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(See Related Information)Federal Register: Natural Rubber-Containing Medical Devices; User Labeling


[Federal Register: September 30, 1997 (Volume 62, Number 189)]

[Rules and Regulations]               

[Page 51021-51030]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr30se97-11]



=======================================================================



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.



-----------------------------------------------------------------------



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





Updated 6/1/1998

horizonal rule

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