Document ID: EPA-HQ-ORD-2006-0798-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-09-27T04:00Z

EPA Reviewer:     Tim McMahon, Ph.D                               
Signature: 

Senior Toxicologist, Antimicrobials Division (7510P)       Date         
                           

	

TXR#:

DATA EVALUATION RECORD

STUDY TYPE:  Skin Sensitization non-guideline (Repeat Open Application
Test)

PC CODEs: 021101                                                        
      DP BARCODE:  331024          

                                                                        
                                

TEST MATERIAL (PURITY):  CopperShield® wood preservative

SYNONYMS:  none

CITATIONS:	Proctor, Deborah M.; Gujral, Jaspreet; Su, Steave (2006):
Repeated Open Application Test for Allergic Contact Dermatitis due to
Hexavalent Chromium [Cr(VI)] as CopperShield® : Risk Assessment for
Dermal Contact with Cr(VI). Study performed by Dermatology Specialists,
PSC, 444 South First Street, Louisville, KY 40202. Project number FPRL
012506.   Unpublished. MRID 46884001.

		Proctor, Deborah M.; Gujral, Jaspreet; Su, Steave (2006): Repeated
Open Application Test for Allergic Contact Dermatitis due to Hexavalent
Chromium [Cr(VI)] as Potassium Dichromate : Risk Assessment for Dermal
Contact with Cr(VI). Study performed by Dermatology Specialists, PSC,
444 South First Street, Louisville, KY 40202. Project number FPRL
012406.   Unpublished. MRID 46930701.

SPONSOR:   Forest Products Research Laboratory, LLC, 4660 Main Street,
Suite B-320, Springfield, OR 97478. 

EXECUTIVE SUMMARY:

A Repeat Open Application Test (ROAT) was performed on 60 human study
subjects who had been confirmed allergic to hexavalent chromium [Cr(VI)]
through closed-patch testing.  The purpose of this study was to develop
a 10% minimum elicitation threshold value (MET10%) for elicitation of
allergic contact dermatitis for hexavalent chromium (as contained within
the CopperShield® wood preservative treatment solution).  The study
design involved the application of five concentrations of hexavalent
chromium (as contained within the CopperShield® wood preservative
treatment solution) to the right forearm of the test subjects and
application of five concentrations of potassium dichromate to the left
forearm of the same subjects.  Ten additional subjects not sensitive to
hexavalent chromium served as controls using the highest concentration
of copper contained within the wood treatment solution.  

Test subjects received application of both CopperShield® treatment
solution and potassium dichromate once per day for 10 days.   Duration
of each exposure was 6 hours after which the forearms were washed using
soap provided to them.  Prior to the next application, participants were
evaluated for occurrence of any skin responses, including erythema,
papules, pruruitis, scaling, and vesicles.  Results were evaluated by
Dr. Fowler, who interpreted them as either allergic or irritant in
nature and graded each response.  Seventy-two hours following the last
testing day, participants were evaluated by Dr. Fowler to determine if
an allergic contact dermatitis response had occurred.   Results from the
ROAT phase of the study were modeled using Benchmark Dose Software
(BMDS) to fit the dose-response data and calculate the 10% Minimum
Elicitation Threshold value.   

Results of closed-patch testing with potassium dichromate using 12mm
Finn Chambers showed that all participants for the ROAT phase of the
study were confirmed to have sensitivity to hexavalent chromium. 
According to the report, the number of participants in the ROAT phase of
the study who exhibited a high grade of ACD response (+3) was
disproportionate to the North American Contact Dermatitis Group database
from 1998-2002  for this grade of reaction. Twenty-six percent (26%) of
the ROAT study participants showed a +3 reaction to the initial patch
test, while the NACDG database of 495 individuals shows a 7.7% response
percentage for a +3 reaction. Thus, to ensure that the dose-response
observed in this study was representative of the hexavalent
chromium-sensitized population in the United States, the dose-response
in the ROAT study was extrapolated to the NACDG population by simulating
the percent response expected to the ROAT if the proportions of +1, +2,
and +3 responders in the current study had been consistent with that of
the general U.S.  hexavalent chromium-sensitized population. 

