PROPOSED
HAZARD
IDENTIFICATION
METHODOLOGY
FOR
ASSESSMENT
OF
DERMAL
SENSITIZATION
RISK
CASE
STUDY
 
Cr(
VI)
in
Wood
Preservative
Jonathan
Chen,
Ph.
D.

Timothy
F.
McMahon,
Ph.
D
Office
of
Pesticide
Programs
U.
S.
EPA,
Washington
D.
C.
May
4­
6,
2004
2
Chromium
(
Cr)
 
General
Properties
Oxidation
states
ranging
from
Cr(­
II)
to
Cr(+
VI).

Chromium
occurs
in
the
environment
primary
in
two
valence
states,
Cr(
III)
and
Cr(
VI).

Cr(
VI)
rarely
occurs
naturally,
but
is
produced
from
anthropogenic
sources.
May
4­
6,
2004
3
Chromium
(
Cr)
 
General
Properties
(
Continued)

Trivalent
chromium
compounds
,
are
generally
insoluble
in
water
(
with
the
exception
of
acetate,

hexahydrate
of
chloride,
and
nitrate
salts).

Most
Cr(
VI)
compounds,
are
readily
soluble
in
water
(
with
the
exception
of
alkaline
salts,
zinc
and
lead
salts).

The
hexavalent
chromium
compounds
are
reduced
to
the
trivalent
form
in
the
presence
of
oxidizable
organic
matter.
May
4­
6,
2004
4
Chromium
(
VI)
is
used
as
a
component
of
Wood
Preservatives.

For
Example:

°
CCA
­
Chromated
Copper
Arsenate
°
ACC
 
Acid
Copper
Chromate
Cr
(
VI)
 
Background
(
Continued)
May
4­
6,
2004
5
CHROMATED
COPPER
ARSENATE
(
CCA)

CCA
contains
chromium,
copper,
and
arsenic.

There
are
three
formulations
of
CCA
CCA­
Type
A,
CCA­
Type
B,
and
CCA­
Type
C
CCA­
type
C
*


CrO3
(
chromic
acid,
Cr(
VI)):
47.5%


CuO
(
cupric
oxide,
Cu(
II)):
18.5%


As2O5
(
arsenic
pentoxide,
As(
V)):
34.0%

*
The
the
standard
is
set
by
American
Wood
Preservatives
Association
(
AWPA).
May
4­
6,
2004
6
ACID
COPPER
CHROMATE
(
ACC)

°
Acid
copper
chromate
(
ACC)
is
a
liquid
that
contains
50%
active
ingredient
(
Cr
and
Copper)

and
50%
diluents
(
water).
May
4­
6,
2004
7
CCA
vs.
ACC
34.0
47.5
18.5
CCA­
C
­

71.6
28.4
ACC
45.1
35.3
19.1
CCA­
B
16.4
65.5
18.1
CCA­
A
As
2
O
5
(%)

CrO
3
(%)

CuO
(%)

Type
May
4­
6,
2004
8
Cr
(
VI)
 
Background
(
continued)

What
is
fixation?

Degree
of
fixation
is
affected
by:


Temperature

Concentration
of
reactants

Moisture
content
of
the
wood

pH

time

wood
species
May
4­
6,
2004
9
Cr
(
VI)
 
Background
(
continued)

Why
Fixation
is
important?

Research
indicate
Cr
(
VI)
may
leach
to
wood
surface
when
the
fixation
process
is
incomplete.
May
4­
6,
2004
10
Cr
(
VI)
 
Background
(
Continued)

One
of
the
most
common
and
potent
contact
sensitizers
Exposure
occurs
in
a
number
of
occupational
settings
Non­
occupational
exposures
also
occur
May
4­
6,
2004
11
°
On
8/
28/
2001,
the
OPP
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
:

"
The
potent
skin
allergenicity
of
chromium
has
been
well
documented
in
the
literature,
and
chromium
compounds
have
been
reported
to
be
the
most
frequent
sensitizing
agent
in
man.
  
No
end
point
will
be
selected
for
risk
assessment.

The
risk
concern
of
the
dermal
contact
of
Cr(
VI)
should
be
addressed
through
warning
language
used
on
the
labels".

°
However,
OPP's
current
concern
is
for
pesticide
chemicals
that
are
in
consumer
products,
some
of
which
are
treated
articles
without
a
chance
to
include
label
warnings.

