Document ID: EPA-HQ-ORD-2006-0384-0067
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-12T04:00Z

Protocol
EMD
003
Protocol
EMD
003
Tick
Repellency
Tick
Repellency
Kevin
Sweeney
Clara
Fuentes
John
Carley
Roger
Gardner
2
Laboratory
Evaluation
Laboratory
Evaluation

Laboratory
assay
with
human
subjects
to
evaluate
the
efficacy
against
ticks
of
three
skin­
applied
formulations
of
the
insect
repellent
IR­
3535

The
protocol
is
similar
in
many
aspects
to
the
draft
EPA
Guideline
for
tick
testing,
especially
to
the
2000
version
3
IR
IR­
3535
3535

Registered
in
the
USA
for
six
years

Used
in
Europe
for
over
20
years

Skin­
applied
repellent

Amino
acid
derivative

Very
low
toxicity
4
Overview
of
Testing
Overview
of
Testing

Three
test
formulations:
20%
lotion,
20%

aerosol
and
a
10%
pump­
spray
liquid.

Formulations
delivered
by
pipette
to
the
limb
of
the
test
subject
as
a
liquid.

Dose
 
1
gram
of
formulation
per
600
cm
2
of
skin
surface.

Tick
 
Ixodes
scapularis
pacificus,
the
Western
black­
legged
tick,
Lyme
disease
vector
in
western
USA.
5
Method
Method
­
1
Five
treatments:


IR3535
10%
Pump
Spray
formulation
(
6
subjects)


IR3535
20%
Lotion
formulation
(
6
subjects)


IR3535
20%
Aerosol
formulation
(
6
subjects)


DEET
positive
control
(
1
subject)


Untreated
negative
control
(
1
subject)
6
Method
Method
­
2

Line
is
drawn
across
wrist
of
each
subject

A
tick
is
placed
on
the
hand,
oriented
toward
the
wrist

A
tick
is
observed
for
3
minutes.
If
it
crosses
the
line
toward
the
elbow
it
is
"
not
repelled"

A
fresh
tick
is
used
every
15
minutes
7
Method
Method
­
3

Subject
selection
of
ticks
may
introduce
variation

Only
one
species
of
tick
is
tested.

Guideline
recommends
three
species,

each
from
a
different
genus.

Cycle
repeated
every
15
minutes.

Guideline
recommends
every
hour.
8
Method
Method
­
4

Protocol
uses
liquid
formulations
applied
by
pipette.
Guideline
calls
for
testing
formulations
as
they
are
to
be
registered

Why
are
untreated
control
subjects
used?

Qualification
of
ticks
before
use,
handling
of
ticks
after
qualification,
and
disposition
of
ticks
after
use
are
inadequately
specified
9
Determination
of
%
Repellency
Determination
of
%
Repellency
For
each
subject:

Repellency
=
100
*
Number
of
ticks
repelled
Total
number
of
ticks
Analysis
yields
a
subject
mean,
a
grand
mean,

and
a
SD
of
the
means.

Application
of
Chi­
square?
 
the
%
repellency
calculated
is
significant
or
not
at
 
=
0.05
10
Ethics
Review:
EMD
Ethics
Review:
EMD­
003
003

Lab
test
of
tick
repellency

18
treated
subjects
recruited
as
described
in
C­
L­
001
and
randomly
assigned
to
one
of
three
treatment
groups

Controls,
one
positive
and
one
untreated,

chosen
from
among
investigators
11
EMD
EMD­
003
Framework
003
Framework
­
1
1.
Value

Purpose
is
poorly
described
in
protocol

Intention
is
to
gather
information
to
support
development
of
personal
repellents
for
future
commercial
marketing

There
is
potential
societal
benefit
in
developing
additional
safe
and
effective
personal
repellents
2.
Scientific
Validity:
Defer
to
others
12
EMD
EMD­
003
Framework
003
Framework
­
2
3.
Subject
Selection

Recruiting
methods
are
well
described
in
C­
L­
001

No
indication
that
subjects
would
be
subject
to
any
coercion
or
undue
influence,
or
be
recruited
or
enrolled
for
reasons
inconsistent
with
the
goals
of
the
research

Exclusion
factors
ensure
exclusion
of
children
and
pregnant
or
lactating
women,
and
students
of
investigators
13
EMD
EMD­
003
Framework
003
Framework
­
3
4.
Risk­
Benefit
Ratio

