1
July
13,
2006
MEMORANDUM
To:
Cathryn
O'Connell,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
MC
7508P)

From:
Ruth
H.
Allen,
PhD,
MPH,
Epidemiologist
Chemistry
and
Exposure
Branch
Health
Effects
Division
(
MC
7509P)

Through:
David
J.
Miller,
Chief
Chemistry
and
Exposure
Branch,
Health
Effects
Division
(
MC
7509P)

Subject(
s):
Three
Pyrethrin/
Pyrethroid
Health
Effects
Reviews
DP
Barcode:
326085
PC
Code:
069001
(
A)
"
The
Risk
of
Asthma
Triggered
by
Pyrethrin/
Pyrethroid
Insecticides
Determined
by
a
Case­
Control
Study
of
Poison
Control
Data,"
by
JE
Mosby
(
4­
29­
2003).

(
B):
"
Human
Exposures
to
Products
Containing
Pyrethrins
and
Piperonyl
Butoxide
Analysis
of
Poison
Control
Center
Data
(
2001­
2003)"
by
TG
Osimitz,
N
Sommers
and
R
Kingston
(
3­
19­
05),
MRID
Document
#
466947­
01.

(
C)
"
Pyrethrins
Allergic
Contact
Dermatitis
in
Man­­
An
Evidence­
Based
Dermatologic
Review"
by
TG
Osimitz,
JA
Franzosa,
DR
Maciver,
HI
Maibach
(
1­
24­
06),
MRID
Document
#
467573­
01.

Chemistry
and
Exposure
Branch
(
CEB)
was
requested
by
Special
Review
and
Reregistration
Division
(
SRRD)
to
review
the
three
above­
named
reports
concerning
Pyrethrins
and
Pyrethroids.
The
Mosby
report,
review
(
A),
was
requested
with
DP#
(
324058)
for
the
Pyrethrins
RED.
The
purpose
of
this
revisit
is
to
highlight
why
US
EPA
is
more
concerned
with
pyrethrins
than
synthetic
pyrethroid
products.
Synthetic
pyrethroid
incidents
are
being
reviewed
separately.
The
two
industry
reports,
reviews
(
B)
and
(
C),
were
requested
with
review
(
A).
2
Conclusions
for
each
of
the
3
reviews
appear
below:

Conclusions
for
(
A):
Mosby's
thesis
study
highlights
deaths
in
the
literature
and
a
scattered
pattern
of
potentially
preventable
rapid
deaths
and
serious
illnesses
in
younger
people
and
people
with
prior
serious
health
conditions,
including
allergies/
asthma,
diabetes
and
heart
disease.
The
Mosby
report
results
are
consistent
for
a
statistically
significant
association
between
exposure
to
pyrethrin/
pyrethroid
products
and
asthma
symptoms
in
national
poison
control
center
data.
The
results
are
stronger
for
pyrethrins
(
Odds
Ratio
=
3.2)
than
pyrethroids
(
Odds
Ratio
=
1.8).
The
bottom
line
is
a
pattern
of
published
clinical
case
reports
over
12
years
linking
various
pyrethrins/
pyrethroids
to
rapid
onset
of
multiple
deaths
and/
or
serious
illnesses
requiring
hospitalizations.
Most
cases
reviewed
by
Mosby
were
in
young
and
middle­
aged
women
with
pre­
existing
disease.

It
should
be
noted
that:
(
1)
national
pesticide
poisoning
surveillance
is
poor,
and
potential
cases
can
go
undiagnosed.
US
General
Accounting
Office
(
GAO)
has
repeatedly
identified
under­
reporting
of
diagnosed
pesticide
poisoning
cases
as
a
problem;
and
(
2)
disease
causation
is
hard
to
prove,
given
competing
environmental
exposures,
such
as
air
pollution.
In
addition,
as
reflected
in
the
government
­
wide
Aging
Initiative,
this
is
a
time
when
the
median
age
of
the
US
population
is
rising,
and
a
greater
faction
of
the
population
is
likely
to
have
multiple
pre­
existing
conditions.

