[Federal Register Volume 62, Number 189 (Tuesday, September 30, 1997)]
[Rules and Regulations]
[Pages 51021-51030]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25728]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 96N-0119]

21 CFR Part 801


Natural Rubber-Containing Medical Devices; User Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
requiring labeling statements on medical devices, including device 
packaging containing natural rubber that contacts humans. The rule 
requires labeling of medical devices containing natural rubber latex 
that contacts humans to state: ``Caution: This Product Contains Natural 
Rubber Latex Which May Cause Allergic Reactions.''; labeling of medical 
devices containing dry natural rubber that contacts humans to state: 
``This Product Contains Dry Natural Rubber.''; labeling of medical 
devices containing natural rubber latex in their packaging that 
contacts humans to state: ``Caution: The Packaging of This Product 
Contains Natural Rubber Latex Which May Cause Allergic Reactions.''; 
labeling of medical devices containing dry natural rubber in their 
packaging that contacts humans to state: ``The Packaging of This 
Product Contains Dry Natural Rubber.''; and that the claim of 
hypoallergenicity be removed from the labeling of medical devices that 
contain natural rubber. These requirements are being established in 
response to numerous reports of severe allergic reactions and deaths 
related to a wide range of medical devices containing natural rubber.

EFFECTIVE DATE: This final rule is effective September 30, 1998.

FOR FURTHER INFORMATION CONTACT: Donald E. Marlowe, Center for Devices 
and Radiological Health (HFZ-100), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20850, 301-443-2444, FAX 301-443-2296.

SUPPLEMENTARY INFORMATION: 

I. Background

    Natural latex is a milky fluid obtained in commercial quantities 
primarily from the Heavea brasiliensis (rubber) tree. There is often 
confusion concerning the terminology used to describe the raw 
agricultural materials derived from rubber-producing plants; products 
made from various intermediate forms of the

[[Page 51022]]

raw agricultural material (e.g., natural rubber latex, dry natural 
rubber); formulations of synthetic latex and synthetic rubber to which 
natural rubber has been added; and synthetic rubber and synthetic latex 
formulations that do not contain natural rubber.
    ``Natural latex,'' for the purposes of this rule, is defined as a 
milky fluid that consists of extremely small particles of rubber 
obtained from plants, principally from the H. brasiliensis (rubber) 
tree, dispersed in an aqueous medium. It contains a variety of 
naturally occurring substances, including cis-1,4-polyisoprene in a 
colloidal suspension (Ref. 1) and plant proteins, which are believed to 
be the primary allergen (Refs. 2, 3, and 4).
    ``Natural rubber,'' for the purposes of this rule, includes all 
materials made from or containing natural latex. Products that contain 
natural rubber are made using two commonly employed manufacturing 
processes, the natural rubber latex (NRL) process, and the dry natural 
rubber (DNR) process.
    The NRL manufacturing process involves the use of natural latex in 
a concentrated colloidal suspension. Products are formed from natural 
rubber latex by dipping, extruding, or coating, and are typically 
referred to as containing or made of ``natural rubber latex.'' Examples 
of products that may contain natural rubber latex include medical 
gloves, catheters, tracheostomy tubes, and condoms.
    The DNR manufacturing process involves the use of coagulated 
natural latex in the form of dried or milled sheets. Products are 
formed from dry natural rubber by compression molding, extrusion, or by 
converting the sheets into a solution for dipping. These products are 
typically referred to as containing or made of dry natural rubber or 
``crepe'' rubber. Examples of products that may contain dry natural 
rubber include syringe plungers, vial stoppers, and injection ports on 
intravascular tubing.
    The phrase, ``contains natural rubber,'' as used herein, also 
includes products described as made of ``synthetic latex'' or 
``synthetic rubber'' that include natural rubber in their formulations. 
This rule does not apply to products made from synthetic latex or 
synthetic rubber that do not include natural rubber in their 
formulations.
     FDA has noted an increase in the number of reports submitted to 
its medical device reporting system regarding sensitivity to natural 
latex proteins contained in medical devices, including deaths following 
barium enemas. These deaths were associated with anaphylactic reactions 
to the natural rubber latex cuff on the tip of barium enema catheters. 
Scientific studies and case reports have documented sensitivity to 
natural latex proteins found in a wide range of medical devices (see 
Refs. 2 through 23).
    Based upon this information, the agency published a proposed rule 
on June 24, 1996 (61 FR 32618), to require labeling statements on 
medical devices containing natural rubber that contact humans. This 
final rule is based upon comments submitted in response to the June 24, 
1996 proposed rule.

II. Highlights of the Final Rule

A. Natural Rubber-Containing Devices; Labeling

    FDA is requiring the labeling for medical devices containing 
natural rubber that contacts humans to include a statement regarding 
the presence of natural rubber. The agency is issuing this rule because 
medical devices composed of natural rubber, or which contain components 
formulated from natural rubber, may pose a significant health risk to 
some consumers or health care providers who are sensitized to natural 
latex proteins. A statement in the labeling of medical devices 
identifying the presence of natural rubber latex is considered to be 
necessary for the safe and effective use of such devices.
    ``Contacts humans,'' for the purposes of this rule, means that the 
natural rubber contained in a medical device is intended to contact or 
is likely to contact the user or patient. This includes contact when 
the natural rubber containing device is connected to the patient by a 
liquid path or an enclosed gas path; or the natural rubber containing 
device is powdered, and the powder may carry natural latex proteins 
that may contaminate the environment of the user or patient.
    The device may bear one or more of four labeling statements 
depending on the type of natural rubber in the device and depending on 
whether the natural rubber is in the device itself or in its packaging. 
The reasoning for requiring one or more of four separate statements is 
discussed more fully in comments 3 and 6 in section III of this 
document.
    Medical devices containing rubber produced by the NRL process that 
contacts humans shall bear labeling with the following statement in 
bold print: ``Caution: This Product Contains Natural Rubber Latex Which 
May Cause Allergic Reactions.'' Representative examples of devices that 
contain NRL include: Cuffed enema/enterolysis catheters, latex condoms 
(with or without spermicidal lubricant), wound drains, cuffed airways, 
latex surgical gloves, and latex examination gloves.
    The agency is also requiring that medical devices containing rubber 
produced by the DNR process that contacts humans include the following 
statement in bold print in their labeling: ``This Product Contains Dry 
Natural Rubber.'' Representative examples of devices that contain DNR 
include: Anesthesia masks, electrode pads, contraceptive diaphragms, 
crutch pads and tips, wheelchair tires, elastic components of bandages/
face masks, syringe plungers, parenteral drug vial stoppers, and 
intravenous injection ports.
    The agency is further requiring medical devices having packaging 
that contains natural rubber that contacts humans bear labeling with 
one of the following statements in bold print: ``Caution: The Packaging 
of This Product Contains Natural Rubber Latex Which May Cause Allergic 
Reactions.'' or ``The Packaging of This Product Contains Dry Natural 
Rubber.'', as appropriate. The purpose of such statements is to inform 
individuals who are sensitive to natural rubber about the presence of 
natural rubber in the packaging of devices that may be, by themselves, 
natural rubber-free.

