Document ID: EPA-HQ-ORD-2006-0384-0065
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-12T04:00Z

U.
S.
EPA
U.
S.
EPA
Draft
Draft
OPPTS
Product
Performance
OPPTS
Product
Performance
Testing
Guideline
810.3700
Testing
Guideline
810.3700
In
Insect
Repellent
Testing
sect
Repellent
Testing
Clara
Fuentes
Kevin
Sweeney
Roger
Gardner
John
Carley
June
27,
2006
2
OPP
Guidelines
OPP
Guidelines

OPP
has
published
many
guidelines
for
many
kinds
of
studies
required
to
support
pesticide
regulation

OPP
is
committed
to
harmonization
with
OECD
and
NAFTA,
as
well
as
with
our
colleagues
in
EPA's
OPPT

Guidelines
are
recommendations,
not
rules
3
Context
of
Repellent
Guidelines
Context
of
Repellent
Guidelines

OPPTS
810:
Product
Performance

810.3000:
General
Considerations
for
Efficacy
of
Invertebrate
Control
Agents

810.3300:
Treatments
to
Control
Pests
of
Humans
and
Pets

810.3400:
Mosquito,
Black
Fly,
and
Biting
Midge
Outdoor
and
Breeding
Ground
Treatments

810.3500:
Premises
Treatments

810.3700:
Skin­
Applied
Repellents
4
Insect
Repellents
Insect
Repellents

EPA
classifies
repellents
as
public
health
products

EPA
therefore
requires
product­
specific
performance
data

Repellents
are
applied
directly
to
the
skin
to
prevent
insect
and
tick
bites

Repellents
are
used
primarily
by
consumers,
but
are
also
important
to
protect
soldiers
in
field
operations
5
Background
&
History
Background
&
History

1998
In
the
DEET
Reregistration
Eligibility
Decision
EPA
proposed
to
require
efficacy
data
for
each
registered
repellent
product
containing
DEET

Registrants
asked
EPA
to
identify
acceptable
testing
protocols

1999
EPA
reviewed
Guideline
810.3300
and
concluded
it
did
not
provide
adequate
detail;

drafted
810.3700
for
public
comment
6
Background
&
History
Background
&
History
­
2

2000
FIFRA
Scientific
Advisory
Panel
(
SAP)
reviewed
draft
810.3700
guideline

EPA
began
revision
of
guideline
in
response
to
SAP
comments

2001
EPA
postponed
further
work
on
guideline
until
human
testing
issues
were
resolved
7
Background
&
History
Background
&
History
­
3

2006
Final
Human
Subjects
Protection
Rule
published

Defines
"
research
involving
intentional
exposure"

to
include
insect
repellent
efficacy
testing

Thus
makes
repellent
testing
subject
to
the
requirement
for
protocol
review
by
EPA
and
HSRB

Guideline
810.3700
revised
to
conform
to
the
new
Rule,
and
brought
to
HSRB
for
review
and
advice
8
List
of
Background
Materials
List
of
Background
Materials

"
EPA
Guidelines"
folder:


"
Final
Brief"
dated
June
9,
2006

Current
Draft
guideline
dated
June
9,
2006

2000
Draft
guideline
as
reviewed
by
SAP
and
published
for
public
comment

2000
SAP
comments
on
draft
guideline
9
Key
issues
to
be
addressed
Key
issues
to
be
addressed

Purpose
of
the
guidelines

Use
of
human
subjects
for
testing

Ethical
requirements

Human
exposure
to
repellents

Guideline
recommendations
for
testing
repellents

Test
methods
for
determining
product
performance

Test
methods
minimizing
exposure
to
WNV
10
Insect
Repellent
Testing
Guideline
Insect
Repellent
Testing
Guideline
810.3700
Purposes
810.3700
Purposes

Covers
skin­
applied
repellents

Covers
laboratory
and
field
testing
of
mosquito
and
biting
fly
repellents

Addresses
laboratory
testing
of
flea,
tick,
and
chigger
repellents
11
Use
of
Human
Subjects
for
Testing
Use
of
Human
Subjects
for
Testing

There
are
no
alternative
hosts,
and
no
good
substitutes
to
evaluate
efficacy
of
insect
repellent
products
on
human
skin
other
than
humans.
12
Ethical
Requirements
Ethical
Requirements

