1

EPA Evaluation 

Pet Spot-On Produ

Analysis and Mitigation Pla

March 17, 2010

Ms. Lois Rossi, MS, DirectoDr. Kit Farwell, DVM, DABT Ms. Kimberly Nesci, MS, Re
2

Outline

• Background• Analysis• Risk management• Next steps• Questions and answers
3

Background

• Spot-On Products

• What are they?• How are they applied?• Why are they registered?

• EPA Evaluation

• Why, what triggered this?• When?
4

Background

• From 2007 to 2008, total numbers o

increased by about 53%

• 2007 Incidents

• About 1.9% of the incidents were deat• About 4% of the incidents were deaths 

incidents 

• 2008 Incidents

• About 1.4% of the incidents were deat• About 3% of the incidents were deaths 

incidents

• In 2008, there were 270,000,000 do

(0.00016 incident per dose) 
5

Background

• April 16, 2009, press advisory

• Concurrent with a Canadian pres• Messages

• EPA is intensifying its evaluation of 

products

• EPA acknowledged the importance • EPA advised consumers to use cau

applying and watch for adverse reac

• EPA advised consumers on what to 

reactions occur
6

Background

• May 5, 2009, Registrant Meetin

• EPA discussed incidents being re• EPA discussed the ongoing inten

and information needs

• EPA provided a summary of the m

online on our Web page

• No decisions were made
7

Background

• After the May 5, 2009, meeting

• Received enhanced reporting info• Established an expert EPA veteri• Analyzed data and additional info• Collaborated and partnered with T

and Drug Administration’s (USFDVeterinary Medicine (CVM) and CManagement Regulatory Authorit

• Held a three-day meeting with CV

PMRA to peer review EPA’s anal
8

Analysis

• Objective: To describe the n

the incidents and to identify asusceptible subpopulations opatterns associated with incr
9

Analysis – Review Pr

• Veterinary Team: 

• Assembled for the purpose of evaluating th

incident data

• Composed of 6 DVMs and other experienc

across OPP

• Chaired by Kit Farwell, DVM

• Review Process:

• Primary Review conducted by a technical r

• Secondary Review conducted by an alterna• Internal Peer Review by Veterinary Team• External Scientific Peer Review with PMRA 

Toxicology teams and USFDA CVM
10

Analysis - Data Rece

• Enhanced incident reporting 

• Product and background informat

• EPA Registration #, product name, 

type, where purchased, active ingrerange for product, date, state, regist

• Pet information: 

• species, breed, age, sex, weight, ro

how applied, body system, clinical sonset, duration, veterinary treatmenmisuse, other drug or pesticide usedEPA severity code, certainty index, 

• Spreadsheet cell with text narrativ
11

Analysis – Data Rev

• Many additional sources of data 

“Weight-of-Evidence” approach

• Incident data

• EPA received and analyzed data from eigh• EPA standardized the format of the data re

• Companion animal safety studies• Toxicology database in laboratory anim

• Acute Studies• Dermal Toxicity 

• Pharmacokinetic Data

• Literature provided by international exp
12

Analysis – Data Evalu

Record

• The primary technical reviewer prepare

evaluation records (DERs) and all DERtechnically peer reviewed internally and 

• The DERs assembled the enhanced in

available animal toxicology information products.

• DERs were developed for spot-on prod

represented a majority of the total incid
13

Analysis – Incident 

Standardization

• Incident data submitted in spreadsheets 

varied in the format and the information p

• Each spreadsheet was standardized by E

data could be compared

• Records were used:

• If they included registration numbers• If the incident occurred in the United States• If only one product used on the animal• If multiple reports reflected the same incident

• If only one pet was reported to be experiencin• If they included species type
14

Analysis – Data Eval

• Key Parameters Evaluated

• Severity : dogs and cats• Use not in accordance with label direc

age, under-weight, wrong species

• # of incidents by gender• Age• Body weight• Product weight range, where appropria• Breed• Body system affected and/or clinical s
15

Analysis – Data Evalu

Severity in dogs and cats

• Severity in Dogs and Cats

• The percentage of incidents for each s

were reported by product. 

• The severity classifications:

• D-A: Death or euthanasia• D-B: Major (life threatening effects or 

residual disability)

• D-C: Moderate (more pronounced or 

minor classification, treatment may harequired

• D-D: Minor (minimally bothersome eff

resolved rapidly)

• Adapted from Pesticide Registration Notice 98-
16

Analysis – Data Evalu

Use not in accordance with label 

• Assessed 

• Cats exposed to dog products• Use on pet weighing less than w

on product label

• Use on pet younger than age on 
17

Analysis – Data Evalu

Sex and Age

• Gender: assessed percent of i• Age: assessed percent of incid

each severity code

• No gender differences were att

treatment with any spot-on

• Most dog incidents occurred in 

years old
18

Analysis – Data Evalu

Body Weight and Breed

• Body weight: assessed percent 

incidents for each severity code

• Breed

• assessed percent of incidents by • this information was compared to 

American Kennel Club (AKC) rannumber of registrations per year
19

Analysis – Data Evalu

Product Weight Range

• Assessed percent of incidents in dog

less than the weight range on produ

• For some dog products, assessed:

• Percent of incidents in dogs weighing le

lowest weight range

• Percent of incidents in dogs in lower 1/2 

range

• Percent of incidents in dogs in upper 1/

weight range
20

Analysis – Data Evalu

Product Weight Range, conti

• Did not assess weight range fo

because weight ranges were veand/or had no lower limit
21

Analysis – Data Evalu

Body Systems and Clinical S

• Examples of reported organ sy

clinical signs:

• Dermal (irritation and scratching)• Gastrointestinal (vomiting and dia• Neurological (tremor, depression• Ocular (tearing, redness)• Respiratory (cough)
22

