 
93

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 of the 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 
94

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-l1-0l4 
95

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 

484671-28. 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 261h, 

1997 by decision of the 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 
96

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 APPLlCA TION RA TE(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 of two dogs each, and the large dogs were blocked into two 

blocks of two 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 of the 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 
97

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 of the 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 of the 

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 of each treatment group. 

In situ tick count efficacy was calculated as follows: 

Efficacy (%) ~ 100 x (Gm, - Gm,) I Gm" where: 

Gme = Geometric mean number of live 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 ANOV A 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 of tick 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 ANOV A with a treatment effect after a logarithmic 

transfommtion on the tick data (count +1) 

4 
98

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. 

5 
99

DAY 

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 of Product 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 
100

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 wmin exposures are shown in Table 11, and tick viability after the 

IO-rnin exposures is shown in Table 12. 

7 
101

Table 7. 24-hr Counts of Dermacentor 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 statisticallY s/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 of Dermacentor 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 
102

Table 9. Effect of Formulation 104.05 Dermacentor variabilis 

., 

•• 0" 

{p<Q,OO) from Group 1. 

Table 10. Viability of Dermacentor 

Formulation 104.05 

variabilis After lO-min Exposures to 

Treatment Group 48Hr 

- .',,::-' 

, 

J GrolJP 1. 

Study Author's Conclusions 

Results of this study indicate that dogs treated with Formulation 104.05 at a dosage of 0.1 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 
103

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 

sanguine us 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 of ticks repelled (mean values of O. 7 to 5.2 were recorded for 

the treated group); however, a marked difference in the percentage of ticks 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 of the 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 of tick for all assessment periods. The concentrations of the active 

ingredients in the test product were not verified or supported by a Certificate of Analysis. 

Reviewer's Recommendations 

Acceptable. However, the concentrations of the 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 
104

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 
105

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 of 40 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 

2 
106

provided. 

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 of the quantitative data given in 

the previously submitted and accepted MRIDS for fipronil and permethrin. The published 

information on permethrin is discussed briefly and copies of the 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. 

Ta bl 1 S e . umma rvo rEm lcacy Data f or Em ItixTM T opical S olution A \.gamst Fleas on D ogs 

Test Species Citation Result 

Cat flea Fouriej 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 Fouriej J.J. 2009. Efficacy Study Against the Brown The use of shampoo 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 

3 
107

I 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 
108

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 of EffitixTM 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 of Action. weeks 

sany;uineus) 

American dog tick, Fourie,1.1. 2009. Efficacy Study Against The duration of efficacy 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 of efficacy 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 of Ticks (Amblyoma 

americanum) on Dogs. 

Deer tick Moran, C. 2010. The Duration of Efficacy ofa Single The duration of efficacy 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 of Ticks 

(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 

5 
109

Brown 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 of the 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 
110

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 of a 65 % Permethrin Unlmown 

Spot-on Formulation for dogs against Aedes 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 
111

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 of Fipronil 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 
112

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 of EffitixTM 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 of EffitixTM 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 (Phtebolomus perniciosus) 

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 
113

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% of the 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 of sarcontic 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 of the registration of 

EffitixTM Topical Solution for Dogs is justified, the infonnation provided was inadequate. It could 

not always be determined if the 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 of MRID 484671-29 claims that imidacloprid 

"is not itself effective on biting flies"). Study author uses data for a 65% pennethrin product to 

support claims of efficacy 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. 

10 
114

Virbae - 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 

tv * tv * tv * tv * tv * tv * tv * tv * tv * tv * tv * tv * 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 
115

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!2011 
116

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 

Page 3 of3 

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, 

This was done to limit the distribution of computer viruses 

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file:IIC:IDocuments and SettingslBAkinloslLocal SettingsITemplnotes87944BI-web3825.... 1119/2011 
117

Effitix- 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.... 1113/2011 
118

Jim 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 

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llnnnl1 
119

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 of importance: 

1. We do not believe it should be necessary to add the phrase - HMA Y 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 of the !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 

of the icon closer to the middle of the package to be better in terms of visibility for the pet 

owner. 

3200 Meacham Blvd .• Fort Worth, TX 76137 Telephone; (817) 831·5030 • (800) 338-3659 Fax (817) 831-8327 
120

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) 831-8327 
121

UNITED 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') 

DP BARCODE No.: 0390814 DECISION No.: 448350 

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 

Formulation Type: Liquid 

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. 

*Product ingredient source information may be entitled to confidential treatment*
122

FILE SYMBOL No.: 2382-RIT 

ACTION CODE: R 310 

DP BARCODE No.: 0390814 DECISION No.: 448350 

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: 
123

FILE SYMBOL No.: 2382-RIT 

ACTION CODE: R 310 

DP BARCODE No.: D390814 DECISION No.: 448350 

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. 
124

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. 

*Product ingredient source information may be entitled to confidential treatment*
125

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. 
126

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): I H-PyrazoIe-3-carbonitrile, 5-amino-I-[2,6-dichioro-4-

(trifluoromethyI)phenyI]-4-[(trifiuoromethYI)suifinyI]-

(IUP AC): 5-amino-I-[2,6-dichioro-4-(trifluoromethyIJphenyI]-4-(1,R,S)-

(trill uoromethyisuifinyl )-1 H -pyrazo Ie-3-carboni tri Ie 

CAS No.: 120068-37-3 

PC CODE NO.: 129121 

EMPIRICAL FORMULA: C12H,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,..~, 
127

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 I Dissociation 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 -'waivers 
128

DP 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 

*Manufacturing process information may be entitled to confidential treatment*
129

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 If CSF is attached complete Item A and the chemical name in item C. 

