Document ID: EPA-HQ-ORD-2006-0384-0068
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-12T04:00Z

Protocol
EMD
004
Protocol
EMD
004
Mosquito
Repellency
Mosquito
Repellency
Kevin
Sweeney
Clara
Fuentes
John
Carley
Roger
Gardner
2
Field
Evaluation
Field
Evaluation

Field
test
with
human
subjects
designed
to
evaluate
the
efficacy
against
mosquitoes
of
three
skin­
applied
formulations
of
the
insect
repellent
IR­
3535

The
protocol
is
similar
in
many
aspects
to
the
draft
2000
version
of
the
EPA
Guideline
for
mosquito
testing.
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
or
syringe
to
the
limb
of
the
test
subject.

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

Mosquitoes
 
species
to
be
determined.
Tests
may
be
conducted
in
Central
California
or
the
Florida
Keys.
5
Method
Method
­
1
Five
treatments:


IR3535
Pump
Spray
formulation
(
6
subjects)


IR3535
Lotion
formulation
(
6
subjects)


IR3535
Aerosol
formulation
(
6
subjects)


DEET
positive
control
(
1
subject)

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

Exposure
of
treated
subjects
is
continuous

Evaluation
intervals
differ
for
control
and
treated
subjects

Single
untreated
control
is
inconsistent
with
EPA
recommendations;
compromises
RP
calculation

Mosquitoes
are
aspirated
upon
landing
to
minimize
bites

No
information
about
specimen
handling,
identification,

and
storage
7
Method
Method
­
3

Formulations
should
be
applied
and
tested
as
they
are
to
be
registered

"
As
registered"
dose
may
vary
with
type
of
formulation;
may
not
equal
1
gm/
600
cm
2

No
example
of
data
recording
sheet
in
protocol
8
Determination
of
Repellency
(
RP)

Determination
of
Repellency
(
RP)

RP
calculated
for
each
subject:

%
repellency
=

1
­
#
mosquito
landings
on
treated
subject
x
100
Total
landings
on
neg.
control
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
9
Repellency
Evaluation
Repellency
Evaluation

Protection
Time
­
time
to
first
confirmed
landing.

Two
other
analyses:


1)
Efficacy
of
formulations
compared
to
the
negative
and
positive
controls;


2)
Change
in
repellency
over
time
­
evaluated
as
a
change
in
distribution
of
repellency
values.

A
more
complete
discussion
of
the
application
of
statistical
analyses
is
needed,
especially
with
reference
to
length
of
protection
time.
10
Ethics
Review:
EMD
Ethics
Review:
EMD­
004
004

Central
California
or
Florida
Keys

18
treated
subjects
recruited
as
described
in
C­
L­
001
and
randomly
assigned
to
Field
test
of
mosquito
repellency
in
central
one
of
three
treatment
groups

Controls,
one
positive
and
one
untreated,

chosen
from
among
investigators
11
EMD
EMD­
004
Framework
004
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
004
Framework
004
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
004
Framework
004
Framework
­
3
4.
Risk­
Benefit
Ratio

Materials
tested
for
acute
toxicity

Candidates
sensitive
to
mosquito
bites
are
excluded

Aspiration
of
landing
mosquitoes
will
reduce
bites
and
therefore
reduce
risk

Test
conducted
where
disease­
carrying
mosquitoes
are
not
known
to
be
present

No
discussion
of
risk/
benefit
assessment
14
EMD
EMD­
004
Framework
004
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
004
Framework
004
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
3rd­
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

IC
vaguely
states
"
Measures
will
be
implemented
to
remove
mosquitoes
before
they
have
an
opportunity
to
bite".
This
should
be
clarified
to
explain
better
the
responsibility
of
the
subjects
to
aspirate
landing
mosquitoes,
and
the
risks
of
getting
bitten
anyway.
19
Deficiencies
Noted
Deficiencies
Noted
­
3
 
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."
20
Deficiencies
Noted
Deficiencies
Noted
­
4

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."

Given
the
possibility
of
a
subject
contracting
a
serious
vector­
borne
disease,
this
is
inadequate
and
unacceptably
exculpatory.
21
Deficiencies
Noted
Deficiencies
Noted
­
5

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
22
Deficiencies
Noted
Deficiencies
Noted
­
6

Protocol
should
acknowledge
the
applicable
standards
of
ethical
conduct,

and
the
obligation
of
the
investigators
to
inform
both
the
cognizant
IRB
and,
if
the
study
is
conducted
in
California,
the
California
Department
of
Pesticide
Regulation
of
any
amendments
to
or
deviations
from
the
approved
protocol
23
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?