Guidance for Industry and FDA
Reviewers/Staff
Premarket Notification [510(k)]
Submissions for Testing for Skin
Sensitization To Chemicals In
Natural Rubber Products
Document issued on: January 13, 1999
This document supersedes document Guidance on the Content and Format of Premarket
Notification [510(k)] Submissions for Testing for Skin Sensitization To Chemicals In Natural
Rubber Products February 13, 1998.
U.S. Department Of Health And Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Infection Control Devices Branch
Division of Dental, Infection Control, and General Hospital Devices
Office of Device Evaluation Preface
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to
Chiu S. Lin, Ph.D., CDRH,   9200 Corporate Blvd., Rockville, MD 20850.  Comments
may not be acted upon by the Agency until the document is next revised or updated. 
For questions regarding the use or interpretation of this guidance contact Chiu S. Lin,
Ph.D., Chief at (301)-443-8913.
Additional Copies
World Wide Web/CDRH page at  http://www.fda.gov/cdrh/ode/944.pdf, or CDRH
Facts on Demand at 1-800-899-0381 or 301-827-0111, specify number 944 when
prompted for the document shelf number.
2 PREMARKET NOTIFICATION [510(K)] SUBMISSIONS FOR
TESTING FOR SKIN SENSITIZATION TO CHEMICALS IN
NATURAL RUBBER PRODUCTS
GUIDANCE  DOCUMENT
A. PURPOSE
This document is intended to provide to manufacturers and FDA
personnel, guidance for the preparation and evaluation of
510(k) submissions of natural rubber (NR) medical devices with
labeling claims for:
(a)   reduced potential for sensitizing users to rubber
chemical additives,   or;
 
(b)   reduced potential for causing reaction in individuals
sensitized to rubber chemical additives.
              
In addition, this document describes testing recommended to
support these claims.
B. BACKGROUND
The increased use of natural rubber (NR) medical gloves and
other NR containing medical devices, which coincided with the
emergence of HIV infection, resulted in the increased
prevalence and intensity of adverse reactions to NR. There are
three distinctive types of adverse reactions to NR that differ
in their mechanisms of induction and resulting clinical
manifestations.  These reactions include irritation, delayed
hypersensitivity (Type IV allergy) and immediate
hypersensitivity (Type I allergy).  The major distinctions
between the three types are: a) irritation is a nonimmunologic
response with symptoms described as irritant contact
dermatitis; b) Type IV allergy is a cell-mediated
immunological reaction resulting in allergic contact
dermatitis that develops 1 to 4 days after the exposure; and
c) Type I allergy is an antibody-mediated reaction occurring
immediately, usually within minutes after the exposure.  While
clinical manifestations of irritation and Type IV allergy are
limited to skin reactions, clinical symptoms of Type I
allergic reactions may range in severity from local skin
reactions, defined as contact urticaria, to life-threatening
anaphylactic reactions.  Irritation can be induced by water,
powder and chemicals, while Type IV allergy is predominantly
3 induced by the residual chemical additives (thiazoles,
thiurams and carbamates) on the finished NR containing medical
devices.  Type I allergy is primarily caused by NR proteins
remaining on the finished products.  Although the term Type IV
allergy is synonymous to Type IV hypersensitivity, the term
Type IV allergy will be used in this document. Both Type I and
Type IV allergic reactions to NR containing medical devices
represent serious problems as the exposure of sensitized
individuals to natural rubber medical devices may be life-
threatening (Type I) or career-threatening (Type I and IV). 
Although Type I allergy is presently an issue of major concern
due to an increase in prevalence and severity of the reactions
in the past few years, Type I allergy is not the subject of
this document.  This guidance document is focused only on Type
IV allergy to residual chemicals (predominantly thiazoles,
thiurams and carbamates) on the finished NR containing medical
devices.  It is important, however, for users of this
document, when selecting the human test subject panel, to
consider the possibility that some of the healthy test
subjects and some of the individuals demonstrating Type IV
allergy may also have Type I allergy.  Irritation reaction, a
nonimmunolgical response, is also not a subject of this
document (Section E.2.1.).
Allergy to chemical additives in NR containing medical devices
has been known for a long time.  Efforts have been made by
industry to alleviate the problem by manufacturing products
with reduced levels of chemical additives which are known to
have sensitizing potential.  In the past, the label
"hypoallergenic" was sometimes applied to distinguish such
products from the rest of the marketed products.  However,
with the apparent recent increase in the prevalence and
severity of Type I allergy to NR proteins, the term
hypoallergenic has been frequently misinterpreted as being
related to protein allergy. Such devices, despite being
labeled hypoallergenic, can cause allergic reactions in
individuals sensitized to NR proteins and should not be used
by such individuals.  FDA published in the Federal Register
(FR, Vol.62, No. 189, September 30, 1997, pages 51021-51030,
Natural Rubber-Containing Devices; User Labeling) a rule
prohibiting the label claim of hypoallergenic" on NR
containing medical devices.  This rule became effective on
September 30, 1998. 
4 The manufacturers of NR containing medical devices can utilize
this guidance document to address the labeling options
presented below regarding Type IV allergy and to conduct
appropriate testing to support these claims: a) reduced
potential for sensitizing users to rubber chemical additives;
and b) reduced potential for causing reaction in individuals
sensitized to specific rubber chemical additives.
C.  CLAIMS AND TESTING RECOMMENDATIONS
Firms wishing to make a claim regarding the reduced potential
of chemical sensitization or reduced reaction-inducing
potential of their products in allergic individuals should
submit to FDA the recommended biocompatibility test data for
each NR containing medical device as described in the FDA
manual Guidance for Medical Gloves: A Workshop Manual (FDA
96-4257).  These tests include skin irritation and dermal
sensitization studies in animals.  In addition to these basic
biological tests, this guidance document should be followed to
support the following claims:
  