Conclusions
for
(
B):
This
industry
review
updates
the
Mosby
Poison
Control
Center
analysis
by
two
years
and
raises
a
number
of
points.
Rate
calculation
methods,
as
described
in
the
submission,
are
non­
standard
and
have
been
standardized
in
this
review.
Using
the
Symptoms
by
Organ
System
data
from
the
industry
report
and
the
actual
number
of
40,000,000
units
sold,
the
incident
rate
estimates
are
as
follows:

 
1814
PY/
PBO
dermal
symptoms
divided
by
40,000,000
PY/
PBO
units
sold
x
100,000
yields
a
dermal
symptoms
rate
of
4.5
/
100,000
(
dermal
symptoms
reported
to
PPCs
in
2001­
2003
per
units
of
PY/
PBO
sold),
and
 
1925
respiratory
symptoms
divided
by
40,000,000
units
sold
x
100,000
yields
a
respiratory
symptoms
rate
of
4.8/
100,000
(
respiratory
symptoms
reported
in
2001­
2003
per
unit
of
PY/
PBO
sold).

Conclusions
for
(
C):
The
industry
dermatology
literature
review
highlights
the
evolution
of
product
chemistry
and
makes
conclusions
not
fully
supported
in
the
document
submitted.
the
published
papers
on
dermal
and
respiratory
effects
should
correct
this.
The
authors
state
that
based
on
current
chemistry
and
the
current
level
of
diagnostic
standards,
allergic
contact
dermatitis
does
not
occur
in
response
to
pyrethrum/
pyrethrin
"
at
a
significant
incidence
in
either
ragweed
sensitive
individuals
or
otherwise"
but
they
do
not
provide
the
detailed
evidence
to
support
this
conclusion.
The
authors
report
on
an
exhaustive
search
of
the
literature
and
attempted
to
score
the
papers
3
for
the
strength
of
the
evidence.
OPP
believes
that
this
is
difficult
to
do
given
the
variability
in
the
literature
over
the
last
200
years,
and
uncertainty
on
the
purity
and
strength
of
material
tested,
appropriateness
of
the
vehicle
used
in
earlier
patch
testing,
and
number
of
persons
tested.

DETAILED
ANALYSIS
Detailed
analyses
of
each
of
the
three
above­
cited
reports
are
presented
here.

(
A)
"
The
Risk
of
Asthma
Triggered
by
Pyrethrin/
Pyrethroid
Insecticides
Determined
by
a
Case­
Control
Study
of
Poison
Control
Data,"
by
Jacqueline
E.
Mosby
(
4­
29­
2003).

Protocol
Approved
by
The
George
Washington
University
Medical
Center
Institutional
Review
Board
IRB
#
UO40217EX.
In
Partial
fulfillment
of
the
Requirements
for
the
Masters
of
Public
Health
Degree
from
The
George
Washington
University
School
of
Public
Health
and
Health
Services
Department
of
Environmental
and
Occupational
Health.

General
Comments:
The
Mosby
document
summarizes
published
clinical
case
reports
on
pyrethrins/
pyrethroids
for
three
separate
fatalities
and
several
serious
allergic
reactions,
including
asthma
requiring
hospitalization.
For
the
Poison
Control
Center
(
PCC)
cases
described
below,
the
primary
route
of
exposure
was
from
householder
use
of
pet
shampoo
products
without
specific
reference
to
shampoo
formulation
details.
The
Mosby
report
also
analyzes
poisoning
incident
data
from
the
American
Association
of
Poison
Control
Centers
(
AAPCC)
using
a
case
control
study
methodology.

Specific
Comments:
See
Mosby
report
and
published
articles
referenced
there
for
more
details.
This
report
refers
to
the
Mosby
thesis
dated
April
29,
2003
Revised
Version.

Poison
Center
Case
Literature
Reports:
Case
#
1:
In
1994,
rapid
death
was
reported
in
a
37­
year
old
female
with
a
history
of
mild
asthma
following
use
of
a
dog
flea
shampoo
containing
0.06%
pyrethrin
and
0.6%
piperonyl
butoxide,
plus
other
ingredients,
including
54%
non­
pesticide
inert
ingredients.