In addition to normalization of the dose-response data, two scenarios
were modeled from the CopperShield® results.  Scenario 1 included only
responses determined to be allergic in nature.  Under this scenario it
was assumed that if a participant reacted to a lower dose, they were
allergic to all higher doses even if they did not actually react to the
higher dose.  Scenario 2 included both irritant and allergic responses
in calculation of a 10% response level. The purpose of this scenario was
to determine the effect on the 10% MET if all of the irritant responses
were allergic in nature. 

For Scenarios 1 and 2, the report stated that of all the models run, the
unconstrained log-probit model provided the best fit for the
dose-response data.   For CopperShield®, the 10% MET values for
Scenarios 1 and 2 of the untransformed dose-response data were 270 and
91.8 ng Cr(VI)/cm2 respectively, while 10% MET values for the patch-test
normalized data were 349 and 166 ng Cr(VI)/cm2 respectively.   With the
exception of the Scenario 2 untransformed data, these 10% MET values are
higher than the previously reported value by Nethercott et al. (1994) of
89 ng Cr(VI)/cm2 from closed patch test data.  Such values may be
expected on the basis that the ROAT protocol is an open application test
procedure that more closely resembles real-life exposures than the
closed-patch test technique.							

This study is classified acceptable/non-guideline and fulfills the
purpose for which it was conducted. However, determination of a single
10% MET value will require further discussion within the Office of
Pesticide Programs. 

COMPLIANCE:   A signed statement of no data confidentiality claims was
submitted.  This study was not conducted according to Good Laboratory
Practice as outlined in 40 CFR Part 160 as this was a human clinical
study and GLP guidelines are not specifically applicable.  A signed
statement by Amy Bradley, Senior Scientist at Exponent, Inc. was
included with the study report.  I. MATERIALS AND METHODS

A. MATERIALS:

1. Test Materials:	

 CopperShield® 

	

Description:	

Wood preservative formulation

	

Lot/Batch #:	

Not provided

	

Purity:	

 35.46% chromic acid and 14.07% copper oxide [according to label]

	

CAS # of TGAI: 	

	

	

Concentration verified by laboratory analysis of test solutions

1. Test Materials:	

 Potassium dichromate 

	

Description:	

Stock solution obtained from Fisher Scientific Co., Houston, Texas

	

Lot/Batch #:	

Not provided

	

Purity:	

  1000 mg Cr(VI)/L

	

CAS # of TGAI: 	

	

	

Concentration verified by laboratory analysis of test solutions

According to the report (page 66), before the ROAT phase of the study,
the concentration of the CopperShield® test solution preparation was
verified.  The stock solution was diluted to an expected concentration
of 250 mg/L Cr(VI).  However, colorimetric analysis showed Cr(VI)
concentration to be 70 mg/L (table 7a, page 67 of the report).  A repeat
analysis was performed using ion chromatography because copper was
suspected to have interfered with colorimetric analysis of Cr(VI) in the
CopperShield® solution. 

Using ion chromatography, the results of dilution gave values closer to
the expected result (246 mg/L Cr(VI)  identified;  250 mg/L expected). 

To verify that all test solutions used during the ROAT study contained
the expected amount of Cr(VI), the CopperShield® solutions and
potassium dichromate solutions were analyzed for total chromium, Cr(VI),
copper, and pH.  Results of theses analyses, presented in Table 7c of
MRID 46884001 and Table 7c of MRID 46930701, showed the measured
concentration of Cr(VI) in the dose solutions to be in good agreement
with the expected concentration.  Tables 7b and 7c are reproduced below
from the reports:

Data copied without alteration from page 68 of MRID 46884001. 

Data copied without alteration from page 64 of MRID 46930701. 

2. Vehicle and/or positive control:   Deionized water containing 153
mg/L copper chloride (the concentration of copper in the highest dose
tested in the ROAT study) was used as a control solution in this study
as part of the ROAT protocol. 

 

B.  STUDY DESIGN and METHODS:

The objective of the present study was to develop a 10% Minimum
Elicitation Threshold value (MET10) for hexavalent chromium (CrVI) as
contained within the ACC wood treatment solution in previously
sensitized individuals.  The results of this experiment would provide a
value for determining a level of exposure to hexavalent chromium as
contained within the ACC treatment solution considered protective for
elicitation of allergic contact dermatitis. An additional concurrent
experiment was also conducted using potassium dichromate for purposes of
providing data for assessing risk from exposure to hexavalent chromium
in environmental media such as contaminated soil. The ROAT study is
designed to represent more realistic dermal exposures that might occur
to potential dermal sensitizers and potential allergic contact
dermatitis reactions in people (i.e. repeated, non-occluded exposures). 