Claim 1: 
   
     Low Dermatitis Potential
This product demonstrated reduced potential for
sensitizing users to chemical additives.     
Warning: Do not use this product if you have a known 
allergy to natural rubber protein or chemical additives.
 
           
Supporting Test Data:
 A negative skin sensitization test (Modified Draize-95 Test)
on a minimum of 200 nonsensitized human subjects, as described
in Section E.
Claim 2:
     
     Low Thiuram, and/or Carbamate, and/or Thiazole
This product demonstrated reduced potential for causing
reaction in individuals sensitized to (name of chemical)
Warning: Do not use this product if you have a known
     natural rubber protein allergy. 
5 Supporting Test Data:  
        
a)   A negative Modified Draize-95 test as recommended for
claim 1 above; 
b)   A negative patch test on 25 individuals who are allergic
to the defined major chemical sensitizers present in
natural rubber products as described in Section F below.
D.   ADDITIONAL REGULATORY INFORMATION REGARDING CLAIMS
1.  The NR containing medical devices labeled
hypoallergenic which are presently on the market may,
upon removal of that claim from all labeling, remain on
the market without the need to supply additional
documentation to the FDA.
2.  Manufacturers who intend to use labeling claim 1 to
market a NR containing medical devices, previously
labeled hypoallergenic, do not need to submit a new
510(k) if they have the supporting test data described
in this guidance.  However, the test data described for
claim 1 should be in compliance with this guidance
document and kept on file to support the claim.
3.  Manufacturers who intend to use claim 2 to market a NR
containing medical devices, previously labeled
hypoallergenic, in addition to the requirements for
claim 1, would have to submit a 510(k) with completed
testing on the 25 sensitized subjects.
4.  For new NR containing medical devices intended to bear
the claims described in this document, a 510(k) should
be submitted with data from testing described in this
guidance document.
A list of testing laboratories equipped to perform the
Modified Draize-95 test on normal subjects is available
through the Office of Health and Industry Programs,
Division of Small Manufacturers Assistance (DSMA) by
telephone at #1-800-638-2041 or DSMA FAX ON DEMAND at
#1-800-899-0381.  A partial list of physicians and groups
with access to sensitized individuals and equipped to
perform testing on sensitized subjects can also be obtained
from DSMA.
6 E.  MODIFIED DRAIZE-95 TEST
The purpose of this test is to evaluate whether residual
chemical additives at the level that may induce Type IV
allergy in the unsensitized general user population are
present in a finished natural rubber (NR) containing medical
device.   The original sensitization test was developed by
John Draize for use with rabbits and later adopted for skin
testing in humans.  For the purpose of this guidance document,
the Modified Draize-95 Test includes additional changes that
specifically evaluate the sensitization potential of chemical
compounds in finished NR containing medical devices.  These
changes were based on the existing data, past experience and
recent knowledge from published literature. This test should
be used for claim 1 and for initial testing to support claim
2. 
E.1. Test Subjects:
The test should be completed on a minimum of 200 nonsensitized
adult human subjects. This sample size, with all negative
results, provides 95% confidence that the chemical
sensitization potential of the NR containing medical device in
the user population is expected to be less than 1.5%.
The criteria for selection of the test subjects should be as
follows:
E.1.1. Inclusion
a.  The test subjects should be normal volunteers who have
     documented informed consent and have not participated in
     other voluntary testing for at least 30 days.
b.  Efforts should be made to provide racial and gender
diversity of the test subjects that reasonably reflects
the general user population in the U.S.
c. Age of the test subjects should range from 18 to 65
years.
    