B. Hypoallergenicity

    FDA believes that it is also necessary to prohibit certain labeling 
statements on medical devices that contain natural rubber. FDA believes 
that the labeling statement ``hypoallergenic,'' traditionally used with 
respect to medical gloves, cosmetics, and other products produced for 
individuals with chemical allergies, is interpreted by consumers to 
mean that the risk of allergic reactions to any component of the device 
would be minimal. This is not the case with devices that contain 
natural rubber. FDA has received reports of allergic reactions to 
medical gloves labeled as ``hypoallergenic.''
    Use of the ``hypoallergenic'' label has been based on results of 
the modified (human) Draize test. While this test may be appropriate 
for detecting sensitization to residual levels of processing chemicals, 
the test does not detect sensitivity to natural latex proteins.
    Thus, there is no reasonable assurance that the risk of allergic 
reactions to products that contain natural rubber, yet have reduced 
levels of processing chemicals, will be reduced for individuals who are 
sensitive to natural latex proteins. Therefore, the agency believes 
that the term ``hypoallergenic'' on the labeling of a device that 
contains natural rubber is misleading in that it

[[Page 51023]]

incorrectly implies that such device may be used safely by persons 
sensitive to natural latex proteins. For these reasons, FDA is 
requiring that the hypoallergenic claim be removed from the labeling of 
devices that contain natural rubber.

C. Effects of This Regulation on Premarket Submission Requirements

    FDA will not require a new submission under section 510(k) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360(k)) based 
upon labeling changes made to comply with this rule, provided that no 
other changes requiring a new 510(k) submission under 21 CFR 807.81 are 
made to the device. Devices subject to an approved premarket approval 
application, however, must submit any change to the device labeling 
that is required by this rule in the next interim report under 21 CFR 
814.39(e). Combination products that have device and drug components 
but are regulated under drug premarket approval provisions shall 
indicate the labeling change in a supplement for changes that may be 
made before FDA approval, as required by 21 CFR 314.70(c). Combination 
products that have device and biological components, but that are 
regulated under the biologic premarket approval provisions, shall 
inform the agency of the labeling change in the manner described under 
21 CFR 601.12.

III. Summary of Comments

    The agency received 62 comments, all of which supported the 
principle of natural rubber labeling for the protection of natural 
rubber sensitive individuals. The comments, however, differed greatly 
in their specific approaches.
    1. A few comments suggested using the term ``crepe rubber,'' 
instead of ``dry rubber,'' and suggested using the term ``synthetic 
rubber'' instead of ``synthetic latex.''
    The agency agrees that ``synthetic rubber'' should be used to 
describe components of certain natural rubber products covered by this 
regulation and has added that term in the definition of ``natural 
rubber'' in Sec. 801.437(b) (21 CFR 801.437(b)). Although the agency 
has discussed the meaning of crepe rubber in the preamble to this 
regulation, the agency does not agree that the term ``crepe rubber'' 
should be used in place of ``dry natural rubber'' in the regulation 
because the agency believes the term ``dry natural rubber'' is the term 
most commonly used to describe rubber manufactured by the DNR process.
    2. One comment pointed out that there are other sources of natural 
rubber besides that identified in the preamble of the proposed rule, 
the H. brasiliensis tree.
    The agency agrees and has clarified in the preamble of this 
regulation that there are other sources of plant-derived natural rubber 
used in the manufacture of devices that are subject to this rule. The 
preamble notes that the H. brasiliensis tree is the primary source of 
commercial natural latex, instead of the only source.
    3. Several comments claimed that there is no information to suggest 
that dry natural rubber has caused allergic reactions in individuals 
sensitive to natural latex proteins; therefore, dry natural rubber 
should not be included in the labeling requirement.
    The agency recognizes that there are lower levels of natural latex 
proteins in products produced by the dry natural rubber process. The 
agency, however, does not agree that there is no information to suggest 
that dry natural rubber has caused allergic reactions in individuals 
sensitive to natural latex proteins. To the contrary, there are 
numerous reports that levels of natural latex proteins found in dry 
rubber can cause allergic reactions (Refs. 24 through 27). Accordingly, 
the agency has concluded that it is in the best interest of the public 
health to provide labeling information that a product contains dry 
natural rubber, so that individuals who are sensitive to the levels of 
natural latex proteins found in dry natural rubber may make an informed 
decision regarding the use of the product.
    While the agency believes that persons who may respond to the 
levels of natural latex proteins found in dry natural rubber need to be 
informed of the dry rubber content in a device, the agency does not 
believe that those individuals need to be informed of the health 
consequences associated with dry natural rubber. Because allergy is a 
dose-response phenomenon, persons who may react to natural latex 
protein levels found in dry rubber would have already experienced 
previous allergic reactions to the higher levels of natural latex 
proteins found in natural rubber latex products (see Ref. 28). 
Therefore, those individuals would generally be aware that dry natural 
rubber may cause them to suffer an allergic reaction. Accordingly, FDA 
is requiring that products that contain only dry rubber have labeling 
that informs consumers of the dry rubber content, but is not requiring 
that such products bear labeling that states the potential health 
consequences from the use of the product. Therefore, FDA is requiring 
in the final regulation, Sec. 801.437(e), that devices that contain dry 
natural rubber bear labeling with the following statement: ``This 
Product Contains Dry Natural Rubber.''
    Persons who would not react to the levels of natural latex proteins 
found in dry rubber, but would react to the higher levels of natural 
latex proteins found in natural rubber latex products, however, may 
never have been aware of previous allergic reactions (Ref. 28). These 
persons, therefore, need to be advised of the potential health 
consequences of natural rubber latex products. Accordingly, FDA is 
requiring products containing natural rubber latex to carry labeling 
that states the potential health consequences of such products, as well 
as a natural rubber latex content statement. Therefore, FDA is 
requiring in the final regulation, Sec. 801.437(d), that devices 
containing natural rubber latex have labeling with the following 
statement in bold print: ``Caution: This Product Contains Natural 
Rubber Latex Which May Cause Allergic Reactions.''
    This statement is also required if a device contains both natural 
rubber latex and dry natural rubber that may contact humans. In this 
instance, the single statement will serve to advise a person who may 
not be aware that natural rubber may cause reactions, and will also 
advise a person who is aware of his or her sensitivity to natural 
rubber that the product contains an ingredient that may cause a 
reaction.
    4. Some comments claimed that the applicability of the labeling 
statement to devices that contain natural rubber ``that may directly or 
indirectly contact humans'' is overly broad. One comment suggested that 
the labeling statement be required only on devices that have an 
``intended use'' that may lead to contact with humans. Other comments 
suggested the statement be limited to devices which would directly 
contact tissues.
    The agency does not believe that the application of the labeling 
statement to devices that contain natural rubber ``that may directly or 
indirectly contact humans'' is overly broad. Latex proteins may elicit 
an allergic reaction in individuals who are sensitive to natural 
rubber, even if the proteins are introduced to the individual through 
an indirect route. The agency, however, recognizes that the term 
``indirect contact'' may be interpreted more broadly than the agency 
intends. Therefore, in order to avoid confusion, the agency has 
modified the regulation to require the labeling statements only if the 
natural rubber contacts humans. The final regulation, Sec. 801.437(b), 
defines the term ``contacts humans'' to mean that the natural rubber 
contained