Study Participants

A two-stage strategy was used to identify study participants for this
study according to the report (page 36).  A list of potentially eligible
participants was first compiled from the patient population of Dr.
Joseph Fowler’s private medical practice (Dermatology Specialists,
PSC).   Second, a research assistant who did not work in the clinic
contacted individuals on this list by telephone to determine willingness
to participate in this study and to verify that they met the inclusion
and exclusion criteria described in this report

Inclusion criteria included age over 18 years, English speaking, able
and willing to travel to the dermatology clinic for all visits, and
known chromium sensitization status.  Exclusion criteria included
current exposure to chromium or copper in the workplace or home, active
eczematous allergic contact dermatitis, fissures or lesions of the skin,
serious systemic disease or medical condition, current use of
immunosuppressive drugs, pregnancy or attempting pregnancy, current
breast feeding, illicit drug or alcohol use, and plans to leave the area
for 2 days or more. 

A total of 148 individuals who had demonstrated a positive reaction to
Cr(VI) in previous patch tests were contacted by the study research
assistants.  

Of these, 88 were found eligible and agreed to come for an initial visit
to the clinic. 

In addition to the above, 12 individuals who were not known to be
sensitive to Cr(VI) were identified among the employees, former
employees, and relatives of employees of Dr. Fowler to participate as
part of the non-sensitized population. 

 Initial Clinic Visit

For individuals who were determined to be eligible and who were
interested in participating in the study, the research staff scheduled
an initial visit to the research facility at the clinic. If consent was
given to participate in the study at the clinic on the initial visit, a
patch test was performed to confirm sensitivity to CrVI. 

The initial visit to the clinic included a brief questionnaire given to
potential participants regarding occupational and medical history
relevant to the conduct of the study. Potential participants were also
examined by Dr. Fowler for presence of any skin disease.  Participants
were asked to refrain from activities during the study period that could
irritate the test sites and also instructed to avoid contact with
anything to which they are known to be allergic.  Participants were
instructed not to use topical steroids or other treatments in the test
areas starting one week before the test, during patch-testing days, and
during the two-week ROAT study period. 

IRB Approval and Informed Consent

Informed consent forms were given to study participants and they were
allowed to decide whether to participate in the study.  Consent
procedures were approved by Schulman Associates Institutional Review
Board (SAIRB).  

Patch Testing

Patch testing was conducted using 12 mm Finn Chambers to verify that
participants were Cr(VI)-sensitive.    Potassium dichromate (0.25%) was
used in a 12mm Finn Chamber applied to an area of skin on the upper
back.  The loaded chamber was secluded with Scanpor® tape to expose an
area of approximately 1 cm2.   The actual concentration of potassium
dichromate applied to the Finn Chamber was not stated in the report. 
Depending on the volume of the solution applied to the test patch, this
dose could vary.  Typically, a 10 or 20 microliter volume is used for
Finn Chamber testing.  If this is the case, then, knowing that a 0.25%
solution was used, the dose could be in the range of 25-50 micrograms
applied to the 1 cm2 area of the skin.  

Participants who were thought to be CrVI sensitive on the basis of
previous patch tests but who were negative in the current patch test
procedure were excluded from participation in the ROAT study. Those
thought to be non-sensitized but who showed a positive reaction in the
patch test were asked if they were interested in participating in the
ROAT as a member of the sensitized group. 

According to the report (page 61), eighty-eight patch tests were
performed on participants who were thought to be sensitive to CrVI in
the past, and 12 participants who were not known to be allergic to CrVI.
 Of the 88 participants, 62, or 70%, had a positive reaction to the
patch test.  One individual who had a positive reaction did not continue
into the ROAT phase of the study based on the presence of active
dermatitis at the time of the ROAT phase.  Three other participants had
scheduling conflicts and chose not to participate in the ROAT phase. 
Thus, in the end, 58 individuals with previous positive patch tests for
CrVI were included in the ROAT phase of the study.  This group consisted
of 25 men and  35 women

Of the 12 tested that were thought to be non-sensitized, ten of these
participants had negative reactions and were included on the control
population for this study.  This population consisted of women only. 
The two who tested positive for CrVI sensitivity agreed to participate
in the ROAT study as part of the test group.