7 E.1.2. Exclusion
a.   Potential test subjects with any visible skin disease
that might be confused with skin reactions caused by the
test material. 
 
b.   Potential test subjects with any knowledge or indication
of existing Type IV allergy to natural rubber chemical  
additives.
 
c.   Potential test subjects with any indication of existing
Type I allergy to natural rubber proteins.
d.   Potential test subjects with a history of frequent
irritation.
e.   Potential test subjects who have used corticosteroids
either systemically or topically on the potential test
site two weeks before testing.
 
f.   Potential test subjects who have received endogenous or
exogenous immunosuppressive treatment (or prolonged
exposure to sun).
g.    Potential subjects who are pregnant or become pregnant  
   during the study.
h.   All lactating women.
E.2. Procedure:
  
 E.2.1. Induction Phase - A sample of the test article,
minimum size 2cmx2cm, should be applied to each test
subject in the study. The patch should be applied to
upper back area and continuously secured on the
edges with a nonreactive adhesive tape.   Complete
occlusion of the patch is essential. 
     The induction phase of the test includes application
of ten patches of the test article on each Monday,
Wednesday, and Friday.  The test article is removed
and replaced by a new one at the same site every 48
hours for a total of ten changes. The patches
applied on Fridays are removed on Mondays.
Any and all skin reactions should be recorded during
this induction phase.  If a reaction to an initial
8 induction test patch is observed, the subject should
be considered a presensitized individual.  A
reaction observed after placement of  the second
patch in the induction phase is generally considered
an irritation.  In each of these cases, the
procedure described in section E.2.5. would apply. 
If a local irritation caused by the occlusion
material occurs, occlusion tape should be replaced
with the non-irritating one, and the induction
patching could be continued.
E.2.2. Rest Period - At the end of the induction period,
the test article is removed.  No test articles are
to be applied to the test subjects for the next
three weeks, until the challenge patches are
applied.
E.2.3. Challenge Phase - Two samples of the same test
article, a minimum 2cm X 2cm in size are applied
consecutively to a virgin site for 48 hours each. 
The test site is evaluated for reaction at the time
of each patch removal and again two to four days
after removal of the second patch.
E.2.4. Scoring Criteria - The intensity of reactions
should be scored according to the following
criteria:
Basic Score: Description:
0 - No visible reaction
0.5  -    Doubtful or negligible erythema reaction
1.0 -    Mild or just perceptible macular erythema
reaction in a speckled/follicular, patchy
or confluent pattern (slight pinking)
2.0  -    Moderate erythema reaction in a confluent
pattern (definite redness)
3.0  -    Strong or brisk erythema reaction that may
spread beyond the test site
9 Supplemental scores:     Description: Label:
0.5 Edema E
0.5 Papules P
0.5 Vesicles V
0.5 Bullae B
The supplemental scores may be added to the basic
score, if the reactions include described symptoms.
The final score should be the sum of basic and
supplemental score values.
E.2.5. General - With any NR containing medical devices
evaluated according to this guidance document, the
surface of the device that the user is mostly
exposed to should be tested.
          In the case of medical gloves, the inside of the
glove should be tested.  The study should be
conducted in two stages.  In the first stage, a
population of 50 human subjects may be tested to
evaluate product for the potential to cause
irritation or sensitization.  If the test product
does not indicate a potential for inducing dermal
irritation and does not show sensitization
capability, the second stage can be initiated on the
remaining 150 individuals.
   During the induction phase of the study, if a
subject develops a positive reaction(a score value
of 1.5) to chemicals or shows signs of irritation
after patch applications, further patching on those
individuals should be stopped.  After 3 weeks of
rest, these individuals should receive a challenge
patch to confirm observed reaction as either
preexisting sensitivity or irritant reaction.  All
such cases should be recorded and reported in
addition to the 200 subjects in the test panel
group.
E.3. Data Presentation:
A detailed study report should be kept on file and/or
submitted in a 510(k), which should include at a minimum such
items as study protocol, test subject selection, scoring
criteria, test results, and interpretation of results.  In
order to qualify for the claim of a reduced sensitization
potential, all 200 individuals completing the study should
10 exhibit a score value of no more than 1.5 based on the scoring
criteria described in section E.2.4. of this document.  The
individuals who were identified as either presensitized to
natural rubber chemicals or presenting irritant reactions,
would be excluded from the statistical evaluation.  However,
the data from each such case should be recorded and reported
in addition to the data for the 200 nonsensitized test
individuals completing the test.
F. PATCH TEST ON SENSITIZED INDIVIDUALS
The purpose of this test is to determine whether a finished
natural rubber containing medical device contains residual
chemicals which might cause a skin reaction in individuals who
are already allergic to one or more of the following classes
of chemicals: thiazoles, thiurams and carbamates.  These test
data combined with the data from the Modified Draize-95 test
described for claim 1, should be completed to support claim 2.
The test subjects with a prediagnosed allergy of a
minimum grade of 1.5 according to the standard scoring of
the North American Contact Dermatitis Research Group
(NACDRG) (Am. J. Contact Dermatitis 2:122-129,1991)
should be selected for this study.  The diagnostic test
determining the sensitivity level of the test subjects
should be completed one month prior to the date that the
subject is being included in this study.
F.1.  Test Subjects:
The study should include a minimum of 25 individuals who were
positively diagnosed to be allergic to one or more of the
above classes of chemical sensitizers in NR containing medical
devices.  This sample size, with all negative results,
provides 95% confidence that chemicals on the tested natural
rubber medical products would be expected to cause reactions
in less than 11.3% of sensitized individuals.
The criteria for selection of the test subjects should be as
follows:
 