[] NO If CSF is not attached complete Item A through C. 

A INFORMATION REQUmED: 

.Q CheckApplicahle Category 

[J Provide PCC and Tolerance Exemption Status For Food-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 if Fragrance 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/ 

/ / 
130

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 of Pesticide 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' 

To: Bonaventure AkinlosotuiRichard Gebken, RM 10 Lr:;-;;t~ Insecticide Branch 

Registration Division (7505P) 

Registrant: VIRBAC AH, INC. 

FORMULA TlON 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 
131

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 Effitex TM. 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 of blood, and/or discolored (seen in 4-5 5X 

animals vs. 0 controls). The 5X animals of both 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 of the 

study, the daily food consumption of the 5X animals was 32-50% less than that of controls 

(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 of the 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 of the effects observed in 3 of the 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. 

2 
132

4. In the other companion animal safety study with 8 week old puppies (MRID 48487302) 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 -I 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). 

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 of dosage 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 of these active ingredients, and it is not 

known whether there is any additive and/or synergistic toxicity when permethrin and fipronil are 

combined. 

3 
133

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 of Pesticide 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 1 42011 

fbtMrn-~ ~~p 1 42QU 

This review may have been altered subsequent to the contractor's signatures above. 
134

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 of companion 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, 13eme 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 of the 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 

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135

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 of dosing. 

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 of 40 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 

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136

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 of test 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-I 4.5 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 of the 

head"to the mid back. To achieve the exaggerated 5x doses, the control or test material was 

7 

*Inert ingredient information may be entitled to confidential treatment*
137

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% of the values were identical, Fisher's exact test was 

used. Otherwise, the data were first analyzed using Bartlett's test for homogeneity of variances. 

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). If the variances were nonhomogenous, logarithmic and square root transformations were done, and the transfonned data 

were analyzed as above if the 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 of vomitus, 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 of the animals while the animals were standing or walking around in order to 

discern any ataxia, loss of coordination, 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 of mucous 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 of changes to the hair, such as matting (tangled mass of hair), 

greasy appearance, clumping (areas of compact clusters or lumps), spiking (hair coming together 

8 
138

in narrow, sharp points), discoloration, and deposits (areas of test 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 the jugular 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 (AL T/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 _200 C until analysis. Where 

9 
139

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; if reanalysis 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 

of these 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 of the 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 of the 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 of loose feces in the post-dosing period (4, 5, 6, 7 and 8 hours after 

the second dose). The incidences of vomiting from IX and 5X animals later in the course of the 

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. 

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140

TABLE 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 dogsb [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 of the treated males and females were 

generally similar to those of their 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 of the 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 of erythema, edema, or matting. On day 0, all of the 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 of cosmetic 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 
141

, 

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 of the 

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 of the statistical findings were considered biologically significant or treatmentrelated because the differences were small in magnitude, with the mean values falling within two 

standard deviations of the control mean and within the background ranges of the testing laboratory 

(data not provided in the study report), The coagulation parameter values of the treated males and 

females were similar to those of their 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 
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values falling within two standard deviations of the control mean and/or within the background 

ranges of the testing laboratory (data not provided in the study report); thus none were considered 

biologically significant. 

3. Thyroid function evaluation: The results of the 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 of the coefficients of variation for T4 >21 % and all of the available 

coefficients of variation for TSH 2: 66%. Some of the 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." 

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143

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 of correlated effects on any of the 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. 

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144

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. 
145

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), 13eme 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 of the 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 of blood, and/or 

discolored (seen in 4-S SX animals vs. 0 controls). The SX animals of both 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 of the study, the daily food consumption of the 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 

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146

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 of the 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 of the 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 of the 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 of 40 CFR Part 160." 

17 
147

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 of two 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 
148

2. Animal assignment: Study design is given in Table 1. The study was conducted in five 

replicates, as pups of the 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 of pups 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 of test 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 of test 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 of the product (two 2.5 

mL applications which were approximately 4 hours apart). 

19 

*Inert ingredient information may be entitled to confidential treatment*
149

. 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 of the syringe was positioned on the dorsal 

cervical area at the base of the pup's head and used to separate the pup's hair so the material could 

be applied at the skin level, and the contents of the 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 of the 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 (RMANCOY A) 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 of the three pretreatment 

baseline measurements in the case of body 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. 

If the group*sex*day interaction was significant (p<0.05), then the statistical analysis was 

considered inconclusive. If the 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 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.1 O. If significant, pair-wise comparisons of each 

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 

*Inert ingredient information may be entitled to confidential treatment*
150

Profile plots were provided for all continuous variables and included baselines (or arithmetic 

means of pre-study data) and all data collected from day 1 through the end of the 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 of the 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 of the 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 of the 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 
151

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 of the 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 of time 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 (AL T/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 _300 C until shipment on dry ice 

22 
152

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 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 of the 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 of the 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 of these (#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 of the 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. 

23 
153

TABLE 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 of blood, 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 of the 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 of the 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 of the mean absolute body weights of the 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 of the study. The SX animals 

had biologically and statistically significantly lower mean food consumption than controls on days 

I-S, and nine of the 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 
154

, 

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. I 7±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. 

25 
155

b 

TABLE 5: Selected food consumption data (g/day, with sexes combined) from puppies treated with 104.5 or 104.05 

Placeboa 

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 
156

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 of the 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 of the 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 of that 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 of the mean values of the treated groups to those of controls 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 of the treated groups to those of controls 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 of the 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 of the 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 
157

" 

• 

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 of the mucosa of the 

duodenum, jejunum, ileum, and colon; hemorrhages and necrosis of the lung tissues; reddish froth 

in the trachea; hemorrhagic lesions in the bronchial lymph node; and pale appearance of the 

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 of the 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 of the 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 of both 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 of the animals contributed to the 

expression of these effects, special attention must be called to the abnormal neurological signs 

28 
158

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 of the 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 of the 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 of the replicates. 