Cr
(
VI)
 
Background
(
Continued)
May
4­
6,
2004
12
°
The
FIFRA
Scientific
Advisory
Panel
(
SAP)
Meeting
Held
for
"
Preliminary
Evaluation
of
the
Non­
dietary
hazard
and
Exposure
to
Children
from
Contact
with
Chromated
Copper
Arsenate
Treated
Wood
Playground
Structures
and
Contaminated
Soil"
in
October
23
­
25,
2001:

"
The
Panel
advises
that
EPA
should
base
risk
assessments
for
noncancer
health
effects
of
dermal
exposure
to
hexavalent
chromium
on
direct
dermal
effects
 
irritant
and
allergic
contact
dermatitis.
The
Panel
was
unable
to
provide
EPA
with
methods
for
establishing
endpoints
and
determining
dose
response
relationships
for
these
effects."

Cr
(
VI)
 
Background
(
Continued)
May
4­
6,
2004
13
Concentration
of
Concern
for
Dermal
Sensitization
(
CCDS)

CCDS
stands
for
Concentration
of
Concern
for
Dermal
Sensitization.
In
other
words,

the
Agency
would
consider
that
when
the
concentration
of
the
chemical
causing
dermal
sensitization
is
below
the
CCDS,
it
is
not
likely
to
start
the
dermal
sensitization
reaction
toward
the
concerned
population.
May
4­
6,
2004
14
Cr
(
VI)
 
Different
CCDS
Two
Types
of
Concentration
of
Concern
for
Dermal
Sensitization
(
CCDS):

CCDS
for
Induction
Phase
CCDS
for
Elicitation
Phase
May
4­
6,
2004
15
Cr
(
VI)
 
CCDS
for
Induction
Phase
Using
Murine
LLNA
data
LLNA
data
(
EC3
values)
for
hexavalent
chromium
using
potassium
dichromate
as
the
test
substance
from
five
different
laboratories
were
reported
by
Kimber
et
al.
(
1995).

Two
different
approaches
have
been
proposed
to
establish
the
CCDS
for
Induction
Phase
:


Griem
et
al.
(
2003)


Gerberick
et
al.
(
2000,
2001)
May
4­
6,
2004
16
Hazard
Assessment
 
Induction
Phase
Using
Murine
LLNA
Data
0.034
0.038
0.037
0.035
0.044
0.038
0.017
CCDS
µ
g/
cm
2
10
10
10
10
10
10
10
UF
Time
(
Repeated
Exposure)
10
10
10
10
10
10
10
UF
intraspecies
3
3
3
3
3
3
3
UF
interspecies
10.36
11.15
11.2
10.77
13.24
11.56
5.12
Area
dose
µ
g/
cm
2
All
US
US
US
UK
US
UK
country
Avg.

E
D
C
B
A
laboratory
Based
on
Griem's
Approach
(
2003)
May
4­
6,
2004
17
Hazard
Assessment
 
Induction
Phase
Using
Murine
LLNA
data
(
Continued)

Default
NOAEL
for
Use
in
Risk
Assessment
­
Gerberick
(
2000,
2001)

1

10
Potent

10
1,000
1000
 
10,000
Weak
1000
 
10,000
10
10
­
100
Strong
10
 
100
100
100
­
1000
Moderate
100
 
1000
10,000
>
10,000
Extremely
Weak
>
10,000
NA
NC
Non­
Sensitizing
NC
Default
NOAEL
(
µ
g/
cm
2)

Experimental
Human
NOAEL
(
µ
g/
cm
2)

Sensitization
Potential
A
LLNA
EC3
(
µ
g/
cm
2)

NC
=
Not
Calculated,
No
Positive
response
is
obtained
at
any
concentration
tested.
An
EC3
value
cannot
be
calculated.

NA
=
Not
Applicable.
The
Material
is
non­
sensitiser.
A
default
NOAEL
is
not
needed
for
risk
assessment.
May
4­
6,
2004
18
Hazard
Assessment
 
Induction
Phase
Using
Murine
LLNA
data
(
Continued)

Based
on
Gerberick
(
2000,
2001) 
s
Approach
10
10
10
10
10
10
1
NOAEL

g/
cm
2
0.01
0.01
0.01
0.01
0.01
0.01
0.001
CCDS

g/
cm
2
10
10
10
10
10
10
10
UF
Use
10
10
10
10
10
10
10
UF
matrix
10
10
10
10
10
10
10
UF
intraspecies
1
1
1
1
1
1
1
UF
interspecies
10.36
11.15
11.2
10.77
13.24
11.56
5.12
Area
dose

g/
cm
2
All
US
US
US
UK
US
UK
country
AVG
E
D
C
B
A
laboratory
May
4­
6,
2004
19
Cr
(
VI)
 