Case
#
2:
In
1998,
emergency
room
treatment
for
acute
asthma
was
reported
in
a
24­
year
old
female
after
she
returned
home
and
slept
45
minutes
in
her
residence
that
had
been
treated
with
Raid
Fumigating
Fogger.
{
This
case
was
included
by
Mosby
as
relevant
based
on
chemical
content
that
is
not
specified
in
the
summary
document.}
4
Case
#
3
In
2000,
a
48­
year
old
woman
with
diabetes
and
severe
asthma
died
of
multisystem
failures
and
complications.
She
was
hospitalized
10
days
following
an
allergic
reaction
to
use
of
two
products
containing
pyrethrins,
permethrin
and
piperonyl
butoxide.

Case
#
4
In
1998,
a
39­
year
old
woman
with
chronic
asthma
died
from
severe
asthma,
two
2
hours
after
treating
her
dogs
with
a
dog
shampoo
containing
9.7%
pyrethrin.

Case
#
5:
In
2000,
an
11­
year
old
asthmatic
girl
with
no
history
of
hospitalization
died
after
shampooing
her
dog
with
a
product
containing
0.2%
pyrethrin.
She
had
used
the
product
twice
before
with
mild
increase
in
her
asthmatic
symptoms.
She
experienced
severe
breathing
problems
10
minutes
after
starting
to
use
the
product.
She
received
aggressive
medical
care,
but
died
of
"
respiratory
arrest
secondary
to
acute
asthmatic
attack"
2
and
1/
2
hours
after
the
initial
exposure.

Additional
Human
Case
Reports:
The
Mosby
report
summarizes
additional
human
case
reports
from
the
National
Pesticide
Medical
Monitoring
Program
(
NPMMP).
For
pyrethrins,
two
cases
were
classified
as
known
(
Type
1).
The
death
of
a
12­
year
old
child
was
reported
from
acute
asthma,
without
laboratory
confirmation
of
pyrethrin
exposure
but
with
a
clinical
case
history
consistent
with
pyrethrin
exposure.
Also,
of
the
cases
classified
as
probable,
three
were
diagnosed
as
asthma,
three
were
hives,
one
was
conjunctivitis,
and
one
was
possible
neuropathy.

Mosby
concludes
that
pyrethrins
cases
are
most
often
related
to
respiratory
or
dermal
effects.
Crude
pyrethrum
is
a
respiratory
allergen,
and
refined
pyrethrins
products,
while
less
allergenic,
appear
to
retain
their
irritant
and
sensitizing
properties
since
cases
exhibiting
anaphylactic
and
pneumonia
manifestations
have
been
reported
from
shampoos
containing
pyrethrins.
The
speed
of
human
death
in
the
dog
shampooing
activity
pattern
cases
suggests
that
inhalation
as
well
as
dermal
exposure
might
be
operating
simultaneously,
and
that
people
previously
sensitized
may
be
more
highly
reactive
at
subsequent
but
much
lower
doses
of
the
chemical.

Mosby
Thesis
Study
Case
­
Control
Results:
Poison
Control
Center
(
PCC)
data
for
pyrethrums,
pyrethrins
and
pyrethroids
were
analyzed
using
a
case
control
study
design
for
n=
13,485
subjects
among
650,000
persons
reporting
exposure
to
all
types
of
pesticides
from
1993­
1999.
Findings
from
analysis
of
the
PCC
data
are
as
follows,
and
all
are
statistically
significant
with
a
p­
value
of
0.001:
(
Odds
ratio*
and
confidence
intervals**
are
defined
further
in
Appendix
A.)