IV. REFERENCES: 

Anonymous (2011) Summary of companion 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 
159

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. F efee. 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 

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. 
160

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 of the 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 of the hair coat, with or without deposits, matting, or spiking were noted within one hour 

31 
161

of the 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 
162

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/ J 00 mL Fipronil and 50,26 gI J 00 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 J 00 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 of two 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. 

33 
163

2. Animal assignment: Study design is given in Table 1. The study was conducted in nine 

replicates, as pups of the 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 of pups 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 of the 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" of the 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 of the 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 

*Inert ingredient information may be entitled to confidential treatment*
164

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 of the syringe was positioned on the dorsal 

cervical area at the base of the 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 mid back. Following application, the pup was restrained 

in an upright position for at least two minutes to prevent run-off of the test or control substance. 

Syringe volumes were visually confinued 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 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 (RMANCQV A) 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 of the 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. If the 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 of each 

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 of pre-study data) and all data collected from day 1 through the end of the study. For each 

endpoint, the individual data were presented separately for each treatment group (with the sexes 

35 
165

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 of the 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 of the 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 of the 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 
166

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 _300 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. 

37 
167

X DIGESTIVE SYSTEM X CARDIOV ASCJHEMA T. 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 ",,- ~ Duodenum IX 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-- X Pancreas Seminal vesicles ex- Skin (application site and untreated skin) 

RESPIRATORY X Ovaries 

C"-

Gross lesions and masses (selected) 

Trachea ~ Ulerus f--

X LUltg Vagina e-- -

Nose I- e-- -- f-- r-- - Pharynx 

Larynx f-- r--

II. RESULTS 

A. ACTUAL DOSES ADMINISTERED: The mglkg doses of the 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 of pain 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 of the first application, all of the animals had 

clumping and a greasy appearance of the hair coat, with or without additional findings such as 

deposits, matting, or spiking. All control and IX animals were free of cosmetic effects by day 2, 

and all 5X animals were free of cosmetic effects by day 5. 

38 
168

C. 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, of the 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 
169

, 

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 of the puppies consumed all of the 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 of the IX and 

5X groups were lower than those of controls 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 of parameters 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 of the 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 of the mean 

values of the 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 of the 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 
170

" 

b 

nmollL for females; TSH: <0.800 nglmL for males and <0.56 ng/mL for females; MRID 

48467118). Some of the 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 of the 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 of the 

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 
171

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 of the 

moribundity of the animal that was sacrificed on day 4, and the neurological signs (ataxia, 

generalized tremors, and salivation) exhibited by this animal are of particular 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 of the 

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 of the 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 of the replicates. Replicate 5 had no control group, 

Replicate 8 had only 2 control animals and Replicate 9 had one 5x female. 

42 
172

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 of companion 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 
173

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 of vomiting and NA U 

Safety / 8 week old abnormal feces, Le. feces that were liquid, loose, 

beagle dog / Charles mucoid, with traces of blood, and/or discolored (seen in 

River Laboratories 4-5 5X animals vs. 0 controls). 5X animals of both 

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 of controls (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 of the 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. 

44 
174

Companion Animal 48487302 One 5X female exhibited profuse salivation on the NA U 

Safety! 8 week old morning of day 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 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.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 
175

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/uSEP AJUS@EPA 

Page I of3 

Ce: Richard GebkenlDC/uSEP AlUS@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 registratian far 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 
176

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 ot 3X 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 safety factors 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 
177

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.... 1119/2011 
178

lNITED 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 of Pesticide 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 
179

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) of the 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 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 performed 

in a similar manner. 

4. The folIowing is the acute toxicity profile of2382-RIT (EFFITEX TOPICAL SOLUTION FOR 

DOGS) based on the results of the acute toxicity studies, and with designation of the 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 / , 

Dennal sensitization Positivea Unacceptable MRID 48467115 /flr 

aIn lieu of an acceptable study, TRB recommends this product be classified as a sensitizer. 

2 
180

5. 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 
181

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 of Pesticide 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£: 
182

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 of testing. 

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 of three fasted, female HanRcc: WIST(SPF) rats were given single oral 

gavage doses of undiluted 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 of the animals gained weight during both weeks of the 

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 of the lungs, gaseous 

distension of the stomach, reddish or yellowish discoloration of the stomach, small intestines, and 

cecum (all noted in both of these animals), and reddish discoloration of the 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. 

5 
183

COMPLIANCE: 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 of toxicity, 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 of three animals was dosed at 500 mg/kg bw with the stated intention of gaining additional 

information about the approximate LD50 of the 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 of the 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 of the animals dosed at 

300 or 500 mg/kg bw. Almost all of the animals gained weight during both weeks of the 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 of the decedent, "step 1" 2000-mg/kg 

animals. These included dark red discoloration of the lW1gs, gaseous distension of the stOl;nach, 

reddish or yellowish discoloration of the stomach, small intestines, and cecum (all noted in both of 

these animals), and reddish discoloration of the colon and rectum (in one animal), 

6 
184

D. Reviewer's Conclusions: It is concluded that in the absence of mortality 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 
185

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 of five 

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% of the 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 of the 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 of the 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 of both 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 J Data Confidentiality 

statements were provided. 

8 
186

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 of both 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 of the 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 
187

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 of both 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 of product are applied per application. Application volume depends 

on the weight of the 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 of product 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 
188

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 of testing. 