CCDS
for
Elicitation
Phase
Two
different
types
of
data
are
considered:


Cr(
VI)
Sensitized
Human
Data;
and

Murine
LLNA
Data
Cr(
VI)
Sensitized
Human
Data
Three
Studies
are
considered:


Nethercott
et
al.
(
1994)


Hansen
et
al.
(
2003)


Basketter
et
al.
(
2001)
May
4­
6,
2004
20
Hazard
Assessment
 
Elicitation
Phase
Using
Sensitized
Human
data
(
Continued)

Nethercott
et
al.
(
1994)

100
possible
volunteers
selected
from
examination
of
6000
patient
files
from
dermatologists.
Eventually,
102
took
part
in
the
study.
All
were
believed
to
be
Cr(
VI)

sensitized
based
on
previous
patch
tests
performed
by
their
physicians.
May
4­
6,
2004
21
Hazard
Assessment
 
Elicitation
Phase
Nethercott
et
al.
1994
(
Continued)

Three
rounds
of
testing:


Round
one­
patch
test
with
4.4

g
of
Cr(
VI)/
cm
2
to
verify
sensitization.
Those
responding
positively
moved
onto
round
two.


Round
two
­
patch
testing
with
0.018
and
0.088

g
Cr(
VI)/
cm
2,
and
four
concentrations
of
Cr(
III).
Those
showing
positive
responses
to
the
Cr(
VI)
were
not
tested
in
round
three.
Only
those
that
did
not
respond
were
moved
to
round
three.


Round
three­
the
negative
responders
in
round
two
were
tested
with
Cr
(
VI)
concentrations
of
0.18
and
0.88

g/
cm
2.
May
4­
6,
2004
22
Hazard
Assessment
 
Elicitation
Phase
Nethercott
et
al.
1994
(
Continued)
May
4­
6,
2004
23
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Nethercott
et
al.
1994
(
Continued)

From
this
study,
a
10%
MET
of
0.089

g/
cm2
was
reported.

However,
lowest
dose
tested,
0.018

g/
cm2
also
showed
a
response.
May
4­
6,
2004
24
Hazard
Assessment
 
Elicitation
Phase
Hansen
et
al.
(
2003)

Purpose:
to
compare
the
10%
MET
for
Cr
(
III)
and
Cr
(
VI)
in
Cr(
VI)­
sensitive
patients.
May
4­
6,
2004
25
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Hansen
et
al.
2003
(
Continued)

Methods:

18
volunteers
confirmed
to
be
Cr(
VI)

sensitized
.

Patch
testing
(
Finn
Chambers)
with
serial
dilutions
of
Cr(
VI)
and
Cr(
III).

~
20
patches
tested
at
the
same
time.
May
4­
6,
2004
26
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Hansen
et
al.
2003
(
Continued)

Using
a
dose
­
response
curve,
the
10%
MET
for
Cr(
VI)
was
determined
to
be
0.03
µ
g
/
cm2
(
1
ppm).

The
10%
MET
for
Cr(
III)
was
determined
to
be
0.18
µ
g
/
cm2
(
6
ppm).

Both
Cr(
III)
and
Cr(
VI)
were
capable
of
eliciting
a
response
at
low
levels.
May
4­
6,
2004
27
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Basketter
et
al.
(
2001)

To
investigate
dose­
response
relationships
for
Cr
(
VI)
elicitation
in
sensitized
persons
using
both
occluded
patch
and
open
application
techniques.
May
4­
6,
2004
28
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Basketter
et
al.
2001
(
Continued)

Methods:
17
volunteers
with
history
of
contact
allergy
to
Cr.

Part
I
of
study:
Finn
chambers
applied
for
2
days
on
the
back
with
aqueous
dilutions
of
potassium
dichromate­
1,
10,
100,
1000
ppmapplied
to
normal
skin
and
also
to
sites
pretreated
with
0.2%
Sodium
Lauryl
Sulfate
(
SLS).
May
4­
6,
2004
29
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Basketter
et
al.
2001
(
Continued)

Part
II
of
study:
Repeat
open
application
tests
(
ROPT)
conducted
on
same
volunteers
using
aqueous
solutions
of
potassium
dichromate
containing
0.1%
SLS.