(
1)
For
combined
pyrethrin,
pyrethoid
and
"
insect_
py"
variables,
an
odds
ratio
(
OR)
of
2.5
with
95%
confidence
limits
(
CI)
(
2.3
to
2.7)
means
a
2.5
times
higher
likelihood
that
persons
exposed
to
both
pyrethrins
or
pyrethroid
products
experience
dermal
or
respiratory
symptoms
compared
to
persons
exposed
to
other
types
of
pesticides.
This
odds
ratio
value
of
2.5
is
significantly
different
from
1
which
indicates
that
there
is
a
statistically
significant
increase
in
the
likelihood.
5
(
2)
For
pyrethrins
only,
an
OR
of
3.2,
and
(
CI)
of
2.7
to
3.8
means
a
3.2
times
higher
likelihood
that
persons
exposed
to
products
containing
pyrethrins
experience
dermal
or
respiratory
symptoms
than
persons
exposed
to
other
types
of
pesticides.
This
odds
ratio
value
of
3.2
is
significantly
different
from
1
which
indicates
that
there
is
a
statistically
significant
increase
in
the
likelihood.

(
3)
For
pyrethroids
only,
an
OR
of
1.8
means
a
1.8
times
higher
likelihood
that
persons
exposed
to
products
containing
pyrethroids
experience
dermal
or
respiratory
symptoms
than
persons
exposed
to
other
types
of
pesticides
This
odds
ratio
value
of
1.8
is
significantly
different
from
1
which
indicates
that
there
is
a
statistically
significant
increase
in
the
likelihood.

Bottom
Line
Conclusions
for
(
A):
The
Mosby
report
results
are
consistent
for
a
statistically
significant
association
between
exposure
to
pyrethrin/
pyrethroid
products
and
asthma
symptoms
in
national
poison
control
center
data.
The
results
are
stronger
for
pyrethrins
(
3.2)
than
pyrethroids
(
1.8).

The
bottom
line
is
a
pattern
of
published
clinical
case
reports
over
12
years,
linking
various
pyrethrins/
pyrethroids
to
rapid
onset
of
multiple
deaths
and/
or
serious
illnesses
requiring
hospitalizations.
Most
cases
reviewed
by
Mosby
were
in
young
and
middleaged
women
with
pre­
existing
disease.

It
should
be
noted
that:
(
1)
national
pesticide
poisoning
surveillance
is
poor,
and
potential
cases
can
go
undiagnosed.
US
General
Accounting
Office
(
GAO)
has
repeatedly
identified
under­
reporting
of
diagnosed
pesticide
poisoning
cases
as
a
problem;
and
(
2)
disease
causation
is
hard
to
prove,
given
competing
environmental
exposures,
such
as
air
pollution.
In
addition,
as
reflected
in
the
government
­
wide
Aging
Initiative,
this
is
a
time
when
the
median
age
of
the
US
population
is
rising,
and
a
greater
faction
of
the
population
is
likely
to
have
multiple
pre­
existing
conditions.

(
B):
"
Human
Exposures
to
Products
Containing
Pyrethrins
and
Piperonyl
Butoxide
Analysis
of
Poison
Control
Center
Data
(
2001­
2003)"
by
TG
Osimitz,
N
Sommers
and
R
Kingston
(
3­
19­
05),
MRID
Document
#
466947­
01.

A
duplicate
registrant
submission
from
Pyrethrins
Joint
Venture
and
PBO
Task
Force
II
(
one
report)
regarding
their
independent
analysis
of
poison
center
data
(
2001­
2003)
is
reviewed
below.
The
same
document
has
2
MRID
numbers
for
two
chemicals
as
follows:

MRID:
466948­
01
­
Pyrethrins
PCC
Review
MRID:
466947­
01
­
PBO
PCC
Review.