Those individuals who consented to participate in the study were patch
tested, as noted above.  This involved three visits to the clinic.  On
the first visit, the patch was applied; on the second visit
(approximately 48 hours after application), the patch was removed; on
the third visit (another 48 hours) the patch test was read. 

Dose levels for ROAT exposures

As stated above, 60 participants who were determined to be
CrVI-sensitive and 10 who were not CrVI-sensitive participated in the
ROAT study.  

Doses used in the ROAT phase of the study were 0, 90, 250, 750, and 2500
ng/cm2.  According to the report, the lowest non-zero concentration
tested in this study represents the MET10 from the study of Nethercott
et al.  (Occup. Environ. Med 51: 371-380, 1994) and was the
concentration used by EPA in determining the level of concern for dermal
contact with CrVI in articles that may contain CrVI.  The top
concentration used in the present study represents, according to the
report, the concentration of CrVI on CopperShield® treated wood
immediately following treatment and is considered the extreme
upper-bound of possible exposures to CrVI from exposure to
CopperShield® treated wood. 

A schematic of the application sites and chemicals applied was shown on
page 51 of the study report.  A flexible transparent plastic template
(consisting of five 1 cm2 cut outs arranged linearly and spaced 2 cm
apart) was used as a guide to administering the test substances on the
forearms.   Study participants were blinded to the control and test
solutions being applied.  Ten microliters of each test solution was
applied with a micropipette in the 1 cm2 square areas marked on the
forearms.  The two highest doses were tested at opposite ends of the
template to reduce the possibility of “excited skin syndrome.”  The
vehicle/control solution was applied in the middle of the template. 
After application, the test solutions on the forearms were dried using a
hair blow-dryer.  According to the report, this procedure had no effect
on the applied dose based on the statement that CrVI is non-volatile. 

Exposure time for each application in the ROAT study was six hours to
both the CopperShield® solutions and to the potassium dichromate
solutions. After the six hour exposure, participants washed their
forearms using soap provided to them.  This was apparently not done at
the clinic, based on the statement in the report that “Each day when
they came in for testing, they were reminded to wash off the test
solutions.  At the subsequent study visit, each participant was asked to
recall the time when they washed their forearms and this was recorded in
their study file.”  (page 51 of MRID 46884001).

Participants received a total of 10 applications of all test solutions
(five times per week, Monday through Friday, for two weeks).  
Participants were divided into three groups, or ‘rounds’ according
to the report (page 52). Round one consisted of 25 participants (22
Cr-sensitive and 3 controls). Round two consisted of 31 participants (26
Cr-sensitive and 5 controls). Round three consisted of 14 participants
(12 Cr-sensitized and 2 controls).  The three rounds were stated to be
identical in terms of procedures conducted and methods used, with the
exception of the soap used to wash the test sites in Round 1 vs. Rounds
2 and 3. 

RESULTS

Interpretation of allergic and irritant responses

On each day of testing, prior to application of the test solution for
that day, skin responses were evaluated.  Evaluation was made for
presence of allergic contact dermatitis as well as irritant responses. 

If the response was determined to be allergic, the challenge to that
dose was discontinued.  If the response was considered irritant or
uncertain, dosing was continued to aid in the interpretation. Dosing was
discontinued only for the dose to which an individual experienced an
allergic response. 

Seventy-two hours after the last testing day, participants were
evaluated by Dr. Fowler to determine the presence of an ACD response.
All skin responses were graded for erythema, vesicle formation, papule,
scaling, and prurutis,  The grading of each of these was performed using
the following criteria (Table 3 of the report, page 54 of MRID
46884001):

Data copied without alteration from page 54 of MRID 46884001. 

Results of Patch Testing

A summary of the responses to patch testing for determination of
Cr-sensitivity and individual responses to the ROAT study is shown in
the following table (Table 8, from pages 70-72 of MRID 46884001). 

addiI

In addition to these data, the study authors were interested in
determining whether the 10% MET from the study population in this report
were representative of the Cr(VI)-sensitized population in the United
States.  To determine this, the number of participants with a +1, +2, or
+3 patch-test reaction were compared to the proportions of individuals
with these same patch test grades in the NACDG database of patch-test
grades for all individuals patch tested by NACDG physicians from 1998
through 2002.  