[[Page 51024]]

in a device is intended to contact or is likely to contact the user or 
patient (e.g., latex medical gloves or latex enema tips). This includes 
contact when the device that contains natural rubber is connected to 
the patient by a liquid path or an enclosed gas path (e.g., intervenous 
administration sets, or blood collection or transfusion tubing with 
natural rubber injection ports, injection syringes with natural rubber 
plungers, or natural rubber tubing or connector components used in 
anesthesia or endoscopic insufflator circuits). This also includes 
contact when the device that contains natural rubber is fully or 
partially coated with a powder, and such powder may carry natural 
rubber proteins that may contaminate the environment of the user or 
patient (e.g., latex tourniquets). This definition makes it clear that 
the labeling statement is required on devices that have an intended use 
that could reasonably be expected to introduce natural latex proteins 
to humans.
    5. Several comments suggested that the natural rubber labeling 
statement be expanded to apply to nonmedical natural rubber latex 
gloves and other consumer products that contain natural rubber. Other 
comments suggested that medical devices sold over-the-counter (OTC) to 
the consumer be exempt from the labeling requirements in order to avoid 
confusion regarding the natural rubber-content of other consumer goods 
that would not be subject to this labeling regulation.
    The agency disagrees that the regulation should apply to nonmedical 
natural rubber latex gloves and other consumer products that contain 
natural rubber. The regulation of such products is beyond the scope of 
this rule. FDA's authority under the act to impose labeling 
requirements is restricted to products that meet the definition of 
foods, drugs, cosmetics, animal drugs, biologics, and devices, as those 
terms are defined under the act. This rule applies to devices as 
defined under section 201(h) of the act (21 U.S.C. 321(h)). Under 
section 201(h) of the act, a device is:
    * * * an instrument, apparatus, implement, machine, contrivance, 
implant, in vitro reagent, or other similar or related article, 
including any component, part, or accessory, which is * * * intended 
for use in the diagnosis of disease or other conditions, or in the 
cure, mitigation, treatment, or prevention of disease, in man or 
other animals * * *, and which does not achieve any of its principle 
intended purposes through chemical action within or on the body of 
man or other animals and which is not dependent upon being 
metabolized for the achievement of its primary intended purposes.
    Latex gloves and other products are subject to this rule, only if 
they meet the definition of device under section 201(h) of the act. 
Latex gloves that are not used in the cure, mitigation, treatment or 
prevention of disease are not devices within the meaning of section 
201(h) of the act, and, therefore, are not subject to this rule. Latex 
medical gloves that are subject to this regulation include surgeon's 
gloves, as classified at 21 CFR 878.4460, and patient examination 
gloves, as classified at 21 CFR 880.6250.
    FDA also does not agree with the suggestion that OTC medical 
devices be exempted from the labeling requirements in order to avoid 
confusion with natural rubber products that are not subject to this 
rule. The purpose of the labeling requirement is to provide essential 
information for individuals sensitive to natural latex proteins. An 
individual who is sensitive to natural latex proteins is equally likely 
to react to an OTC device that contains natural rubber, as to a 
prescription device that contains natural rubber. Therefore, it is 
equally important to provide essential information about OTC devices 
that contain natural rubber, as it is to provide information about 
prescription devices that contain natural rubber. Moreover, the agency 
does not believe that labeling, as required by this rule, on OTC 
devices, will cause significant confusion regarding the natural rubber 
content of consumer products that are not devices.
    6. Several comments requested clarification on the applicability of 
the requirements to certain devices. Specifically, the comments asked 
whether the rule would apply to: Bandages with natural rubber in the 
adhesive; natural rubber-free devices packaged in a wrapper using 
natural rubber in the adhesive, especially where the adhesive would 
contact human tissue while unwrapping the device; foods or natural 
rubber-free devices handled or applied with natural rubber latex 
gloves; covered elastic stretch bands used to attach an accessory or 
component to a device; or, devices intended to contact only 
subcutaneous tissue.
    A labeling statement is required for devices that contain natural 
rubber when the natural rubber contacts humans, as described in 
Sec. 801.437(b) of the final rule. Accordingly, devices intended to 
contact subcutaneous tissue would be required to bear the appropriate 
statement.
    Moreover, bandages with natural rubber in the adhesive would 
require the labeling statement. For this product, the natural rubber is 
intended to be applied directly to the skin. If natural rubber-
containing adhesives in tapes, bindings, and similar items are intended 
to contact, or are likely to contact, the user or the patient, they are 
required to be labeled under this regulation. Covered elastic bands 
would not be considered to be in contact with humans, provided the 
covering blocks the migration of natural rubber proteins to the patient 
and user.
    FDA does not believe it would be appropriate to require natural 
rubber labeling statements for natural rubber-free devices or foods 
that may be handled with latex gloves. As described previously in 
comment 5 of this document, requiring natural rubber labeling for 
products, such as foods, that are not devices is beyond the scope of 
this regulation. Moreover, FDA does not believe that requiring products 
that are handled by latex gloves, regardless of whether such products 
could be within the scope of this regulation as devices, is appropriate 
if such products do not contain natural rubber. Requiring labeling on 
products that may or may not come into contact with latex gloves would 
confuse consumers and would be impracticable to implement. Furthermore, 
FDA is not aware of any reports of allergic reactions to rubber-free 
products that latex gloves have contacted.
    Under the final rule, natural rubber-containing packaging adhesives 
that typically are in areas that hold the flaps of packaging together 
would meet the criteria to subject the product to this rule only if 
they contact the patient or user. However, the agency is not aware of 
any evidence or reports of reactions to packaging adhesives. Given the 
pervasiveness of the use of adhesives that contain some amount of 
natural rubber latex, the lack of evidence that these adhesives cause 
adverse reactions, and the ability to open packaging with adhesives 
without coming into contact with the adhesives, the agency concludes 
that the adhesives in device packaging are not intended to contact 
humans and are not likely to contact humans. Therefore, if such 
adhesives are the sole source of natural rubber in the device packaging 
or the device itself, a device with such packaging would not be subject 
to this rule.
    The agency stresses, however, that it considers device packaging to 
be an integral part of a device. Under section 201(h) of the act, a 
device includes any components, parts, or accessories. As an accessory 
to a device, the packaging is a device under section 201(h) of the act. 
A device that contains natural rubber in