Purpose:
The
report
entitled
"
Human
Exposures
to
Products
Containing
Pyrethrins
(
PY)
and
Piperonyl
Butoxide
(
PBO)
Analysis
of
Poison
Control
Center
(
PCC)
Data
(
2001­
2003)"
was
prepared
by
Safety
Call
International
­
Science
Strategies
Consulting
Group
6
for
the
Piperonyl
Butoxide
(
PBO)
Task
Force
II
(
PBTF
II)
under
the
auspices
of
the
Consumer
Specialty
Products
Association.
The
purpose
of
the
report
is
to
support
reregistration
and
to
address
issues
in
three
EPA/
OPP
reviews
on
PBO
and
Pyrethrins
Incident
Report
Memoranda
prepared
by
Jerry
Blondell
on
April
6,
2005
and
August
16,
2005).
One
specific
issue
is
language
for
precautionary
labeling
warning
users
and
the
medical
community
about
the
potential
of
asthma
or
allergic
reactions
in
sensitized
individuals,
especially
those
with
preexisting
respiratory
disease.
Thus,
special
attention
is
paid
to
dermal
and
respiratory
effects.

General
Comments/
Highlights:
The
report
summarizes
PCC
data
for
a
narrower
and
more
recent
time
period
than
the
Mosby
report,
and
it
uses
a
descriptive
analysis
methodology.
It
raises
a
number
of
relevant
points,
and
contains
useful
information
on
product
use
and
usage
patterns.

Specific
Comments:
Background
on
poison
center
operations
described
in
(
B)
is
not
repeated
here.
The
point
of
this
review
is
to
determine
which
products
are
currently
causing
the
most
concern,
i.
e.,
the
incidents
with
the
highest
number
and
severity.

(
1)
Classification
of
Cases:
Registrants
who
market
end
use
products
state
that
for
the
period
of
the
EPA
data
review
(
1993­
2001)
no
products
were
marketed
with
pyrethrins
(
PY)
only
and
thus
label
their
analysis
of
pyrethrins
and
piperonyl
butoxide
(
PY/
PBO)
products.
PCC
Toxic
Exposure
Surveillance
System
(
TESS)
data
classification
for
the
1990s
makes
it
difficult
to
separate
natural
PY
(
the
focus
of
the
Pyrethrin
Joint
Venture)
from
pyrethroids.
Around
2000,
TESS
changes
eliminated
this
false
distinction
so
the
industry
2001­
2003
analysis
makes
no
distinction
between
the
different
chemicals.

(
2)
Exclusions:
The
industry
analysis
excludes
pediculicide
use
(
intentional
administration
to
the
skin)
because
FDA,
not
EPA,
regulates
them
now.
The
analysis
also
excludes
multiple
substance
products,
which
is
reasonable
given
the
report
purpose.
For
public
health
education
purposes,
it
would
be
helpful
to
know
how
many
case
calls
were
excluded
for
these
reasons.

(
3)
Wide
Usage:
For
2001­
2003,
household
insecticide
sales
were
40,000,000
units,
according
to
the
industry
reports.
Further
extrapolation
by
the
industry
report
to
number
of
uses
per
units
sold
(
n=
4)
and
the
number
of
people
per
household
to
(
n=
3)
are
not
necessary,
as
40,000,000
units
is
a
valid
large
number.

(
4)
Overall
PCC
Call
Volume
and
PY/
PBO
Rates:
For
2001­
2003,
there
were
7,043,589
human
exposure
cases
to
chemicals
of
all
kinds
reported
to
participating
PCCs
nationwide
with
a
mean
of
38,388
or
8.1
per
1000
individuals
per
year.

Specifically,
of
that
total
of
over
7
million
calls
to
PCCs
across
the
USA,
there
were
15,427
calls
related
to
PY/
PBO
with
a
mean
of
5,142
per
year.
The
industry
report
(
B)
description
of
the
PCC
classification
scheme,
caller
characteristics,
caller
ages
and
medical
outcome
details
and
not
repeated
here.
7
(
5)
Exposures:
Residential
exposure
accounted
for
94%
of
exposure
sites,
and
3.6%
occurred
at
a
workplace.
Eighty­
one
percent
of
cases
were
managed
onsite;
12
%
were
treated
en
route
to
a
health
care
facility,
and
6%
were
treated
at
a
health
care
facility.
Most
exposures
were
classified
as
unintentional
cases,
11%
were
due
to
misuse
situations,
and
1%
was
intentional
suicide
or
abuse
cases.
Routes
of
exposure
for
PY
were:
ingestion
(
34.2%),
inhalation/
nasal
(
27.6%),
and
dermal
(
27.2%).
Some
cases
could
not
be
classified
as
to
route
of
exposure.