F.1.1.  Inclusion
   
a.  Individuals who have a prediagnosed allergy to NR
chemicals of a minimum of 1+ reaction according to the
NACDRG standard.
11 b.   The test subjects with documented informed consent.
c.   Efforts should be made to provide racial and gender 
diversity of the test subjects that reasonably reflects
the general user population in the U.S.
d. Age of the test subjects should range from 18 to 65
years.
 
F.1.2  Exclusion
   
a.   The test subjects with any visible skin disease that
might be confused with skin reactions caused by the
test material. 
b.  The test subjects with any indication of existing Type I
allergy to natural rubber proteins.
  
c.   The test subjects who have used corticosteroids either
systemically or topically on the potential test site two
weeks before testing.
d.    Test subjects who have received endogenous or exogenous 
   immunosuppressive treatment(or prolonged sun exposure).
e.    All subjects who are pregnant or become pregnant during 
   the study.
f.    All lactating women.
F.2. Test Procedure:
A minimum 2cm x 2cm sample of the test article is applied to
each of the 25 human subjects who were previously diagnosed to
be allergic to one or more of the three classes of known
chemical sensitizer(s) in NR containing medical devices;
thiurams, carbamates and thiazoles.
In this test procedure the patch is applied with all edges
continuously secured with non-reactive adhesive tape for 48
hours.  Complete occlusion of the patch is essential.  If the
test article causes discomfort to the individual, it should be
removed earlier.  The test sites are evaluated at the time of
the patch removal and again two to four days later.
12 F.3. Data Presentation:
A detailed study report should be submitted in a 510(k), which
at a minimum should include such items as study protocol, test
subject selection, scoring criteria, test results, and
interpretation of results.  The sensitivity level score for
each allergic subject before involvement in the testing should
be recorded and reported with the test results.  In case of
allergy to more than one chemical, the score should be
reported for each chemical.  All tested individuals in this
group should present negative results (a score of less than
1.0 based on the scoring criteria in section E.2.4. of this
document) as a prerequisite for the claim of reduced reaction-
inducing potential. 
G. INVESTIGATIONAL DEVICE REQUIREMENTS:
This guidance document applies to the NR containing medical
devices which have gone through additional manufacturing
processes to reduce levels of residual chemical additives, and
which have shown negative results in the irritation and dermal
sensitization studies in animals.  Therefore, the level of
risk to the nonsensitized subject during a skin patch test
would be considered nonsignificant risk.  In addition, the
studies performed on sensitized subjects with a patch test of
NR containing medical devices should be nonsignificant risk
studies because the products should, as a prerequisite, have
passed the Modified Draize-95 test.
A nonsignificant risk device study, under IDE regulations (CFR
812), requires an institutional review board approval and
affords the patient informed consent.  Studies conducted in
foreign countries are not subject to the IDE regulations,
although FDA recommends that they be conducted according to
the IDE provisions.   At a minimum, they need to be conducted
in compliance with the Helsinki Declaration.
13 H. FOR FURTHER INFORMATION OR QUESTIONS REGARDING THIS 
GUIDANCE PLEASE CONTACT:
    Chief, Infection Control Devices Branch (HFZ-480)
    Division of Dental, Infection Control and General
Hospital Devices
     Office of Device Evaluation
     Center for Devices & Radiological Health, FDA
    9200 Corporate Blvd.
    Rockville, MD 20850
    Telephone: (301)-443-8913     FAX:  (301)-480-3002
14