[[Page 51025]]

its packaging, beyond that found in the adhesive (e.g., a device 
packaged in a latex sheath) is likely to contact the user or patient 
and must be labeled as containing natural rubber.
    In order to avoid confusion and to clarify to the consumer whether 
it is the device itself or its packaging that contains natural rubber, 
however, the agency believes that a distinct labeling statement is 
appropriate for devices that have packaging that contains natural 
rubber that contacts humans. Accordingly, under Sec. 801.437(f) and (g) 
of the final regulation, such devices shall have labeling with one of 
the following statements: ``Caution: The Packaging of This Product 
Contains Natural Rubber Latex Which May Cause Allergic Reactions.'' or 
``The Packaging of This Product Contains Dry Natural Rubber.''
    The agency notes that if one of these packaging statements is 
required, it shall appear regardless of whether there is a natural 
rubber statement relating to the product itself. For example, a device 
that contains dry natural rubber that contacts humans and is also 
packaged in dry natural rubber that contacts humans shall be labeled 
with both the statements: ``Caution: The Packaging of This Product 
Contains Dry Natural Rubber.'' and ``This Product Contains Dry Natural 
Rubber.''
    7. Several comments suggested that the labeling statements be 
required only on finished medical devices, and that device components 
be exempt.
    The agency agrees in part. The regulation applies to all finished 
devices and components that are intended to contact or are likely to 
contact the user or patient. The labeling statement does not apply to 
components shipped directly to a manufacturer or processor for use in 
the manufacture of a device because these components, during the time 
before distribution to consumers, would not be intended to contact, or 
likely to contact the user or patient. Under these circumstances, the 
parts or components are not accessible to health care workers or 
patients. If, however, a device component is sold directly to a 
consumer, including a patient or health care worker, and it is intended 
to contact or likely to contact a user or patient, it is required to be 
labeled under this regulation, regardless of whether it must be 
attached, inserted, or used in conjunction with other devices. 
Replacement parts marketed as accessories for medical devices that are 
intended to contact or likely to contact a user or patient also require 
the labeling statement.
    8. One comment suggested that in vitro diagnostic devices be exempt 
because only dry natural rubber is used, there is usually no patient 
contact with the natural rubber components, and space is very limited 
for labeling. One comment suggested that other devices that do not 
contact the patient be exempted, regardless of whether the natural 
rubber contacts the tissues of the health care worker.
    The agency believes that in vitro diagnostic devices should be 
exempt only to the extent that the natural rubber used in vitro 
diagnostic devices is not intended to contact or is not likely to 
contact the user or the patient. FDA, however, is requiring labeling 
for such devices if they are intended to contact or are likely to 
contact health care workers or other users, as well as the patient, 
because all latex-sensitive persons who use the device need to be 
informed of the product's natural rubber content.
    9. One comment requested an exemption for the labeling of natural 
rubber latex condoms because such condoms clearly contain latex. The 
comment also believed an exemption should apply to latex condoms 
because space for labeling is limited, a warning regarding allergic 
reactions may have a chilling effect on the use by individuals who are 
not sensitive to natural rubber, and the statement may lead to 
confusion in differentiating between latex and natural skin condoms 
because natural skin condoms also contain some natural rubber latex and 
would require the statement as well.
    The agency disagrees and will require latex condoms to bear a 
labeling statement that the product contains natural rubber latex that 
may cause allergic reactions. Even though consumers may be aware that 
the product contains latex, FDA believes that the additional 
information that natural rubber latex may cause allergic reactions is 
essential information to individuals who are not aware that natural 
rubber latex may cause allergic reactions. The agency believes that 
there is sufficient room on condom packaging for the required 
statement.
    FDA does not believe that the statement will have a chilling effect 
on the use of condoms by individuals who are not sensitive to natural 
latex proteins. The statement, however, would clearly provide important 
information to individuals who are sensitive to natural latex proteins.
    The agency further disagrees with the suggestion that the labeling 
statement would be required on natural skin condoms, and thereby 
confuse consumers with respect to the differences between latex and 
natural skin condoms. Although natural skin condoms do contain a 
natural rubber elastic band, this band is wrapped within the natural 
skin sheath, and there is no evidence to indicate that the natural 
rubber ever contacts the user. Therefore, natural skin condoms that 
have a latex component that is not intended to contact or likely to 
contact the user do not require the labeling statement. Accordingly, 
the absence of any latex labeling requirement for natural skin condoms 
obviates the comments concern about confusion that may result from 
latex labeling statements on both latex and natural skin condoms.
    10. Although most comments supported the requirements of standard 
labeling requirements, some comments suggested that the proposed 
labeling statements were overly prescriptive, and that manufacturers 
should have wide latitude in the wording of the statement provided it 
contain a general latex ingredient statement. Other comments stated 
that the labeling statements did not provide sufficient warnings, and 
suggested that the agency require a caution stating that use of the 
device may lead to chronic asthma, dermatitis, or even anaphylactic 
shock and death.
    The agency does not agree with comments suggesting the labeling 
should state possible reactions with specificity. FDA believes that the 
statement advising consumers that a product may cause an allergic 
reaction is specific enough to provide adequate warning.
    The agency also does not believe that the required labeling 
statements are overly prescriptive and that manufacturers should be 
given wide latitude in the wording of labeling statements. The agency 
has determined that requiring standardized statements for devices 
containing natural rubber is the best approach for providing the 
essential information in a clear, consistent, and accurate manner.
    FDA realizes that there may be some circumstances where it may be 
appropriate to tailor specific information concerning a device. If a 
manufacturer believes use of statements that vary from those prescribed 
by this regulation is appropriate, Sec. 801.437(i) of the final 
regulation provides that the manufacturer may petition the agency for 
an exemption or variance from these requirements by submitting a 
citizen petition under 21 CFR 10.30. Unless the agency has specifically 
granted an exemption or variance, the agency will consider any 
variation from the required statement to be noncompliant, and the 
device will be deemed misbranded.
    11. Several comments suggested that the agency recommend the use of

[[Page 51026]]