The number of participants in each patch-test grade and dose group was
extrapolated (scaled up or down) depending on the relative proportion of
the total number of people in each of the three patch-test grades. The
data from the patch-test normalized population were the used for
estimating the 10% MET values that are representative of the general
Cr(VI)-sensitized population in the United States. 

A corollary to this determination was finding out if the results of
prior patch-testing on the study population, which was performed using
8-mm Finn chambers, was comparable to the 12-mm chambers that were used
to make the current determination of sensitivity to Cr(VI) in the same
study population.  As discussed in Nethercott et al. (1994), it has been
suggested that a sub-MET concentration could induce a sensitization
response based on an increase in surface area of the patch due to
greater systemic uptake of the chemical.  Although shown not to be the
case from experimentation done in the Nethercott et al. study, the
current investigation also looked into this possibility.  These data are
summarized in Table 6 of the report, pages 64-65 of MRID 46884001 and
are shown below: 

The table shows (and as discussed in the report), that 41 of the 58 test
subjects, or 71%, had the same patch test grade with the 8-mm and 12-mm
patch.  Fourteen subjects had a higher test grade with the 12-mm patch
than the 8-mm patch, and 3 subjects had a lower patch test grade with
the 12-mm patch than the 8-mm patch.  The report also stated (page 59)
that there were 26 participants who tested positive with the 8-mm patch
but did not have a positive response with the 12-mm patch in this study.
 It is assumed from examining the data in Table 6 that these were
subjects who eventually did not participate in the ROAT phase of the
study as shown in Table 8.   

 Results of ROAT

Summary dose-response data for the ROAT phase of the study were
presented in Table 12, page 95 of MRID 46884001 for the CopperShield®
treatment solution and on page 89 of MRID 46930701 for potassium
dichromate.  Individual reactions were presented in Tables 10 and 11,
pages 90-94 of MRID 46884001 and Tables 10 and 11, pages 85-88 of MRID
46930701.  It is to be noted that the statement was made in MRID
46884001 (page 69) that “participants who had a higher grade of
reaction (2+ and 3+) on the initial patch test were far more likely to
develop an allergic response during the ROAT.”   It would not be known
what the initial induction dose of CR(VI) was for the study participants
nor what elicitation doses these participants would have received over
the years.  Thus, the relationship between the patch test data and the
results of the ROAT could not be examined further. It is known from
previous experimental work in animals (Scott et al., 2002) that doses
required for both induction and elicitation are dose-responsive in
nature, that is, elicitation doses can be affected by the induction dose
and vice-versa.  

The summary table notes responses interpreted under two scenarios.
Scenario 1 included responses determined only to be allergic in nature,
while Scenario 2 included both allergic and irritant responses combined.

Data reproduced unaltered from page 95 of MRID 46884001 for the
CopperShield® treatment solution. 

Data copied unaltered from MRID 46930701 for potassium dichromate. 

Dose-Response Modeling and Calculation of 10% Minimum Elicitation
Threshold

Two scenarios were modeled with respect to calculation of the 10% MET in
both studies.  Dose-response modeling in both cases was done following
the USEPA benchmark dose approach and using the Benchmark Dose Software
distributed by EPA. 

In the first scenario, the statistical analysis included all allergic
responses. While in the second scenario, the statistical analysis
included both allergic and irritant responses; that is, the assumption
in the second scenario was that all visible irritant responses were
allergic in nature.  The equations used for patch–test normalization
for both Scenario 1 and 2 are given in Appendix F, pages 322-324 of the
report. 

The summary data on page 95 of MRID 46884001 show the dose-response for
the various concentrations of CopperShield® applied to the skin in the
ROAT phase of the study.  For Scenario 1, the point closest to the 10%
response level was the 250 ng/cm2 concentration of Cr(VI), [response of
12%], while modeling of this result predicted a 9.6% response.  From the
best fitting model for Scenario 1 (allergic responses only), a value of
270 ng/cm2 concentration of Cr(VI) is determined. 

For Scenario 2 [allergic and irritant responses combined], the data
point closest to the 10% response level was the 90 ng/cm2 concentration
of Cr(VI) from the study (7% response). The modeled 10% response would
be 91.8 ng/cm2 concentration of Cr(VI)

	

Summary data on page 89 of MRID 46930701 for potassium dichromate and
modeling results on page 92 of this same report show that for Scenario
1, the point closest to the 10% response level was  the 90 ng/cm2
concentration of potassium dichromate [response of 8%], while modeling
predicted an 8.7% response.  From the best fitting model for Scenario 1,
a value of 118 ng/cm2 was determined as the 10% MET.