(
6)
Severity
of
Outcome
(
Dermal
and
Respiratory):
For
all
cases,
whether
followed
to
completion
or
not,
59.4%
were
classified
as
minor
effects.
Of
cases
followed
to
completion,
23.4%
were
classified
as
minor.
Taking
account
non­
toxic
and
presumed
non­
toxic
cases,
96%
were
coded
minor.
Moderate
outcomes
were
seen
in
381
(
7.7%
of
all
dermal
calls)
exposed
by
inhalation
with
11
(
0.2%)
of
all
dermal
calls
experiencing
major
outcomes.
Dermal
exposure
to
PY/
PBO
resulted
in
163
callers
(
5.3%)
and
2
were
major
outcome
cases
(
0.1%
of
all
dermal
calls).
Ocular
irritation
was
the
most
frequently
reported
symptom
overall,
and
gastrointestinal
(
GI)
symptoms
were
most
common
for
ingestion
cases.

(
7)
Sensitive
Populations
with
Pre­
Existing
Disease:
Dermal
symptoms,
including
dermal
irritation,
were
seen
in
14%
of
cases.
Serious
dermal
symptoms
(
moderate
or
major)
were
rare
and
seen
in
2
cases.
Respiratory
symptoms
were
reported
in
1,925
cases
(
12%
of
all
cases).
The
duration
of
respiratory
symptoms
was
24
hours
in
87%
of
the
cases.
Ten
callers
received
bronchodilator
treatment
associated
with
symptoms.
Four
were
classified
as
minor
and
6
had
moderate
outcomes.
No
major
(
i.
e.
life­
threatening)
outcomes
were
seen
in
the
time
period
of
study.
See
the
report
for
a
summary
of
TESS
data
limitations,
such
as
lack
of
narrative,
no
pre­
existing
condition
information,
lack
of
quantitative
information
on
exposure
and
limited
cause
and
effect
information.
The
authors
note
that
in
spite
of
their
limitations,
the
TESS
data
do
provide
important
clues
and
safety
findings
for
PY/
PBO
products.

(
8)
Prevalence
of
Allergic
Sensitization
and
Asthma:
As
summarized
in
industry
report
(
B),
the
Third
National
Health
and
Nutrition
Examination
Survey
(
NHANES
III)
reported
on
10,508
individuals
tested
for
common
allergens
and
half
were
positive
for
one
or
more
allergens.
For
short
ragweed,
positive
test
results
were
seen
in
26.2%
of
those
tested.
In
the
National
Health
Interview
Surveys
(
NHIS)
from
1997
data,
26.7
million
people
(
96.6/
1000)
reported
having
a
physician
diagnosis
of
asthma,
and
11.1
million
asthmatic
individuals
(
40.7/
1000)
reported
having
an
asthma
attack
or
episode
in
the
last
12
months.

The
industry
report
authors
argue
that
if
PCC
callers
are
evenly
distributed
among
asthma
sufferers,
then
there
should
be
more
PY/
PBO
calls
and
more
severe
cases
requiring
treatment.
Alternately,
asthma
sufferers
may
be
less
likely
to
use
products
a
second
time
,
if
they
were
previously
exposed
and
sensitized.
Or,
the
gap
in
PCC
data
reporting
followup
treatment
may
be
too
great
to
capture
the
outcomes
of
interest.
PCC
data
are
known
to
be
an
incomplete
window
on
rare
serious
cases
or
mortality.
8
(
9)
Relative
Risk:
The
industry
report
authors
compute
rates
of
exposure
using
the
higher
300,000,000
people
exposed
estimate
as
a
denominator
and
they
derive
1
per
20,000
exposures
for
PY/
PBO
calls
and
1
per
156,000
exposures
or
1
per
165,000
exposures
for
reported
respiratory
and
dermal
effects,
based
on
the
breakdown
for
15,427
reported
calls
related
to
PY/
PBO
in
2001­
2003.