Initial
concentrations
of
5
and
10ppm
used;
if
negative,
20
and
50
ppm
used
after
one­
month
rest
period.
May
4­
6,
2004
30
Cr
(
VI)
Hazard
Assessment
 
Elicitation
Phase
Basketter
et
al.
2001
(
Continued)

Results:
Closed
patch
test:


normal
skin,
no
reactions

SLS
treatment:
2/
17
responded
at
1
ppm
Repeated
Open
Application
Test
(
ROAT)
:


3/
15
showed
response
at
5
and
10
ppm
May
4­
6,
2004
31
Hazard
Assessment
 
Elicitation
Phase
Human
Data:
Nethercott
et
al.
1994
is
a
wellcontrolled
study
and
was
used
for
CCDS
calculation.
May
4­
6,
2004
32
CCDS
 
Elicitation
Phase
(
Based
on
Human
Data
­
Nethercott
1994)

3
3
UF
intraspecies
3
3
UF
LOAEL
to
NOAEL
0.0089
0.0018
CCDS
µ
g/
cm2
1
1
UF
exposure
1
1
UF
interspecies
0.089
0.018
Area
dose
µ
g/
cm2
MET
(
10%)

LOAEL
Nethercott
1994
Study
May
4­
6,
2004
33
CCDS
 
Elicitation
Phase
(
Based
on
Human
Data
­
Nethercott
1994)

A
similar
approach
can
be
applied
to
the
MET
values
from
Hansen
et
al.
(
2003)
and
Basketter
et
al.
(
2001)
studies.
The
calculated
CCDS
for
Elicitation
Phase
would
be
0.001,
and
0.003

g/
cm2
for
persons
previously
sensitized
to
hexavalent
chromium.
May
4­
6,
2004
34
CCDS
 
Elicitation
Phase
(
Based
on
Murine
LLNA
Data)

Murine
LLNA
hazard
data
reported
by
Kimber
et
al.
(
1995)
from
five
different
laboratories
reported
EC3
values
for
hexavalent
chromium
was
used
to
assess
the
Cr(
VI)
CCDS
for
Elicitation
phase.

Based
on
Griem's
Approach
(
2003
and
Public
Comments)
CCDS
 
Elicitation
Phase
(
Murine
LLNA
Data
 
Kimber
et
al.
(
1995)
10
10
10
10
10
10
10
UF
Time
(
Repeated
Exposure)
0.007
0.007
0.007
0.007
0.009
0.008
0.003
CCDS
µ
g/
cm
2
15
15
15
15
15
15
15
UF
(
Induction/

Elicitation
10
10
10
10
10
10
10
UF
intraspecies
1
1
1
1
1
1
1
UF
interspecies
11.36
10.156
11.2
10.77
13.24
11.56
5.12
Area
dose
µ
g/
cm
2
All
US
US
US
UK
US
UK
country
Avg.

E
D
C
B
A
laboratory
Based
on
Griem's
Approach
(
Public
Comments)
May
4­
6,
2004
36
SUMMARY
°
Cr
(
VI)
is
a
potent
dermal
sensitizer.
It
is
able
to
induce
and
to
elicit
ACD.

°
Cr(
III)
is
also
capable
of
eliciting
ACD,
but
studies
indicate
that
it
is
less
potent
than
Cr(
VI).

°
Using
LLNA
data,
two
different
approaches
have
been
proposed
to
estimate
the
CCDS
for
induction
phase
of
dermal
sensitization.
May
4­
6,
2004
37
SUMMARY
(
Continued)

CCDS
for
Induction
Phase:


Proposed
Average
induction
CCDS
for
Cr(
VI)

is
:


0.034

g/
cm2
 
Griem
(
2003)


0.01

g/
cm2
 
Gerberick
(
200,2001)
May
4­
6,
2004
38
SUMMARY
(
Continued)

CCDS
for
Elicitation
Phase:


Based
on
the
Human
Data
(
Nethercott
et
al,
1994),

Proposed
Cr(
VI)
CCDS
for
Elicitation
Phase
is

0.0018

g/
cm2
(
based
on
the
LOAEL).


0.0089

g/
cm2
(
based
on
MET10%)


Based
on
the
LLNA
Data
and
using
Griem's
approach,

Proposed
average
Cr(
VI)
CCDS
for
Elicitation
Phase
is

0.007

g/
cm2
(
based
on
the
Kimber
et
al.
1995)