For Scenario 2 in MRID 46930701, which included both irritant and
allergic responses, page 89 of the report showed the 90 ng/cm2
concentration as the 10% response level.  The model predicted a 10.2%
response at this concentration.  From the bet fitting model, the 10% MET
value for Scenario 2 was determined to be 86.6 ng/cm2 for potassium
dichromate. 

Extrapolation of Study Results to NACDG Cr(VI)–Sensitized Population

Details of the process used to extrapolate results from the present
study to the NACDG clinical population were discussed on page 101 of the
study report.  Table 15 reproduced below from the report shows
comparison of the patch-test grades in this study with the NACDG (North
American Contact Dermatitis Group) database.  As compared to the NACDG
database, there appeared to be a higher proportion of subjects in the
present study with a +3 reaction to patch testing (26.7%) as compared to
the NACDG clinical database (7.7%), and a lower percentage of responses
at the +1 and +2 reaction levels. 

Data copied unaltered from page 101 of MRID 46884001. 

From the data presented in this table, it is observed that the
proportion of participants showing a +3 reaction in the patch test was
considerably higher than the proportion of participants showing a +3
reaction from the NACDG database.  To ensure that the dose-response
observed in this study was representative of the chromium-sensitized
population in the United States, results from the present ROAT study
were extrapolated to the NACDG database as described on page 96 of MRID
46930701 and page 102 of MRID 46884001. 

Calculated values for the 10% MET for both the original data and the
normalized data are shown in the following table from page 108 of MRID
46884001 and page 103 of MRID 46930701. 

Data copied unaltered from page 108 of MRID 46884001. 

When normalized to the U.S. population (on the basis of the NACDG
database of 495 individuals from 1998-2002), the resulting 10% MET
values of 349 ng/cm2   and 166 ng/cm2  for Scenario 1 and 2 respectively
are higher than the 10% MET values of 270 ng/cm2 and 91.8 ng/cm2 that
were derived from the dose-response data set prior to normalization of
the data.  

 

Data copied unaltered from page 103 of MRID 46930701. 

Calculated 10% MET values for scenarios 1 and 2 using the original
dose-response data show values of 118 and 86.6 ng/cm2  for potassium
dichromate.  When normalized to the U.S. population (on the basis of the
NACDG database of 495 individuals from 1998-2002), the resulting 10% MET
values are 364 ng/cm2  and 269 ng/cm2  for Scenario 1 and 2
respectively.     

It is of interest that the 10% MET value obtained from the
non-normalized dose-response data in the study with potassium dichromate
(118 ng Cr(VI)/cm2) is approximately 30% higher than the 10% MET value
derived from the Nethercott et al. (1994) study (89 ng Cr(VI)/cm2).  The
closeness of these two values from different studies suggests that for
potent dermal sensitizers, results from open or closed tests may not
differ significantly, and also suggests that for both the Nethercott et
al. study and the present study, the test population may have been
composed of persons more sensitive to Cr(VI) than the general
Cr-sensitive population.   

E. REVIEWER’S CONCLUSIONS: 

The current submitted study was designed to obtain a 10% Minimum
Elicitation Threshold value (or 10% MET) from subjects known to be
sensitive to Cr(VI) employing the Repeat Open Application Test protocol.
 From the FIFRA Science Advisory Panel review of this issue in May of
2004, it was suggested that such a test would provide a more realistic
basis for conducting a risk assessment of dermal sensitization risk from
contact with treated wood containing Cr(VI).  Previously, the Agency
relied upon the study of Nethercott et al, (1994) in which a
‘sensitization reference dose’ of 9 ng/cm2 was derived from a 10%
MET value of 89 ng Cr(VI)/cm2.  An uncertainty factor of 10 was applied
to the 10% MET from the Nethercott et al. study to account for lack of
data on human variability in the dermal sensitization response to
Cr(VI), especially from repeated dermal contact.  It is known that
repeated contact with dermal sensitizers can lower the concentration
subsequently needed to cause an elicitation of allergic contact
dermatitis, and the Nethercott study was based on a single dermal
exposure. 