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, 1 ere 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 of the 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 of each 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 of corneal opacity or iritis. One hour after instillation of the 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 
189

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 of 2 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 of corneal opacity or iritis. One hour after instillation 

of the 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 
190

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 of testing. 

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 of undiluted 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 of edema. Very slight erythema (score=l) was noted on all three sites one 

hour after patch removal with resolution within 24 hours of patch 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 
191

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 of patch 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 
192

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 of testing. 

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 of the animals gained weight over the course 

of the 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 of three successive weekly 

inductions, 0.5 mL of the 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 of the 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 
193

C. Naive Controls: At challenge, a separate "naive" group often previously untreated animals was 

also treated with 0.5 mL of the 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 of the application sites of the treated 

animals following any of the induction or challenge doses. Following challenge, no erythema was 

noted on any of the 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 of the in-life dates (January 14 to February 19, 2009) of the 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 of this 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 
194

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 of dennal sensitization, 

Harlan Laboratories Ltd. but positive control study not within 6 

Study #C24664 I March 20, 2009 months of this 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 
195

June 21, 2011 

Bonaventure Akinlosotu, PM Team 10 

Office of Pesticide 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 of this 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 of the 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 of proposed labeling that 

we request be utilized in the label review process of this submission. For security, please shred 

for us the original labels carrying the date of April 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 
196

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. 

EFFITIX TM TOPICAL SOLUTION FOR DOGS 

Alternate brand names: 

(EFFIXTM TOPICAL SOLUTION FOR DOGS) 

(EFFICANIXTM TOPICAL SOLUTION FOR DOGS) 

(EFFIPROTIX TM 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 212011 
197

FIRST 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, 
198

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 t 
199

Only 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 
200

• 

• 

• 

• 

• 

{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] t 
201

Repels 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 I 
202

NO 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 2011 
203

UNITED 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% 
204

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. 
205

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 
206

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. 
207

ix Topical Solution for Dogs 

H, Inc. 

Chemical - Fipronil 6.01 % 

Permethrin 44.88% 

August 3, 2011 

tiveness failure is failure to access the tube contents in the prescribed test time of 5 minutes for the first 

e second package, not accessing the tube contents in the correct manner in the prescribed test time of 5 

ge or 1 minute for the second package. 

o 1 unit. Access to 1 unit is more than 28.5mg of Fipronil for all sizes greater than 0.43 ml. 

he tube or any partial or complete access to the placebo (water). 

ul amt = 28.5mg = 28.5mg divided by [ll14mg/ml x 0.0601 Fipronilj = 0.426ml = 0.43ml for Fipronil & 

 EPA REG # 2382-RIT 

 

the child-resistant feature. 

re filled in mi. 
208

:2 

amt PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

I prod Pkg Get at 

ml (ml # unitlpkg, child Begin 

= fail = # units, Test 

0.0338 color, tox/harm = 

ft. oz.) # units 

1ml a 1 ml size tube 1 tube 50 child test 100% Meet 16 CFR 1700.20 eRE Criteria - yes 

with1ml - 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements forCRP per 16 CFR 1700.20 -yes 

2ml a 3 ml size tube 1 tube 50 child test 100% Meet 16 CFR 1700.20 CRE Criteria yes 

with 2ml 5 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 

4ml a 6 ml size tube 1 tube 50 child test 100% Meet 16 CFR 1700.20 CRE Criteria yes 

with 4ml 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 

------- ----- -
209

J 

amt PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

/ prod Pkg Get at 

ml (ml # unitJpkg, child Begin 

= fail = # units, Test 

0.0338 color, tox/harm = 

fl. oz.) # units 

6ml a 6 ml size tube 1 tube 50 child test 100% Meet 16 CFR 1700.20 eRE Criteria yes 

with 6ml - 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label IS limited to SAUE 

test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

1ml a 1 ml size tube 3 tube 50 chHd test 98% Meet 16 CFR 1700.20 CRE Criteria - yes 

with1ml - no chHd SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

2ml a 3 ml size tube 3 tube 100 child 98% Meet 16 CFR 1700.20 CRE Criteria - yes 

with 2ml test - 9 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

---_ .... -
210

4 

amt PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

I prod Pkg Get at 

ml (ml # unitlpkg, child Begin 

= fail = # units, Test 

0.0338 color, tax/harm :::: 

fl. oz.) # units 

4ml a 6 ml size tube 3 tube 50 child test 100% Meet 16 CFR 1700.20 eRE Criteria - yes 

with 4ml - 4 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

6ml a 6 ml size tube 3 tube 50 child test 98% Meet 16 CFR 1700.20 CRE Criteria· yes 

with 6ml • 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria· yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 170020 -yes 

1ml a 1 ml size tube 6 tubes 50 child test 95% Meet 16 CFR 1700.20 CRE Criteria· yes 

with1ml • 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria· yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status· 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

-
211

5 

amt PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

I prod Pkg Get at 

ml (ml # unitJpkg, child Begin 

= fail = # units, Test 

0.0338 color, tox/harm = 

fl. oz.) # units 

2ml a 3 ml size tube 6 tubes 50 child test 99% Meet 16 CFR 1700.20 eRE Criteria - yes 

with 2ml - 4 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

4ml a 6 ml size tube 6 tubes 50 child test 99% Meet 16 CFR 1700.20 CRE Criteria - yes 

with 4ml - 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

6ml a 6 ml size tube 6 tubes 50 child test 98% Meet 16 CFR 170020 CRE Criteria -yes 

with 6ml - no child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 
212

6 

amt PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

/ prod Pkg Get at 

ml (ml # unitlpkg, child Begin 

= fail = # units, Test 

0.0338 color, tax/harm = 

ft. oz.) # units 

lml a 1 ml size tube 36 50 child test 98% Meet 16 CFR 1700.20 eRE Criteria - yes 

with1ml tubes - 1 child SAUE Meet 16 CFR 1700.20 SAUE Criteria yes 

(placebo/product) failure pass 4/13/2011 master label (pin punched 4/28/2011) on p 2 

sequential matches SAUE test pkg instruct. Note p4 after tube 

test 16 CFR text not allowed picture of applicator tube as not part 

1700.20 of SAUE test pkg instruct. Label is limited to SAUE 

test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

2ml a 3 ml size tube 36 50 child test 99% Meet 16 CFR 1700.20 eRE Criteria - yes 

with 2ml tubes 4 child SAUE Meet 16 CFR 1700.20 SAUE Criteria yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status 4/28/2011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