natural rubber-free devices, or require a labeling statement that 
nonnatural rubber alternatives are available. In contrast, some 
comments supported natural rubber labeling provided that the label be 
``ergonomically equitable'' (sic) (i.e., not giving natural rubber-free 
devices a perceived advantage).
    The agency does not recommend the use of one legally marketed 
device over another. Rather the agency is requiring that labeling for 
devices that contain natural rubber provide information upon which an 
individual may make an informed choice regarding the use of the device. 
The benefits of devices that contain natural rubber are well 
established, and the agency does not intend to discourage their use by 
persons who are not sensitive to natural rubber. Therefore, the agency 
will not require the labeling statement to recommend the use of rubber-
free devices.
    Furthermore, because the agency is not requiring a statement that 
recommends the use of natural rubber-free devices, the agency does not 
believe that this rule gives natural rubber-free devices an advantage 
over devices that contain rubber. Accordingly, the agency does not 
believe that further modifications to the required statements are 
necessary to address comments that suggested the labeling not give the 
impression that natural rubber-free products have an advantage over 
products that contain natural rubber.
    12. One comment requested clarification on the labeling of 
combination products consisting of drugs that are packaged in device 
container vials with dry natural rubber stoppers.
    This final regulation provides authority to require natural rubber 
labeling on all devices containing natural rubber, including devices 
that are contained within combination products. As discussed in more 
detail in this comment, FDA intends to apply the natural rubber 
labeling requirement to combination products, such as drugs in device 
containers that are regulated currently under drug authorities.
    In a final rule that published in the Federal Register of November 
21, 1991 (56 FR 58754), the agency explained that ``the term 
combination product means a product comprised of two or more different 
regulated entities, e.g., drug, device, or biologic * * *'' or two or 
more different regulated entities that are produced together as a 
single entity, packaged together, or used together to achieve the 
intended effect (see 21 CFR 3.2(e)). The fact that a single product 
contains two or more regulated entities does not in itself change the 
regulatory status of the individual entities.
    Because the entities that comprise a combination product meet more 
than one jurisdictional definition, the agency may apply one or more 
sets of regulatory provisions to the product. The agency, for example, 
has applied both drug and device authorities, and both biological and 
device authorities, to certain combination products. (See Intercenter 
Agreement Between the Center for Drug Evaluation and Research and the 
Center for Devices and Radiological Health (the Drug/Device Agreement 
(Ref. 29)), and Intercenter Agreement Between the Center for Biologics 
Evaluation and Research and the Center for Devices and Radiological 
Health (the Biologics/Device Agreement (Ref. 30)) (hereinafter referred 
to collectively as the Intercenter Agreements).)
    Device container vials with dry natural rubber stoppers, when used 
in combination with a drug product, may be subject to regulation under 
the statutes and regulations applicable to devices. A vial that has a 
natural rubber stopper meets the definition of a device under section 
201(h) of the act, in that such vial is ``an instrument, apparatus, 
implement, machine, contrivance, implant, in vitro reagent, or some 
other similar or related article, including any component, part, or 
accessory * * *'' that is intended to cure, mitigate, treat, or prevent 
disease, which does not achieve any of its principal intended purposes 
through chemical action within or on the body of man or other animals 
and which is not dependent upon being metabolized for the achievement 
of its primary intended purposes. The agency regulates these empty 
vials, as well as other empty drug or biologic containers (such as 
stoppered vials for use in blood collection, intravenous containers, 
and blood bags), as devices.
    When the drug is contained in a vial, however, the result is a 
combination product. The combination status of devices that serve as 
containers for drugs is specifically recognized in the Drug/Device 
Agreement. (See Ref. 29, p. 14.) To date, these combination products 
have been regulated only under the drug authorities (Id).
    The agency intends to require that all combination products that 
contain natural rubber device components be labeled in accordance with 
this regulation. Although the agency could require all combination 
natural rubber products to comply with the regulation on its effective 
date, this regulation will be applied as follows: Natural rubber 
combination products that are currently listed in the Intercenter 
Agreements as being regulated under device labeling provisions will be 
required to comply with this rule on its effective date; natural rubber 
combination products that are listed in the Intercenter Agreements as 
being regulated under drug or biologic labeling provisions, however, 
will be subject to this regulation at the time of the effective date of 
this regulation, or at the time the Intercenter Agreements are amended 
to provide that these types of combination products are subject to this 
labeling regulation, whichever is later. FDA will provide notice in the 
Federal Register of the amendments to the Intercenter Agreements to 
apply this natural rubber labeling provision to all combination 
products that contain natural rubber device components.
    At this time, the agency anticipates that the Drug/Device 
Intercenter Agreement will be amended to reflect that prefilled drug 
vial containers, transdermal patches, infusion pumps, and prefilled 
syringes that presently are regulated under drug authorities are also 
subject to this regulation. The agency believes, however, that this 
requirement will not affect many drug vial containers, because most 
drug stoppers are not being manufactured from dry natural rubber.
    13. A few comments requested clarification on the applicability of 
the requirements to devices already in the marketplace or intended 
solely for export.
    This rule is not intended to require manufacturers to recall any 
devices already in interstate commerce. Therefore, this rule does not 
apply to devices initially introduced or initially delivered for 
introduction into interstate commerce before the effective date of this 
regulation.
    Devices intended solely for export will not be deemed misbranded 
for failure to comply with this regulation provided that the exporter 
meets the criteria of sections 801(e) and 802 of the act (21 U.S.C. 
381(e) and 382). Nevertheless, FDA encourages the application of a 
natural rubber content statement to all exported devices containing 
natural rubber that may contact humans.
    14. A few comments suggested that devices containing less than a 
minimum quantity of natural rubber, the amount to be determined by the 
agency, be exempt from the labeling requirement. One comment suggested 
that devices be labeled with the extractable natural latex protein 
content.
    The agency agrees in principle, however, insufficient information 
currently exists regarding the minimum

[[Page 51027]]