Repellent
efficacy
studies
involve
"
intentional
exposure";
thus
IRB­
approved
protocols
and
supporting
materials
must
be
submitted
for
EPA
and
HSRB
review

Guidelines
address

Subject
selection

Risk
minimization

Independent
ethics
oversight

Fully
informed,
fully
voluntary
consent
13
Risks
in
Repellent
Testing
Risks
in
Repellent
Testing

Risks
from
exposure
to
the
repellent

Risk
of
allergic
reaction
to
the
insect
bite

Risk
of
contracting
an
arthropod­
borne
disease
as
a
consequence
of
a
bite

Received
by
an
untreated
control
subject

Received
as
a
result
of
repellent
failure
14
Exposure
to
the
Repellent
Exposure
to
the
Repellent

Most
repellents
do
not
have
a
toxic
mode
of
action
and
are
of
low
toxicity

Exposure
levels
are
high,
because
repellents
are
deliberately
and
repeatedly
applied
directly
to
the
skin

Repellent
application
is
directed
by
the
product
label,
e.
g.,
the
amount
applied,
the
location,

number
and
frequency
of
applications.
15
Exposure
to
the
Repellent
Exposure
to
the
Repellent
­
2

The
primary
route
of
exposure
is
dermal

The
skin
can
act
as
a
barrier
restricting
absorption

The
skin
can
be
sensitive
to
the
effects
of
the
repellent

The
skin
can
alter
the
toxicity
profile
of
the
repellent
16
What
is
known
about
the
risk
and
hazard
What
is
known
about
the
risk
and
hazard
of
candidate
repellents?

of
candidate
repellents?

It
depends
on
the
stage
of
product
development

Some
screening
efficacy
testing
occurs
early
in
the
development
cycle

Full­
scale
field
efficacy
testing
is
likely
to
occur
only
late
in
the
development
cycle
17
Developing
an
Effective
Repellent
18
What
we
What
we''
d
like
to
know
before
a
repellent
d
like
to
know
before
a
repellent
is
tested
in
humans
is
tested
in
humans

Endpoints
from
single­
and
multiple­
dose
toxicity
studies
in
animals,
by
more
than
one
route
of
exposure

A
dose­
response
relationship
showing
a
LOAEL,
or
a
limit
dose
level

A
dermal
absorption
study

Results
of
pharmacokinetics
studies

Data
on
mechanisms
of
action
or
biological
activity

Data
on
structurally
related
substances
19
Exposure
to
Biting
Arthropods
during
Exposure
to
Biting
Arthropods
during
Laboratory
and
Field
Testing
Laboratory
and
Field
Testing

Subjects
may
experience
discomfort,

irritation,
or
allergic
reactions
from
arthropod
bites
in
both
laboratory
and
field
studies

Laboratory­
reared
arthropods
can
be
bred
and
maintained
disease­
free.

Field
tests
present
the
additional
risk
of
contracting
a
vector­
borne
disease.
20
SAP
Recommendations
SAP
Recommendations

SAP
recommended
that
only
field
studies
be
used
to
determine
efficacy
of
skin­
applied
repellents

Laboratory
tests
are
not
necessary
to
verify
performance
of
mosquito
and
stable
fly
repellents.


EPA
included
field
tests
for
mosquito
repellents
based
on
SAP
recommendations.
Laboratory
testing
is
also
described
in
the
draft
guideline.

SAP
recommended
field
tests
for
ticks
and
chiggers

Protocols
have
not
been
developed

EPA
questions
field
testing
deer
tick
repellents
due
to
high
incidence
of
Lyme
disease

EPA
currently
recommends
lab
tests
for
tick
repellents.
21
Possible
Exposure
to
Vectors
of
Arthropod
Possible
Exposure
to
Vectors
of
Arthropod­

Borne
Diseases
in
Field
Testing
Borne
Diseases
in
Field
Testing

In
many
areas
of
the
USA,
common
mosquito
species
transmit
West
Nile
virus.

In
the
field,
investigators
have
no
way
to
prevent
bites
from
infected
mosquitoes.
22
23
24
Definitions
of
Terms
Describing
Definitions
of
Terms
Describing
Arthropods
Arthropods'
Behavior
Behavior

Bite:
penetration
human
skin
by
arthropod
mouthparts
and
ingestion
of
blood.

Probe:
piercing
of
human
skin
with
mouth
parts
without
ingestion
of
blood.