Materials
tested
for
acute
toxicity

Candidates
phobic
to
ticks
are
excluded

Ticks
are
removed
before
biting

Captive­
bred
disease­
free
ticks
used

No
discussion
of
risk/
benefit
assessment
14
EMD
EMD­
003
Framework
003
Framework
­
4
5.
Independent
Ethics
Review

Unanimously
approved
by
Independent
Investigational
Review
Board,
Inc.,
of
Plantation
FL

IIRB
is
registered
with
OHRP,
and
is
independent
of
the
investigators
15
EMD
EMD­
003
Framework
003
Framework
­
5
6.
Informed
Consent

Written
consent
from
all
subjects
promised

Procedures
for
consent
adequate

Deficiencies
in
content
of
consent
materials
should
be
corrected
7.
Respect
for
Subjects

Subject
privacy
would
not
be
compromised

Subjects
would
be
free
to
withdraw
16
Applicable
Standards
Applicable
Standards

This
is
a
3
rd
­
party
intentional
exposure
study
intended
for
submission
to
EPA
under
the
pesticide
laws.
The
applicable
standards
are:


40
CFR
26,
Subparts
K
and
L

FIFRA
§
12(
a)(
2)(
P)


California
Code
of
Regulations
Title
3,
Section
6710
17
Deficiencies
Noted
Deficiencies
Noted
­
1

IC
materials
tell
subjects
they
will
be
randomly
assigned
to
treated
or
control
groups.
C­
L­
001
states
that
only
investigators
will
serve
as
controls.

Conflict
should
be
reconciled;
it
may
require
separate
consent
documents
for
treated
and
control
subjects.
18
Deficiencies
Noted
Deficiencies
Noted
­
2

Test
procedures
are
inadequately
described
to
subjects
in
IC
materials:


 
The
ticks
are
then
applied
.
.
.
and
you
will
record
any
crossings
or
repulsions 
in
IC
materials.

Should
be
clear:


pick
up
a
tick
with
an
artist s
paint
brush

place
it
on
their
wrist
and
orient
it
toward
their
elbow

monitor
its
behavior
for
3
minutes

dispose
of
the
tick

record
its
behavior

and
repeat
the
process
every
15
minutes
for
several
hours
19
Deficiencies
Noted
Deficiencies
Noted
­
3

Vague
language
in
IC
""
Measures
will
be
implemented
to
make
sure
that
ticks
are
removed
before
they
have
an
opportunity
to
bury
in
the
skin"
should
be
clarified

Suggest
"
You
will
be
taught
how
to
remove
ticks
from
your
arm
before
they
have
an
opportunity
to
bury
in
the
skin
or
bite
you.

Although
it
is
unlikely,
because
it
takes
a
tick
about
10
minutes
to
bury
before
biting,
you
may
be
bitten
by
a
tick.
The
ticks
used
in
this
test
are
captive­
bred
and
free
of
disease."
20
Deficiencies
Noted
Deficiencies
Noted
­
4

The
word
"
NOT"
is
missing
from
the
IC
discussion
of
"
Pregnancy
Risks"
which
should
read
".
.
.
it
is
important
that
you
do
NOT
participate
in
this
study
if
you
are,
or
think
you
may
be
pregnant."
21
Deficiencies
Noted
Deficiencies
Noted
­
5

IC
promises
to
cover
costs
of
"
treatment
required
for
injury
resulting
from
being
in
the
study,"
but
then
excludes
injuries
"
resulting
from
normal
work
activities",
and
then
further
excludes
compensation
for
"
such
things
as
lost
wages,
disability,
or
discomfort
due
to
injury."
This
is
unacceptably
exculpatory.
22
Deficiencies
Noted
Deficiencies
Noted
­
6

The
IC
materials
inappropriately
discuss
compensation
to
the
subjects
as
a
benefit,
but
are
silent
about
expected
societal
benefits
and
how
they
were
weighed
against
risks
to
subjects

The
California
Department
of
Pesticide
Regulation
should
be
added
to
the
list
of
parties
to
whom
personal
information
may
be
disclosed
23
Deficiencies
Noted
Deficiencies
Noted
­
7

Protocol
should
acknowledge
the
applicable
standards
of
ethical
conduct,

and
the
obligation
of
the
investigators
to
inform
both
the
cognizant
IRB
and
the
California
Department
of
Pesticide
Regulation
of
any
amendments
to
or
deviations
from
the
approved
protocol
24
Charge
Questions
Charge
Questions

Is
this
proposed
research
likely
to
generate
scientifically
reliable
data,

useful
for
assessing
the
efficacy
of
the
repellent(
s)?

Does
this
proposed
research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?