amount of extractable natural latex protein that would not elicit an 
allergic reaction for this option to be practicable. Evidence indicates 
that some persons are reactive to extremely low levels of proteins 
(Ref. 31). The agency is unable to determine what minimum amount of 
natural latex proteins fails to elicit a reaction in some individuals, 
and, therefore, cannot exempt devices containing less than that 
minimum.
    15. Several comments requested clarification on the level of 
packaging that would require a labeling statement. Some comments 
requested additional flexibility in the placement of the statement so 
that the statement may be put on the device labeling other than the 
label, especially where the device label may be too small to carry such 
a statement. Another comment recommended that the statement be required 
not only on the label and in other labeling, but on the device itself 
if the device is dispensed in bulk, as in the case with natural rubber 
latex examination gloves. Other comments suggested that bulk devices 
either remain in the original package in order to preserve the label, 
or that the agency require the user facility to educate and monitor the 
use of bulk devices containing natural rubber. Still another comment 
suggested that where bulk devices are removed to a separate dispensing 
container, the dispensing container also be required to be labeled with 
a natural rubber content statement.
    FDA believes that the required labeling statements may be fitted on 
small labels. Because of the importance of the information contained in 
the labeling statements for individuals sensitive to natural latex 
proteins, the agency will require the appropriate statements concerning 
the natural rubber content of the products to be prominently and 
legibly displayed on all device labels, and other labeling, and to 
appear on the principal display panel of the device packaging, the 
outside package, container or wrapper, and the immediate device 
package, container, or wrapper.
    This means, for example, that the labeling statement for adhesive 
bandages that are individually wrapped and sold in a box would appear 
on each individually wrapped bandage, on the box, and on any individual 
pieces of labeling, such as an instructions for use sheet included in 
the box. Devices packaged and sold in bulk dispensing containers would 
be required to display the appropriate statement on the dispensing 
container, as it is the immediate device container or package.
    If the packaging of a device contains natural rubber, the final 
regulation requires that a separate statement that specifically 
cautions the user that the natural rubber is contained in the packaging 
itself. Statements relating to the natural rubber content of the 
packaging do not have to appear on the same levels of labeling as the 
cautionary statements relating to natural rubber content in the actual 
product. The statements cautioning the user that the packaging contains 
natural rubber shall appear, instead, only on the packaging that 
contains the natural rubber, and the outside package, container, or 
wrapper. Placement of cautionary statements in these locations should 
warn consumers adequately of the possible risks of allergic reactions 
to the packaging, while avoiding the potential for confusion that the 
actual products contain natural rubber.
    FDA believes that requiring devices to remain in their original 
package at the user site, requiring labeling statements on dispensers 
that are sold separately from the natural rubber containing devices, 
and requiring user facilities to provide education concerning latex 
products and to monitor bulk product use, is impracticable and beyond 
the scope of the regulation. Furthermore, because of the potential 
manufacturing difficulties, the agency will not require devices to be 
embossed, imprinted, or otherwise labeled on the individual, unwrapped 
device. The agency believes that the labeling requirements in this 
regulation will provide adequate protection to the users and patients.
    16. The vast majority of comments supported the removal of the 
``hypoallergenic'' claim from the labeling of medical devices that 
contain natural rubber. Those comments that expressed unease about the 
removal of the claim stated that the term does convey meaningful 
information to the user. These comments suggested that an alternative 
term be applied, or that the regulation allow device labeling to state 
that the device presents a reduced potential for sensitizing users to 
natural rubber, or that the device contains less than a specified limit 
of natural latex proteins or processing chemicals as established by the 
agency. One comment stated that, until the agency proves that the tests 
currently employed are insufficient to support the ``hypoallergenic'' 
claim, the claim should be allowed.
    The agency agrees that the term ``hypoallergenic'' provides 
important information to the consumer who is sensitive to processing 
chemicals, but believes that the term ``hypoallergenic'' on products 
containing natural rubber will mislead consumers to conclude 
erroneously that the product may not cause latex protein allergic 
reactions.
    In the past, manufacturers have labeled their products 
``hypoallergenic'' on the basis of results of the modified (human) 
Draize test. While this test may be appropriate for detecting 
sensitivity to residual levels of processing chemicals, the test cannot 
detect the presence of natural latex proteins. Furthermore, current 
manufacturing processes cannot reduce the levels of natural latex 
proteins below that to which some individuals may react.
    The agency disagrees that the ``hypoallergenic'' label should be 
allowed to remain on devices that contain natural rubber until the 
agency proves that the tests currently employed are insufficient to 
support the ``hypoallergenic'' claim, or that claims should be allowed 
regarding reduced levels of latex proteins. The agency has received 
reports of allergic reactions to natural rubber gloves labeled as 
hypoallergenic. Given that the modified (human) Draize Test is not 
designed to detect levels of natural latex proteins that would not 
induce allergic responses, and that the agency is not aware of any 
current manufacturing processes that are designed to remove latex 
proteins below a level that may cause adverse reactions, the agency 
believes that it has sufficient evidence that the tests currently 
employed do not support the claim ``hypoallergenic'' with respect to 
the potential for allergic reactions to natural latex proteins.
    The agency does agree that alternative statements should be applied 
to convey information about devices with reduced residual chemical 
levels to consumers who are sensitive to chemicals. For this reason, 
the agency is developing guidance for manufacturers who want to make 
claims relating to latex devices that have reduced manufacturing 
chemical residues. FDA will announce the availability of this draft 
guidance document entitled ``Testing for Skin Sensitization to 
Chemicals in Latex Products'' in a future issue of the Federal 
Register.
    17. A few comments stated that the reference to the draft guidance 
document entitled ``Testing for Skin Sensitization to Chemicals in 
Latex Products'' in the preamble to the June 24, 1996 proposed rule, 
upon which this final rule is based, was inappropriate because the 
document is still in draft form, while another comment suggested the 
agency reference the draft guidance document in the regulation itself.
    The agency does not believe it is appropriate to incorporate a 
draft guidance document into a regulation. The agency, however, does 
believe that

[[Page 51028]]

it is appropriate to use the preambles of a proposed and final rule 
relating to latex devices to inform the public that the agency is in 
the process of developing a guidance document relating to claims about 
the sensitizing potential of manufacturing chemical residues in latex 
devices.
    18. The vast majority of comments supported the use of a symbol to 
indicate the presence of natural rubber in a device. These comments 
stated that the symbol would promote consumer recognition and could be 
used on devices that have labels that are too small to fit the full 
text of the statement. One comment suggested that the symbol be stamped 
on the actual devices, especially those sold in bulk packages. Some 
comments stated that the symbol should supplement, not replace the text 
of the statement. Those comments not supporting the use of a natural 
rubber symbol cautioned that a symbol should not be used until it is 
universally accepted. Another comment suggested that the agency 
establish the symbol and require its use.
    The agency agrees that a symbol would be useful. The agency 
stresses, however, that any symbol is intended to supplement, not 
replace the required written labeling statements, and its use would be 
voluntary. The agency appreciates the comments and the suggested symbol 
designs that were submitted, but does not believe that there is 
sufficient acceptance of a symbol to require the use of a symbol at 
this time.
    19. Several comments stated that the health benefits of the 
labeling statement are potentially so great that the effective date of 
the requirement should be less than 180 days from the date of 
publication of this final rule. Other comments complained that a 180-
day implementation period is not sufficient to change the labeling on 
the numerous devices affected by this rule. These comments requested at 
least a 12-month implementation period. One of these comments further 
requested that implementation be a two-stage process, and that devices 
containing dry natural rubber not be required to carry the labeling 
statement until 24 months after publication of this final rule. Another 
comment requested a two-stage implementation process so that devices 
that only indirectly contact humans would not be required to carry the 
labeling statement until 36 months after publication, or that such 
devices not be required to carry any labeling statement.
    The agency agrees that the public health concerns relating to 
allergic responses to natural rubber are great. The agency also 
acknowledges, however, that at the time of the publication of this 
regulation, manufacturers have labeling in stock that does not have the 
required statements. In order to minimize the burden to manufacturers 
of discarding labeling that has already been printed, and to allow 
sufficient time to reformat labeling, the agency is providing that the 
effective date of this final rule is 1 year after the date of 
publication. This effective date will allow most manufacturers 
sufficient time, before the effective date of this rule, to exhaust 
their existing supply of labeling stock. If a manufacturer uses the 
existing labeling stock before the effective date of this rule, 
however, FDA encourages manufacturers to add the required labeling 
statement at that time.
    The agency does not believe that a two-stage implementation process 
is necessary, or that a period of longer than 1 year is necessary 
because 1 year should be adequate time to phase in new labeling, and 
reformat the labeling. Furthermore, the agency believes that a longer 
delay in the implementation of this rule would not be in the interest 
of the public health. The comment suggesting that devices that only 
indirectly contact humans not carry any natural rubber labeling 
statement is addressed in comment 4 of this document.
    20. One comment suggested that manufacturers, distributors, and 
user facilities all be responsible for following the labeling 
requirements.
    The agency agrees with the underlying concern that the labeling 
statement remain on devices. It is only necessary, however, to require 
manufacturers to properly label their products to ensure that consumers 
receive appropriate information concerning natural rubber products. 
Distributors and user facilities may not alter the device labeling. Any 
such alteration may be grounds for a charge of misbranding a device 
under sections 201(n) and 502(a), (c), and (f) of the act (21 U.S.C. 
352(a), (c), and (f)).
    21. A few comments complained that the rule could be misinterpreted 
to require labeling on all devices containing any natural rubber 
whatsoever. Others stated that the requirement would have a major 
impact on multinational companies, costing at least $15,000 per device 
for labeling. Another comment stated that the agency underestimated the 
impact of the rule, as each manufacturer will need to draft, review, 
and relabel primary and secondary packages of hundreds, if not 
thousands of devices.
    The agency has clarified the scope of this regulation in order to 
minimize the possibility of misinterpretation. Under final 
Sec. 801.437(b), an appropriate labeling statement is required on 
medical devices that contain natural rubber latex or dry natural rubber 
that contacts humans. The agency does not believe that this rule would 
require relabeling for hundreds or thousands of devices. In fact, the 
agency has only identified approximately 70 generic types of medical 
devices including combination products that are subject to this rule.
    Furthermore, FDA does not agree that this rule will have a major 
impact on multinational companies because it would cost at least 
$15,000 per device for labeling. FDA estimates that the cost to revise 
the labeling would be between $1,000 and $2,000 for each type of device 
that is relabeled. Moreover, the cost of implementing this regulation 
is further minimized because the 1-year effective date of this 
regulation should allow most manufacturers to exhaust their current 
labeling stock prior to using the labeling that is required under this 
regulation.