Part
(
B)
Bottom
Line/
Conclusions:
Using
the
Symptoms
by
Organ
System
data
from
the
industry
report
and
their
actual
number
of
40,000,000
units
sold,
and
converting
to
a
more
standard
rate
/
100,000
changes
the
rate
calculation
as
follows:

 
1814
PY/
PBO
dermal
symptoms
divided
by
40,000,000
PY/
PBO
units
sold
x
100,000
yields
a
dermal
symptoms
rate
of
4.5
/
100,000
(
dermal
symptoms
reported
to
PPCs
in
2001­
2003
per
units
of
PY/
PBO
sold),
and
 
1925
respiratory
symptoms
divided
by
40,000,000
units
sold
x
100,000
yields
a
respiratory
symptoms
rate
of
4.8/
100,000
(
respiratory
symptoms
reported
in
2001­
2003
per
unit
of
PY/
PBO
sold).

(
C)
"
Pyrethrins
Allergic
Contact
Dermatitis
in
Man­­
An
Evidence­
Based
Dermatologic
Review"
by
TG
Osimitz,
JA
Franzosa,
DR
Maciver,
HI
Maibach
(
1­
24­
06),
MRID
Document
#
467573­
01.

General
Comments:
This
descriptive
study
covers
61
literature
references
on
pyrethrum/
pyrethrins
botany,
chemistry,
refining
process,
allergic
reactions
and
contact
dermatitis.
According
to
the
authors
interpretation,
the
evidence
is
lacking
for
allergic
contact
dermatitis
resulting
from
exposure
to
pyrethrum
in
man
and
for
cross
reactions
in
ragweed
sensitive
people.

Moreover,
they
note
that
since
1967
use
of
refined
pyrethrins
has
lowered
the
level
of
putative
sensitizers
compared
to
the
ground
chrysanthemum
flowers
or
less
refined
extracts
used
earlier
in
the
twentieth
century.
The
flowers
for
commercial
production
of
pyrethrins
are
grown
mainly
in
East
Africa
and
Australia,
and
solvent
extraction
to
produce
a
resin
for
further
commercial
refining,
production
and
formulation
is
also
done
overseas.
See
Appendix
B
for
a
description
of
EPA/
SRRD
pyrethrins
and
related
terminology.

Part
(
C)
Specific
Comments:

The
following
points
are
of
note:

(
1)
Terminology:
Pyrethrins
are
the
insectically
active
ingredient
in
pyrethrum.
Not
all
authors
use
the
same
terminology,
so
unless
there
is
a
distinction
made
the
terms
are
consider
synonymous.
9
(
2)
Known
History
of
Sensitization:
Sensitization
for
pyrethrum
exposure
has
been
known
in
the
medical
literature
for
100
years,
and
according
to
the
industry
report
are
products
used
to
treat
head
lice
are
so
labeled
when
regulated
by
FDA.

(
3)
Chemistry
of
Commercial
Pyrethrins:
Pyrethrins
are
a
mixture
of
biologically
active
esters
that
vary
in
composition
and
sensitizing
properties.
Of
those
compounds,
terpenoids
are
of
interest
as
putative
dermal
sensitizers.

(
C)
Bottom
Line
Conclusions:
The
authors
state
that
based
on
current
chemistry
and
the
current
level
of
diagnostic
standards,
allergic
contact
dermatitis
does
not
occur
in
response
to
pyrethrum/
pyrethrin
"
at
a
significant
incidence
in
either
ragweed
sensitive
individuals
or
otherwise"
but
they
do
not
provide
the
detailed
evidence
to
support
this
conclusion.

The
authors
report
on
an
exhaustive
search
of
the
literature
and
attempted
to
score
the
papers
for
the
strength
of
the
evidence.
OPP
believes
that
this
is
difficult
to
do
given
the
variability
in
the
literature
over
the
last
200
years,
and
uncertainty
on
the
purity
and
strength
of
material
tested,
appropriateness
of
the
vehicle
used
in
earlier
patch
testing,
and
number
of
persons
tested.