Landing
("
Lite"):
a
flying
or
jumping
arthropod
that
alights
but
does
not
probe
or
bite.

Questing:
ticks
or
chiggers
seeking
a
host.
25
Definition
of
Terms
for
Determination
Definition
of
Terms
for
Determination
of
Repellent
Performance
of
Repellent
Performance

PT
(
Protection
time):
Time
from
application
of
repellent
until
it
is
no
longer
effective.
Expressed
as
hours
of
protection.

FCB
(
First
Confirmed
Bite):
A
probe
or
bite
followed
within
30
minutes
by
a
second
confirming
bite
or
probe.

Time
to
FCB
is
the
endpoint
for
determining
PT
with
the
FCB
method.

RP
(
Relative
Protection):
Percent
reduction
in
number
of
probes
or
bites
in
treated
subjects
relative
to
untreated
controls.

Time
at
which
the
repellent
no
longer
repels
at
least
95%

of
the
mosquitoes
relative
to
an
untreated
control
is
the
endpoint
for
determining
PT
with
the
RP
method.
26
Metrics
of
Product
Performance
Metrics
of
Product
Performance

FCB

Long
used
to
define
protection
time

Supported
by
public
comment

Consistent
with
intermittent
exposures
of
subjects

RP

Statistically
more
robust
measure
of
PT

SAP
recommended
95%
RP
for
regulatory
standard
of
effectiveness

Entails
longer
exposures
of
more
subjects
to
potential
disease
vectors
27
Test
Methods
for
minimizing
Exposure
to
Test
Methods
for
minimizing
Exposure
to
West
Nile
Virus
West
Nile
Virus

FCB
minimizes
exposure
of
test
subjects
to
mosquito
species
that
may
vector
West
Nile
virus
in
the
field

FCB
measures
the
average
protection
time
a
product
is
100%
effective
(
no
bites)

FCB
can
be
established
with
only
intermittent
(
as
opposed
to
continuous)
exposure
of
untreated
control
subjects
28
Charge
Questions
Charge
Questions
a.
What
actions
should
an
investigator
routinely
take
to
minimize
the
risks
to
human
subjects
exposed
during
laboratory
and
field
research
on
the
efficacy
of
repellents?

b.
What
types
of
toxicity
data
should
be
routinely
generated
before
an
investigator
conducts
repellent
efficacy
testing
on
human
subjects
with
a
new
product?
29
Charge
Questions
Charge
Questions
c.
Investigators
themselves
have
sometimes
served
as
research
subjects
when
assessing
chemical
for
insect
repellent
activity.

°
What
scientific
and
ethical
issues
would
such
a
practice
raise?

°
Under
what
conditions,
if
any,
would
such
a
practice
be
acceptable?
30
Charge
Questions
Charge
Questions
d.
Please
comment
on
the
scientific
and
ethical
issues
arising
from
the
use
of
(
or
decision
not
to
use)
negative
control
groups
in
repellent
efficacy
studies,
in
both
laboratory
and
field
studies.
31
Charge
Questions
Charge
Questions
e.
Please
comment
on
the
scientific
and
ethical
issues
raised
by
the
design
of
studies
to
collect
data
sufficient
to
support
assessment
of
repellent
efficacy
using
the
two
different
efficacy
metrics:

°
Time
to
first
confirmed
bite
(
TFCB),
and
°
Time
providing
x%
protection
of
treated
subjects
relative
to
untreated
controls
32
Charge
Questions
Charge
Questions
f.
Please
comment
on
appropriate
approaches
for
estimating
the
minimum
number
of
subjects
needed
to
evaluate
the
level
of
efficacy
of
a
repellent
in
laboratory
and
field
studies.
33
Charge
Questions
Charge
Questions
g.
Please
comment
on
whether
or
not
investigators
should
have
an
ethical
obligation
to
provide
subjects
of
efficacy
research
with
insurance
to
cover
possible
future
medical
costs
or
other
losses
that
result
from
injury
or
illness
experienced
by
the
subjects
as
a
consequence
of
their
participation
in
the
research.
34
Charge
Questions
Charge
Questions
h.
Please
comment
on
any
special
considerations
that
should
be
addressed
in
the
informed
consent
materials
provided
to
potential
subjects
in
insect
repellent
efficacy
research
i.
Does
the
HSRB
recommend
that
the
draft
guideline
be
revised?
If
so,
please
explain
what
aspects
or
sections
might
improve
with
revision.