The present study utilized a study population of 60 human subjects who
were exposed to various concentrations of Cr(VI) once a day over a
period of 10 days using the ROAT protocol.  Exposure was to Cr(VI) both
as contained within the CopperShield® wood preservative treatment
solution and as potassium dichromate.  Values from these two experiments
are intended for different applications.  The 10% MET value obtained
from study of the CopperShield® wood treatment solution is for
determination of a ‘safe’ area dose for protection against
elicitation of allergic contact dermatitis that could occur from contact
with the treated wood.  The 10% MET value obtained from study of
potassium dichromate is for application to environmental cleanup, for
example, soil contaminated with Cr(VI).  It is noted that both test
materials were examined concurrently on the same subjects.  

The study participants were first confirmed to be Cr(VI) sensitive
through patch testing using 12mm Finn Chambers.  The participants also
had a previous history of testing for Cr(VI) sensitivity and the results
of these previous tests were compared to the current patch testing. 
Comparison of the results of the previous patch testing with the current
patch test showed that 41 of the 58 test subjects, or 71%, had the same
patch test grade with the 8-mm and 12-mm patch.  Fourteen subjects had a
higher test grade with the 12-mm patch than the 8-mm patch, and 3
subjects had a lower patch test grade with the 12-mm patch than the 8-mm
patch.  The results of the ROAT test showed that participants who had an
initial patch test grade that was 2+ or 3+ also appeared more likely to
show allergic contact dermatitis reactions in the ROAT phase and at
lower concentrations (Table 8 of MRID 46884001). 

The patch test results also showed what appeared to be a
disproportionate percentage of participants who had a 3+ reaction grade
to the patch test when compared to a population whose patch test
reactions were obtained from the North American Contact Dermatitis Group
(NACDG) database of 1998-2002.  This database consisted of 495
individuals. The history of these individuals is not known. It was
desired that the dose-response observed in this study be representative
of the Cr(VI) sensitized population in the United States.  To accomplish
this, the following procedure, from page 102 of MRID 46884001, was
followed, as reproduced from the report (below):

 

On the basis of the normalized results, benchmark dose modeling was
conducted on the dose-response data.  Modeling was conducted on both the
original data and the normalized data.  Results for the calculation of
10% minimum elicitation thresholds were derived and presented on page
108 of the report in summary form. 

When considering only allergic reactions, the original calculated 10%
MET of 270 ng/cm2 is approximately 3-fold higher than the 10% MET value
derived from the study of Nethercott et al. (88 ng/cm2).  The normalized
value of 349 ng/cm2 is even higher.  Reasons that the calculated 10% MET
in this study are higher than previously reported by Nethercott et al.
include normalization of the test results in this study, use of a wood
treatment solution containing Cr(VI) compared to use of potassium
dichromate, and use of an open application test compared to use of
occluded conditions. Occluded conditions might be expected to result in
lower threshold values compared to open application tests.  The present
ROAT study included experimentation on the same test subjects using
potassium dichromate, a form of hexavalent chromium that is typically
used for examination of dermal sensitization to hexavalent chromium. 
Results of that study showed original 10% MET value of 118 ng/cm2 for
non–normalized data involving only allergic responses, and a 10% MET
of 86.6 ng/cm2 when allergic and irritant responses were combined.  The
patch test normalized values for potassium dichromate were 364 and 269
ng/cm2 for allergic responses and allergic plus irritant responses,
respectively.  Of interest is the comparison of the MET values for both
the CopperShield® treatment solution and the potassium dichromate
solution.  The original, non-normalized dose-response data show a
difference in the 10% MET values between the wood treatment solution and
potassium dichromate.  That is, the potassium dichromate 10% MET value
is lower (118 ng/cm2 ) compared to the wood treatment solution 10% MET
(270 ng/cm2 ).  However, when the dose-response data was normalized on
the basis of patch test data from the NACDG database, the 10% MET values
are almost the same between the two forms of Cr(VI) tested (349 and 364
ng/cm2 for the wood treatment solution and potassium dichromate,
respectively).  A similar result can be seen using the dose-response
data that combined allergic and irritant responses.  

Classification

This study is classified acceptable/non-guideline and fulfills the
purpose for which it was conducted. However, determination of a single
10% MET value will require further discussion within the Office of
Pesticide Programs. 

  

	Skin Sensitization Study (ROAT)  (2006) / Page 	-   PAGE  1  -

[CopperShield® Wood Preservative containing Cr(VI)]	Non-guideline