4ml a 6 ml size tube 36 50 child test 100% Meet 16 CFR 1700.20 CRE Criteria yes 

with 4ml tubes 2 child SAUE Meet 16 CFR 1700.20 SAUE Criteria yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg Instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

test 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 412812011 acceptable 

all requirements for CRP per 16 CFR 1700.20 -yes 

------
213

'j 

ami PKG Description # Pkges CRE SAUE Conclusion 

placebo Include ml per Child # child test 

I prod Pkg Get at 

ml (ml # unit/pkg, child Begin 

= fail = # units, Test 

0.0338 color, tax/harm = 

fl. oz.) # units 

6ml a 6 ml size tube 36 50 child test 100% Meet 16 CFR 1700.20 eRE Criteria - yes 

with 6ml tubes - no child SAUE Meet 16 CFR 1700.20 SAUE Criteria - yes 

(placebo/product) failures 4/13/2011 master label (pin punched 4/28/2011) on p 2 

pass matches SAUE test pkg instruct. Note p4 after tube 

sequential text not allowed picture of applicator tube as not part 

lesl 16 CFR of SAUE test pkg instruct. Label is limited to SAUE 

1700.20 test pkg instruct. 

CRP Cert date & status - 4/28/2011 acceptable 

all requ'lrements for CRP per 16 CFR 1700.20 -yes 
214

Richard 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 itself is 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 of the components included with this application: 

1. Cover Letter; 

2. Transmittal Document; 

3. Application for Pesticide Form 8570~1 for EffitixtM Topical Solution For Dogs; . 

4. Confidential Statement of Formula for Effitix"" Topical Solution for Dogs· 2 Copies; 

5. nata Matrix Fotnl 8570·4 for Effitix'" Topical Solution for Dogs; 

6. Cerdfication of Data 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 of bound PR 86·5 compliant study reports supporting registrati\>n; , 

9. Waiver Request for Acute Inhalation Study (attached to Cover Letter); 

10. Letter of Self -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 ,(, , 

485107·00 
215

Fipronil 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 of all proposed presentations of the 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 
216

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 

'. 
217

DensitylRelative Density (C2471O) 

Acute Toxicity 

Target Animal Safety 

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 
218

Studv~ > No. 

21 IOPn~ 

Companion Animal Safety 

48487120 

TSH. Validation of an 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 

24 ~'in 

Product Performance (F 104.05·60016) 

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,::, 

Product Performance (F 104-05·60018) 

"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 of efficacy of a 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. 

3 
219

Product Performance (F 104-05-60022) 