IV. Paperwork Reduction Act of 1995

    The warning statements required by this regulation are ``public 
disclosure of information originally supplied by the Federal government 
to the recipient for the purpose of disclosure to the public * * *'' (5 
CFR 1320.3(c)(2)). Accordingly, FDA concludes that the labeling 
requirements in this final rule are not subject to review by the Office 
of Management and Budget under the Paperwork Reduction Act of 1995 (44 
U.S.C. 3501-3520).

V. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(11) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-4). Executive Order 12866 directs agencies to assess 
all costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The

[[Page 51029]]

agency believes that this final rule is consistent with the regulatory 
philosophy and principles identified in the Executive Order. In 
addition, the final rule is not a significant regulatory action as 
defined by the Executive Order and so is not subject to review under 
the Executive Order.
    If a rule has a significant economic impact on a substantial number 
of small entities, the Regulatory Flexibility Act requires agencies to 
analyze regulatory options that would minimize any significant impact 
of a rule on small entities. This rule primarily requires a labeling 
change which would not have a significant economic impact on small 
entities. Although this rule will require a labeling change on a 
substantial number of medical devices, manufacturers will be allowed up 
to 1 year after the effective date of this regulation to exhaust their 
existing supply of labeling, therefore, most manufacturers would 
exhaust their existing supply of labels. Moreover, the cost of 
reformatting the labeling, which is $1,000 to $2,000 for each different 
kind of device, is not significant. Accordingly, under the Regulatory 
Flexibility Act (5 U.S.C. 605(b)), the agency certifies that the final 
rule will not have a significant economic impact on a substantial 
number of small entities. Therefore, under the Regulatory Flexibility 
Act, no further analysis is required.

VII. References

    The following references have been placed on display in the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. ``Introduction to Latex Compounding and Processing,'' The 
Vanderbilt Latex Handbook, 3d ed., 1987.
    2. Tomazic, V., T. Withrow, B. Fisher, and S. Dillard, ``Short 
Analytical Review--Latex-Associated Allergies and Anaphylactic 
Reactions,'' Clinical Immunology Immunopathology, 64:89-97, 1992.
    3. Slater, J., and S. Chabra, ``Latex Antigens,'' Journal of 
Allergy and Clinical Immunology, 89:673-678, 1992.
    4. Hamann, C. P., ``Natural Rubber Latex Protein Sensitivity in 
Review,'' American Journal of Contact Dermatitis, 4:1, 4-21, March 
1993.
    5. Turjanmaa, K., ``Incidence of Immediate Allergy to Latex 
Gloves in Hospital Personnel,'' Contact Dermatitis, 17:27-275, 1987.
    6. Turjanmaa, K., K. Laurila, S. Makinen-Kiljunen, and T. 
Reunala, ``Rubber Contact Urticaria-Allergenic Properties of 19 
Brands of Latex Gloves,'' Contact Dermatitis, 19:362-364, 1989.
    7. Turjanmaa, K., and T. Reunala, ``Condoms as a Source of Latex 
Allergen and Cause of Contact Urticaria,'' Contact Dermatitis, 
20:360-364, 1989.
    8. FDA Medical Alert--Allergenic Reactions to Latex-Containing 
Medical Devices, March 29, 1991.
    9. Heese, A., J. Hintzenstern, K-P Peters, H. Koch, and O. 
Hornstein, ``Allergic and Irritant Reactions to Rubber Gloves in 
Medical Health Services,'' Journal of the American Academy of 
Dermatology, No. 5 (Part 1): 831-839, November 1991.
    10. Hintzenstern, J., A. Heese, H. Koch, K-P Peters, and O. 
Hornstein, ``Frequency, Spectrum and Occupational Relevance of Type 
IV Allergies to Rubber Chemicals,'' Contact Dermatitis, 24:244-252, 
1991.
    11. Lahti, A., and K. Turjanmaa, ``Prick and Use Tests With 6 
Globe Brands in Patients With Immediated Allergy to Rubber 
Proteins,'' Contact Dermatitis, 26:259-262, 1992.
    12. Jaeger, D., D. Kleinhans, A. Czuppon, and X. Baur, ``Latex-
Specific Proteins Causing Immediate-Type Cutaneous, Nasal, 
Bronchial, and Systemic Reactions,'' Journal of Allergy and Clinical 
Immunology, 89:759-768, 1992.
    13. Berky, Z., J. Luciano, and W. James, ``Latex Glove Allergy--
A Survey of the U.S. Army Dental Corps,'' Journal of the American 
Medical Association, 268:2695-2697, 1992.
    14. Gonzalez, E., ``Latex Hypersensitivity: A New and Unexpected 
Problem,'' Hospital Practice, pp. 137-151, February 15, 1992.
    15. Stehlin, D., ``Latex Allergies: When Rubber Rubs the Wrong 
Way,'' FDA Consumer, pp. 16-21, September 1992.
    16. ACAI (American College of Allergy & Immunology) Interim 
Recommendations to Health Professionals & Organizations Regarding 
Latex Allergy Precautions, March 1992.
    17. Young, M., M. Meyers, L. McCulloch, and L. Brown, ``Latex 
Allergy--A Guideline for Perioperative Nurses,'' Association of 
Operating Room Nurses Journal, 56:488-502, 1992.
    18. Dias, M., I. Conchon, M. Cortes, F. Pereira, and R. Alonso, 
``Anaphylactic Intraoperative Reaction to Latex,'' Contact 
Dermatitis, 32:305-306, 1995.
    19. Safadi, G. S., T. J. Safadi, G. T. Terezhalmy, J. S. Taylor, 
J. R. Battisto, and A. L. Melton, ``Latex Hypersensitivity: Its 
Prevalence Among Dental Professionals,'' Journal of the American 
Dental Association, 127:83-88, 1996.
    20. Kaczmarek, R. G., B. G. Silverman, T. P. Gross, R. G. 
Hamilton, E. Kessler, J. T. Arrowsmith-Lowe, and R. M. Moore, 
``Prevalence of Latex-Specific IgE Antibodies in Hospital 
Personnel,'' Annals of Allergy, Asthma and Immunology, 76:51-56, 
1996.
    21. Safadi, G. S., E. C. Corey, J. S. Taylor, W. O. Wagner, L. 
C. Pien, and A. L. Melton, ``Latex Hypersensitivity in Emergency 
Medical Service Providers,'' Annals of Allergy, Asthma and 
Immunology, 77:39-42, 1996.
    22. Kibby, T., and M. Akl, ``Prevalence of Latex Sensitization 
in a Hospital Employee Population,'' Annals of Allergy, Asthma and 
Immunology, 78:41-44, 1997.
    23. Marzulli, F. N., and H. I. Maibach, ``The Use of Graded 
Concentrations in Studying Skin Sensitizers: Experimental Contact 
Sensitization in Man,'' Food, Cosmetics, and Toxicology, 12:219-227, 
1974.
    24. Lear, J. T., and J. S. C. English, ``Anaphylaxis After 
Hepatitis B Vaccination,'' Lancet, 345:1249, 1995.
    25. Towse, A., M. O'Brien, F. J. Twarog, J. Braimon, and A. C. 
Moses, ``Local Reaction Secondary to Insulin Injection,'' Diabetes 
Care, 18:1195-1197, 1995.
    26. MacCracken, J., P. Stenger, and T. Jackson, ``Latex Allergy 
in Diabetic Patients,'' Diabetes Care, 19:184, 1996.
    27. Jones, J. M., G. L. Sussman, and D. H. Beezhold, ``Latex 
Allergen Levels of Injectable Collagen Stored in Syringes With 
Rubber Plungers,'' Urology, 47:898-902, 1996.
    28. ``Hypersensitivity Type I,'' Immunology, pp. 19.1-19.18; 
edited by I. M. Roitt, J. Brostoff, and D. K. Male, Grower Medical 
Publishing, Ltd., London, 1985.
    29. Intercenter Agreement Between the Center for Drug Evaluation 
and Research and the Center for Devices and Radiological Health, 
October 31, 1991.
    30. Intercenter Agreement Between the Center for Biologics 
Evaluation and Research and the Center for Devices and Radiological 
Health, October 31, 1991.
    31. Kelly, K. J., K. Viswanath, M. Zacharisen, A. Resnick, and 
J. N. Fink, ``Skin and Serologic Testing in the Diagnosis of Latex 
Allergy,'' Journal of Allergy and Clinical Immunology, 91:1140-1145, 
1993.