Analysis – Inert Ingre

• Inert ingredients are chemicals added with active in

the final product formulation. These may be of heasome inert ingredients result in:

• Enhanced dermal absorption• Skin sensitization• Species-specific toxicity to cats

• A specific review of the potential risks posed by ine

initiated if the incident data indicated a concern witproduct

• Currently, a product cluster was not identified that would in

posed a unique risk compared to other products with simila

• As part of this review, the Agency identified all iner

included in these spot-on products and identified asuspected inert ingredient of potential health risk

• The Agency will continue to evaluate the safety con

associated with inert ingredients
23

Results of the Ana

• Overall Findings 

• Most incidents were minor, but al

products had deaths & major incireported 

• Types of effects - organ systems 

commonly affected were dermal, gastrointestinal, and nervous sys

• Labels often have warnings but, i

cases, warnings are not specific, or buried in the text
24

Results of the Ana

• Dog Findings

• Small breed dogs were adversely af

of these products more frequently th

• Weight/dose ranges may be too wid

products (smaller animals get more ingredient per pound).
25

Results of the Ana

• Cat Findings

• Misuse or inadvertent exposure of d

cats is a major problem in the United globally.

• Label warnings against use of dog p

are not working and do not provide protection to prevent incidents in ca
26

Results of the Ana

• Safety Testing Requirements

• Companion animal safety data do not a

predict the toxicity seen in the incident 

• Need for adequate testing requirement

the following:

• Differences between individual dogs,• Longer-term exposure (as a result of the re

• Route of exposure (for example, dermal an

from grooming).

• Collaborating with PMRA and FDA
27

Questions?
28

Risk Manageme

• Agency concluded, based on th

that mitigation is necessary to punreasonable adverse effects

• Regulatory Action Plan – EPA w

the following:

• Product-specific, immediate furth• Tighter regulation• Public outreach campaign
29

Risk Managemen

Further Restrictions

• Address dosing concerns

• Pursuing label and/or packaging 

would result in more narrow pet wper vial size
30

Risk Managemen

Further Restrictions

• Address concerns about cat exposu

products

• Pursuing label changes that prohibit th

same brand names for both dog and ca

• Determining appropriate, clear labels s

address concerns with cat exposure to 

• as a result of direct application or • as a result of interactions between dogs an

application of dog products
31

Risk Managemen

Further Restrictions

• Address concerns about label c• Address product specific conce

• Pursuing further label restrictions • Pursuing other changes, as need

individual product assessments (
32

Risk Managemen

Further Restrictions

• Address uncertainties about ine

ingredients 

• Pursuing disallowing alternate for• Determining whether additional in

certain inerts is needed and, if sothat information

• When inerts with suspected toxic 

identified, EPA will not allow the uchemicals in pet products
33

Risk Managemen

Tighter Regulation

• Pursue standardized adverse e

reporting 

• Standard format• Standard content• Analysis of the information • Will allow EPA to efficiently contin

market surveillance of these prod
34

Risk Managemen

Tighter Regulation

• Pursue standardized sales repo

• Will allow EPA to accurately com

numbers of incidents between pro
35

Risk Managemen

Tighter Regulation

• Revise Data Requirements - taking 

bring data requirements in line with requirements for similar products

• Will allow EPA to be consistent with FD

pre-market clinical trials

• Will allow EPA to more thoroughly ass

of these products prior to registration

• Will allow effective post-market surveil
36

Risk Managemen

FDA and EPA Requirem

Current EPA Requirements Curren

Pre-Market Animal Safety Study

Guideline No: 870.7200

Title: Companion Animal SafetyNumber of Animals: 6 per sex per dose

Level of Concern: 5X

Other: Harmonized with previous FDA/CVM 

Guidance #33 

Guideline No: 1

Title: Target An

Pharmaceutical 

Number of Anim

Level of Concern

Other: Internatio

Pre-Market Clinical Trials

None Guideline No: 85 

Title: Good Clin

Number of Anim

control). Repres

rather than only contributes to th

Post-Market Surveillance

Aggregate summary reporting of summary numbers of adverse effects under FIFRA Section 6(a)(2). Generally only used to trigger a more detailed review. 

Ten veterinarianevaluate detailed 

new products. Fproduct, label, in

and the public.
37

Risk Managemen

Tighter Regulation

• Conditional Registrations

• Future pet spot-on registrations (

products) and amendments to exregistrations will contain appropriconditions and time limitations

• Will allow EPA to conduct approp

market surveillance
38

Risk Managemen

Potential Implementation Mec

• Anticipated further restrictions

• Will be meeting with individual registra

individual products and product lines

• Considering preparing a guidance docu

• Tighter regulation

• Will be discussing with Canada’s PMR• Will be discussing with FDA’s CVM• Will be obtaining public input• May require changes to rules and guid

regulatory process
39

Public Outreach Campa

• The Agency is taking steps to init

prong communication campaign

• inform the public and other intereste

results of the investigation

• steps the public can take to ensure 

flea and tick products
40

Questions?
41

Today’s Activities

• Registrant Meeting 9:30 am – 1• Press Release• Web page update• Public Webinar 4:00 pm – 6:00 
42

Next Steps

• Registrant Meetings (summarie

docketed)

• FR Notice 

• Docket: EPA–HQ–OPP–2010–0

• www.regulations.gov

• 60-day public comment period

• Implementation• Announcements of any addition
43

Contact informatio

• For press inquiries:

• Dale Kemery• kemery.dale@epa.gov

• For all other inquiries:

• Kimberly Nesci, Registration Division, O

Pesticide Programs

• pets@epa.gov

• Web page

• http://www.epa.gov/pesticides/he

ctseval.html
44

Thank You