''Determination of efficacy of a combination of Fipronil 

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 

water, 36 applicator 

~~~~I--~:"< tubes test as a Poison Prevention 48487137 

Virbac 

water, I applicator tube test as a Poison Prevention 48487138 
220

· , 

Volume Study Title MRIDNo. 

40 Evaluation of the 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 of the 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 of the 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 of the 6 ml Applicator Tube with 6.0ml 

water, 36 applicator tubes test as a Poison 48487146 

Prevention Package for Virbac SA (! 710-08'71 

,', , ,{ . ,{, , 

'" , 

5 
221

UNITED 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 of Analysis for Compliance with PR Notice 86 R 5 

OFFICEOl' 

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES 

Thank you for your submittal of 19 R MA Y-ll. Our 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 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. 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 [03]: 

* You must include one of the 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 

of two alternative forms of the Statement of Data 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, and 
222

UNITED 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. 
223

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 of Pesticide Programs has received your application and certification of 

payment. If you submitted data with this application, the results of the PRN-86-5 screen will be 

communicated separately. During the administrative screen, the Office of Pesticide 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. 

Fron7n~ 

Sincerely, 

ocessin~~Sta· 

~~ ... 

I,orma on Tech7 & Resources Management DIVIsIOn 

, 

/ t 

L 
224

TRANSMITTAL DOCUMENT 

Submission to US EPA Document Processing Desk 

Document Processing Desk 

Office of Pesticide 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 of new product application for EFFITIXTM Topical Solution for Dogs. 

Confinuation of receipt by US EPA Document Processing Desk 

SEP A Document Processmg Desk 

0'-( &G/JOI/ 

Datell'ime 1 
225

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 
226

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 
227

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 of the 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. 
228

,', 

• 

• 

• 

*Commercial/financial information may be entitled to confidential treatment*
229

V,rbac 

ANIMAL HEALTH 

April 28, 2011 

Richard Gebken, PM 10 

Office of Pesticide 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 itself is 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 of the 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 of Fonnula for EffitixTM Topical Solution for Dogs - 2 Copies; 

5. Data Matrix Form 8570A for EffitixTM Topical Solution for Dogs; 

6. Certification of Data 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 of bound 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 
230

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 of the 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) 831-8327 
231

Virbac 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) 

I 
232

Volume Studv Title MRIDNo. 

9 OPPTS 830.7000 

pH (C24743) 48~Oa-..., 

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 

Target Animal 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 -

2 
233

Volume Study Title MRIDNo. 

21 OPPTS 870.7200 

Companion Animal Safety 

48487120 

TSH. Validation of an 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 of action" 

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 

scapular is) on dogs 

3 
234

28 OPPTS 

30 

31 

32 

34 

35 

39 

Product Performance (F 104-05 -60022) 

"Detennination of efficacy of a 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 

of the 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 

of the 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 
235

Volume Studv Title MRIDNo. 

40 Evaluation of the 6ml Applicator Tube with 4.0ml 

water, 3 applicator tubes test as a Poison Prevention 48487139 

Package for Virbac SA (1710-81) 

41 Evaluation of the 6ml Applicator Tube with 4.Oml 

water, 6 applicator tubes test as a Poison Prevention 48487140 

Package for Virbac SA (1710-82) 

42 Evaluation of the 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 of the 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 of the 6 ml Applicator Tube with 6.0ml 

water, 36 applicator tubes test as a Poison 48487145 

Prevention Package for Virbac SA (1710-087) 

5 
236

Unl1ed 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) 
237

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 of the 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 of the use of that 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 copy 

*Product ingredient source information may be entitled to confidential treatment*
238

Form 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. 
239

Apri128,2011 

Richard Gebken, PM 10 

Office of Pesticide 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 of 40 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. 
240

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 of the 

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 of product 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 of the 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) 831-8327 
241

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

s!z 401 M Street, S.W . 

. ,;" 

'M no, . . \be instruction and 

. . 'oed, 

II ; ; ·.:.:'.:othe burden to Dinx,:lor; OPPE Infonnalion , J I) U.S. Environmental Protection Ag

'. DC 20460. 0,"" ",d "dd";'. 

DATA MATRIX f.,

, 

, ,N,,", . Pro,"o, 

'?'."':;76161 EFFITIX TM TOPICAL SOLUTION FO

; , 

, 

",d' N,w 'AH. 100. 

>or , U,cd N,w. Y b"AH,bo 

, Pro"" Now. b"AH. 100. 

830.1650 Now. b"AH.bo 830.1670 i ,of N,w b"AH, 100. 830.1750 Limit> N,w. bocAH.loo 830.1800 Now. .boc AH, 100. 

, 830 Seci" Go 'cp 

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401 M Street, S.W. 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

WASHINGTON D.C. 20460 

Paperwork Reduction Act Notice: The public reporting burden for this collection ofinfonnation is estimated to average 0.25 hours per response for registrntion activit

for reregistration and special review activities, including time for reading the instruction and completing the necessary forms. Send commcnts regarding the burden esti