The
Pyrethrin
Joint
Venture
(
PJV)
provision
of
known
standards
for
future
diagnostic
testing
is
a
worthwhile
intiative.
10
Appendix
A:
Odds
Ratio
and
Confidence
Intervals
Defined
[*
An
odds
ratio,
cross
product
ratio
or
relative
odds
is
defined
differently
according
to
the
situation
under
discussion.]
Consider
the
following
example:
Used
pyrethrins
No
use
of
pyrethrins
Asthma
a
b
No
asthma
c
d
The
odds
ratio
(
cross
product
ratio)
is
ad/
bc.

**
Confidence
intervals,
or
confidence
limits
are
the
range
of
values
determined
by
the
degree
of
presumed
random
variability
in
the
data,
within
which
the
value
of
a
parameter
(
e.
g.,
a
mean)
is
thought
to
lay,
with
a
specified
degree
of
confidence,
often
95%.
The
boundaries
of
a
confidence
interval
are
the
confidence
limits.
JD
Last
(
1983)
A
Dictionary
of
Epidemiology,
p.
73
and
p.
21.]

_______________________________________________________________________

Appendix
B:
Pyrethrins
and
Related
Terminology
from
EPA/
SRRD
Pyrethrins
are
botanical
insecticides
that
come
from
the
pyrethrum
flower,
Chrysanthemum
cinerariaefolium.
Pyrethrins
have
limitations
because
of
the
cost
of
production
and
instability
in
sunlight;
therefore,
many
synthetic
pyrethrins­
like
compounds
were
developed
to
be
more
stable
in
sunlight
and
cost
effective.
These
compounds
are
referred
to
as
synthetic
pyrethroids.

There
are
no
active
end­
use
product
registrations
that
contain
pyrethrum.
All
enduse
products
contain
the
refined
chemical
pyrethrins.

The
term
"
pyrethrins"
refers
to
all
six
isomers
found
in
pyrethrum,
extracts
which
are
obtained
from
the
dried
and
ground
flowers
of
the
pyrethrum
plant,
Chrysanthemum
cinerariaefolium.
The
CAS
Registry
No.
for
the
mixture
is
8003­
34­
7.

The
individual
isomers
are
referred
to
by
the
common
names
of
the
acid
followed
by
an
Arabic
number
1
or
2
(
i.
e.,
pyrethrin
1,
pyrethrin
2,
cinerin
1,
cinerin
2,
jasmolin
1,
jasmolin
2).
If
the
term
pyrethrin
is
followed
by
a
roman
numerical
designation,
than
it
refers
to
all
of
the
isomers
of
that
number
in
the
pyrethrum
extract
(
e.
g.,
pyrethrins
I
includes
pyrethrin
1,
cinerin
1,
and
jasmolin
1).
See
Table
12
for
a
summary
of
terms.

Table
1:
Pyrethrins
Terms
Pyrethrum
Plant
extract
from
Chrysanthemum
cinerarieaefolium,
containing
all
6
isomers
Pyrethrins
pyrethrin
1,
pyrethrin
2,
cinerin
1,
cinerin
2,
11
jasmolin
1,
jasmolin
2
Pyrethrins
I
pyrethrin
1,
cinerin
1,
and
jasmolin
1
Partial
List
of
synthetic
pyrethroids:
(
Case
chemicals
*
in
the
Mosby
report
(
A)
and
related
NIOSH
SENSOR
OR
documents
**
were
reviewed
separately
and
excluded
from
the
final
version
of
this
review
of
pyrethrin
only,
and
other
pyrethroids
allethrin
bioresmethrin
*
cyfluthrin
*
cypermethrin
cyphenothrin
deltamethrin
d­
phenothrin
*
*
esfenvalerate
fenvalerate
fluvalinate
*
permethrin
resmethrin
sumethrin
tetramethrin
cc:
Hans
Allender,
HED
Monica
Hawkins,
HED
David
J.
Miller,
HED
HED
pyrethrin/
pyrethroids/
piperonyl
butoxide
files