List of Subjects in 21 CFR Part 801

    Labeling, Medical devices, Reporting and recordkeeping 
requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 801 is amended as follows:

PART 801--LABELING

    1. The authority citation for 21 CFR part 801 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 507, 519, 520, 701, 704 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
352, 357, 360i, 360j, 371, 374).

    2. Section 801.437 is added to subpart H to read as follows:

Sec. 801.437  User labeling for devices that contain natural rubber.

    (a) Data in the Medical Device Reporting System and the scientific 
literature indicate that some individuals are at risk of severe 
anaphylactic reactions to natural latex proteins. This labeling 
regulation is intended to minimize the risk to individuals sensitive to 
natural latex proteins and protect the public health.
    (b) This section applies to all devices composed of or containing, 
or having packaging or components that are composed of, or contain, 
natural rubber that contacts humans. The term ``natural

[[Page 51030]]

rubber'' includes natural rubber latex, dry natural rubber, and 
synthetic latex or synthetic rubber that contains natural rubber in its 
formulation.
    (1) The term ``natural rubber latex'' means rubber that is produced 
by the natural rubber latex process that involves the use of natural 
latex in a concentrated colloidal suspension. Products are formed from 
natural rubber latex by dipping, extruding, or coating.
    (2) The term ``dry natural rubber'' means rubber that is produced 
by the dry natural rubber process that involves the use of coagulated 
natural latex in the form of dried or milled sheets. Products are 
formed from dry natural rubber by compression molding, extrusion, or by 
converting the sheets into a solution for dipping.
    (3) The term ``contacts humans'' means that the natural rubber 
contained in a device is intended to contact or is likely to contact 
the user or patient. This includes contact when the device that 
contains natural rubber is connected to the patient by a liquid path or 
an enclosed gas path; or the device containing the natural rubber is 
fully or partially coated with a powder, and such powder may carry 
natural rubber proteins that may contaminate the environment of the 
user or patient.
    (c) Devices containing natural rubber shall be labeled as set forth 
in paragraphs (d) through (h) of this section. Each required labeling 
statement shall be prominently and legibly displayed in conformance 
with section 502(c) of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 352(c)).
    (d) Devices containing natural rubber latex that contacts humans, 
as described in paragraph (b) of this section, shall bear the following 
statement in bold print on the device labeling:
    ``Caution: This Product Contains Natural Rubber Latex Which May 
Cause Allergic Reactions.''
This statement shall appear on all device labels, and other labeling, 
and shall appear on the principal display panel of the device 
packaging, the outside package, container or wrapper, and the immediate 
device package, container, or wrapper.
    (e) Devices containing dry natural rubber that contacts humans, as 
described in paragraph (b) of this section, that are not already 
subject to paragraph (d) of this section, shall bear the following 
statement in bold print on the device labeling:
    ``This Product Contains Dry Natural Rubber.''
This statement shall appear on all device labels, and other labeling, 
and shall appear on the principal display panel of the device 
packaging, the outside package, container or wrapper, and the immediate 
device package, container, or wrapper.
    (f) Devices that have packaging containing natural rubber latex 
that contacts humans, as described in paragraph (b) of this section, 
shall bear the following statement in bold print on the device 
labeling:
    ``Caution: The Packaging of This Product Contains Natural Rubber 
Latex Which May Cause Allergic Reactions.''
This statement shall appear on the packaging that contains the natural 
rubber, and the outside package, container, or wrapper.
    (g) Devices that have packaging containing dry natural rubber that 
contacts humans, as described in paragraph (b) of this section, shall 
bear the following statement in bold print on the device labeling:
    ``The Packaging of This Product Contains Dry Natural Rubber.''
This statement shall appear on the packaging that contains the natural 
rubber, and the outside package, container, or wrapper.
    (h) Devices that contain natural rubber that contacts humans, as 
described in paragraph (b) of this section, shall not contain the term 
``hypoallergenic'' on their labeling.
    (i) Any affected person may request an exemption or variance from 
the requirements of this section by submitting a citizen petition in 
accordance with Sec. 10.30 of this chapter.
    (j) Any device subject to this section that is not labeled in 
accordance with paragraphs (d) through (h) of this section and that is 
initially introduced or initially delivered for introduction into 
interstate commerce after the effective date of this regulation is 
misbranded under sections 201(n) and 502(a), (c), and (f) of the act 
(21 U.S.C. 321(n) and 352(a), (c), and (f)).

    Dated: September 22, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-25728 Filed 9-29-97; 8:45 am]
BILLING CODE 4160-01-F