collection ofinfonnation, including suggestions for reducing the burden to Director: OPPE Infonnation Management Division (2137) U.S. Environmental Protection Ag

Washington, DC 20460. Do not send the fonn to this address. 

DATA MATRIX 

Date: A iii 13 2011 EPAR . No.lFilc S mhol 2382-new 

Applicant's/Registrnnt's Name & Address Product: 

Virbac AH, Inc 

PO Box 162059 EFFrnX n< TOPICAL SOLUTION FOFort Worth TX 76161 

" 

ient: Fi roml Penncthrin 

Guideline Reference Number Guideline Stud Name MRIDNumber Submitter 

Efficacy and safety data 

-Floroni! 

810.3300 ProductPcnormance Effica -flea 44942106 Mcrial 810.3300 Product Performance Effica -flca 45618501 Mcrial 810.3300 Product Performance Efficac -flea 45620502 Merial 810.3300 ProduclPerformance Efficac -flea 45620503 Merial 810.3300 Product Performance Efficac _flea 45628104 Merial 

810.3300 Product Performance Efficaev-flea 45628105 Merial 810.3300 Producl Performance Efficacy-flea 45866901 Merial 810.3300 Product Performance Efficacy-tick 43577712 Merial 

810.3300 Produci Pcrformance Efficacy-tick 43121114 Merial 810.3300 Product Pcnormancc Efficacy-tick 43121115 Merial 810.3300 Produci Pcnormancc Efficacy-tick 43121117 Mcrial 

810.3300 Product Pcnormancc Efficacy-tick 43121122 Mcrial 810.3300 Product Performance- EfficaC'j Bathing 43121118 Merial 

Signature Name and Title 

Craig Parks 

Vice President, Research & Developme

, , EPA fonn 85i{l.35 (9 9i) EI«1",n,e ""d raper =to .. Availioble. Su only aper \er'lOn. A Of

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Vitbac AH, Inc 

PO Box 162059 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

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401 M Street, S.W. 

;'tUN. D.C. 

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and completing 

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248

UNITED STATES ENVmONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

VN, D.C. 20460 

, A" Noli,,, ' 11 I , 

1 . for reading the instruction and completing :- 1 

" , . I' I burden (0 Direclor: OPPE Infonnalion ManagemCl\t OJ, i ) U.S. Environmental Protection A

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249

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

WASHINGTON D.C. 20460 

Papcrwork Reduetion Act Notice: The public reporting burden for this col1ection ofinfonnatioil is estimated to avernge 0.25 hours per response for registrntion activi

for reregistrntion and special review activities, including time for reading the instruction and completing the necessmy fonns. Send comments regarding the burden esti

collection of infonnation, including suggestions for reducing the burden to Director: OPPE Infonnation Management Division (2137) U.S. Environmental Protection A

Washington DC 20460. Do not send tbc fonn to this address. 

DATA MATRIX 

Date: A Iii 13 2011 EPAR . No.lFileS bol 2382-new 

AITlicant'siRegistrnnt's Nalne & Address Product: 

Virbac AH, Inc 

PO Box 162059 EFFlTIX TM TOPICAL SOLUTION FOFort Worth TX 76161 

Ingredient: Fi ronil Pennetbrin 

Guideline Reference Number Guideline Stud Name MRIDNumber Submitter 

Child Resistant Packae:lng 

40 CFR 157 Evalualion ofthc Iml ApplicalorTube with l.0 ml water, I New Submission VirbacAH, Inc. 

applicator tube test as a Poison Prcvenlion Package for 

Virbac SA 

40 CFR 157 Evaluation of the Iml Applicator Tube with 1.0 ml water, 3 New Submission Virbac AH, Inc 

applicator tubes test as a Poison Prevention Package for 

Virbac SA 

40 CFR 157 Evaluation oflhe Iml ApplicatorTube wilh 1.0 ml water, 6 New Submission Virbac AH, Inc. 

applicator tubes lesl as a Poison Prevention Package for 

Virbac SA 

40 CFR 157 Evaluation of the Iml ApplicalorTube with l.OmI water, 36 New Submission Virbac AH, Inc 

applicator tubes test as a Poison Prevenlion Package for 

Virbac 

40CFR 157 Evalualion ofthe 3ml Applicator Tube with 2.OmI water, I New Submission Virbac AH, Inc. 

applicalor tube tcst as a Poison Prevention Package fur 

Virbac SA 

40 CFR 157 Evaluation ofthc 3ml Applicator Tube with 2.0ml water, 3 New Submission Virbac AH, Inc 

applicalor tubes lest as a Poison Prevention Package for 

Virbac SA 

40CFR 157 Evaluation of the 3ml Applicator Tube with 2.0ml water, 6 New Submission Virbac AH, Inc. 

applicator tubes tesl as a Poison Prevention Package for 

Virbac SA 

Signature Name and Tide 

Cmig Parks 

Vice President, Researcb & Developm

. . , EPA Fonn 8570 3519 97) a.worne ond POp<r Verno"" AvailiW" SUOmII only ""per """mlL 
250

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

WASHINGTON D.C. 20460 

Paperwork Reduction Aet Notice: TIle public reporting burden for tlus collection ofinfonuation is estimated to avcmge 0.25 hours per response for registmtion activi

for reregistrntion and special review activities, including time for reading the instruction and completing the necessary forms. SClld comments regarding the burden esti

coi1ection ofinforruation, including suggestions for reducing the burden to Director: OPPE Infonuation Managemcnt Division (2137) U.S. Environmental Protection A

Washington, OC 20460. Do not send the fonu to this address. 

DATAMATRlX 

Date: A ri113, 20 II EPARe . No.lFile S mhol 2382-ncw 

Applicant'sJRegistmnt's Name & Address Product; 

Virnac AH, Inc 

PO 80); 162059 EFFITIX TM TOPICAL SOLUTION FO

Fort Worth TX 76161 

ill ient; Fi ronil, Pennethrin 

Guideline Guideline Study Name MRIDNumber Submitter 

Reference Number 

40 CFR 157 Evaluation of the 3ml Applicator Tube with 2.0ml water, 36 New Submission VirbacAH, Inc. 

applicator tubes lesJ as a Poison Prevention Package for Virbac 

SA 

40 CFR 157 Evaluation of the 6ml ApplicaJor Tube with 4.0ml waler, I New Submission Virbac AH, Inc 

applicator tube test as a Poison Prevention Package for Virbac 

SA 

40 CFR 157 Evaluation ofthe 6ml Applicator Tube with 4.OmI waler, 3 New Submission Virbac AH, InC. 

applicator tubes test as a PoiSOn Prevenlion Package for Virbac 

SA 

40CFR 157 EvaluaJion ofthe 6ml Applicator Tube with 4.0ml water, 6 New Submission Virbac AH, Inc 

applicator tubes test as a Poison Prevenlion Package for Virbac 

SA 

40 CFR 157 Evaluation of the 6ml Applicator Tube wilh 4.0ml water, 36 New Submission Virbac AH, Inc. 

applicator tubes lesl as a Poison Prevention Package for Virbac 

SA 

40CFR 157 Evaluation of Ihe 6 ml Applicalor Tubc with 6.0ml water, I New Submission Virbac AH, Inc 

applicator tube test as a Poison Prevention Package for Virbac 

SA 

Signature Namc and Title 

Craig Parks 

Vice Presidcnt, Research & Developm

; 

"" form 8,70 3> t9 97) Eb:tmruc and Paper VcrslO"" Availablo. Subm I only l'aper vers,on. 

, 
251

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

WASHINGTON, D.C. 20460 

PapcrworkReduetion Act Notice: TIle public reporting burden for this collection ofinfoooation is estimated to average 0.25 houffi per response for registration activi

for reregistration and special review activities, including time for reading the instruction and completing the necessary fooos. Send comments regarding thc burden esti

collection ofinfonnation, including suggestions for reducing the burden to Director: OPPE Infoooation Management Division (2137) U.S. Environmental Protection A

Washington, DC 20460. Do not send the fonn to this address. 

DATA MATRIX 

Date: A ril13 2011 EPA Re . No.lFile S mbol 2382-new 

Applieant'slRcgistrant's Name & Address Product: 

Virbae AH, Inc 

PO Box. 162059 EFFITlX TM TOPICAL SOLUTION FO

Fort Worth TX 76161 

m ient: Fi roni!, Peooethrin 

Guidcline Reference Guideline Study Name MRIDNumber Submitter 

Number 

40 CFR 157 Evaluation oflhe 6 ml Appliealor Tube with 6.0ml water, 3 New submission VirbaeAH, Inc. 

applicator tubes lesl as a Poison Prevention Packagc for 

Virbae SA 

40 CFR 157 Evalualion of the 6 ml Applicator Tube with 6.0ml water,6 New submission Virbae AH, Inc 

applicator lubes test as a Poison Prevenlion Package Virbae 

SA 

40 CFR 157 Evalualion of the 6 ml Applicator Tube with 6.0ml water,36 New submission Virbac AH, Inc. 

applicator tubes test as a Poison Prevenlion Package for 

Virbac SA 

Signature Name and Title 

Craig Parks 

Vice President, Research & Developm

EM FOM 8570 3S 19 . 97) Electro,"c:md Paper v ; .... 0 .. Av.,l.bk Su bmilonl Fa • " y per CfSt<> • ,. , 
252

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DATA MATRIX 

] 

, Virbac 

Corporate Product Innovation Direclor 

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253

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

:& 401 M Street, S. W. 

" "W'" i,. • ",dO

i . . ,i' the instruction and completing the necessary fonllS . 

:"0,;'"", ,';'d ;;;;d;:rn to Dim:lor: OPPE lnronnation Management Division {2137} U.S. , 

DATA 

'1 

'1 

I V.b," SA 

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Jean-pascal Marc 

.. Corporate Product Innovation Director 

" 

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Note: 830.6317 and 830.6320: Per Agency policy, storage stability and corrosion characleristics data arc not required to be submitted unless specifically re

has initiated these studies and will submit the final reports if required when the studies are completed. 
254

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8\-8 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

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Dim.:tor; OPPE Infonnation, ,I D 

DATAMATRTX 

43279706 

AcUtO 0 (o,icity 

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I I i 

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u.s. Environmental Protection Agency, 

BASF 

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J! 

N,mo!,' Title. 

lean-Pascal Marc 

Corporate Product Innovation Director 

""" , 
255

Form 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

:& 401 M Street, S.W. 

WASHINGTON D.C. 20460 

Paperwork Reduction Act Notice: The public reporting burden forthis collection ofinfonnation is estimated to average 0.25lioun; pcr responsc for registrntion activities and 

for reregistration and special revicw activities, including time for reading thc instruction and completing the necessary fonns. Scnd comments regardiug thc burden estimate o

collection ofiufonnation, including suggestions for reducing the burden til Director: OPPE Infonnation Managemcnt Division (2137) U.S. Environmental Protection Agency, 

Washington, OC 20460. Do not send thc fonn to this address. 

DATA MATRIX 

Date A ri125,2011 EPA Re No.lFile S mbol 

Applicant'sJRegistrnnt's Name & Address Product: Fipronil Technical 

Virbac SA 

I cre avenuc2065 M • LID 

F-06516Carros, France 

I" icnl: Fi nil 

Guidcline Rcference Number Guidelinc Study Name MRIDNumber Submitter 

40 CFR 158.340 Data Requirements (Continued 

84·2 Structural chromosomal aberration 42918680 BASF 84·2 Structural chromosomal aberration 42918653 BASF 84·2 Other genotoxic effects 42918651;42918653 BASF 

43501703 

85·1/870.7485 General metabolism 42918655 BASF 

85·1/870.7485 General melabolism 43253701 BASF 85-1/870.7485 General metaboltsm 43737308 BASF 

85-1/870.7485 General metabolism 42918654 BASF 85-1/870.7485 General metaboHsm 42977904 BASF 85-1/870.7485 General metabolism 43253701 BASF 

85-2/870.7600 Dennal penetration 43737308 BASF 85-7/870.7600 Immunotoxicity DATA GAP 

40 CFR 158.490 Wildlife and Aquatic Organisms Data Requirements 

71-1/850.2100 Avian oral LD 50 mallard or bobwhite 42918617 BASF 

42918616 

72·1/850.1075 Freshwater fish LC 50 rainbow or 42918624;42918673; BASF 

bluegHi 42918674;42977902 

43279703;43291718 

Signature Name and Title 

"c. Jean·Pascal Marc 

Corporate Product Innovation Director 

EPA Fonn &570·)5 (9·97 EI""lroni< .nd PaperV .... ;o'" A .. it"ble. Submit only Paperv=ion. ". Intern.
256

. I 

• LID 

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i 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

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i 

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, 

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I 

I 

, 

" 

. plie burdcn to Director. OPPE information Management Division (2137) U.S. Environmcntai Protection Agency, 

DATAMA,!!!!X 

. ",do", 48 

iOI 

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, 

, " .... ;on. 

Prod,," Fipro,iI' 

, BASF 

I BASF 

I BASF 

IASF 

BASF 

Jean*Pascal Marc 

Corporate Product Innovation Director 
257

i 20460 .. Do I e 

., 

, 

F-06S16' - LID 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

401 M Street, S.W. 

WA. "V", D.C . 

. ,Ii<. 

rrr; Infonnation I) u.s. Environmental 

DATA MATRIX 

A<uto L?!"a) 

NIA 

I NIA 

.,ma,aa} ,42918669 BASF 

,(Soot) - FiDroni! 

j tor exposure studies44433303 M,ri, 

'THI'. 

Jean-Pascal Marc 

Producl Innovation Dire

* Pursuant to 40 CfR 152.96 (c), Virbac hereby certifies that Virbac has no basis to believe that this requirement is not II data gap and, further, that Virbac has sen

011 the eurrent EPA Data Submitters List for fipronil II. lctlcr requesting that the company identify, wHhin 60 days of rcecipt, any valid study that would flllfill tltis d

period expires, Virbae will update the Agency as to the information, If any, Virbae receives in response to this "dala gnp" [eUer. 
Pages 258-259 - *Confidential Statements of Formula may be entitled to c