Latex-containing Devices; User Labeling

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 96N-0119]

RIN 0910-AA34

21 CFR Part 801

Latex-containing Devices; User Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the regulations to require all medical devices containing natural

rubber latex that may directly or indirectly contact living human

tissue to be labeled with a statement identifying the product as one

which contains natural rubber latex and which may cause allergic

reactions. The agency is also amending the regulation to require that

hypoallergenicity claims be removed from latex medical gloves and other

natural rubber latex medical devices because the modified human Draize

test currently used to support hypoallergenicity claims addresses only

chemical sensitivity, and it is inappropriate for determining protein

sensitivity in humans. These requirements are being proposed in

response to numerous reports that have been received of severe allergic

reactions to a wide range of medical devices containing natural rubber

latex.

DATES: Comments by September 23, 1996. FDA is proposing that the final

regulation based on this proposal be effective 180 days after the date

of its publication in the Federal Register.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),

Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,

MD 20857.

FOR FURTHER INFORMATION CONTACT: Donald E. Marlowe, Center for Devices

and Radiological Health (HFZ-100), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-443-2444.

SUPPLEMENTARY INFORMATION:

I. Background

Natural rubber latex is a milky fluid produced by the Heavea

brasiliensis (rubber) tree. There is often confusion concerning the

terminology used to describe the raw agricultural material derived from

the rubber tree and the chemical nomenclature that refers to emulsions

of synthetic rubbers and plastics to which natural rubber latex has

been added.

Latex, either natural or synthetic, is a colloidal dispersion of a

polymeric material in a liquid system mostly aqueous in nature (Ref.

1). ``Natural rubber latex,'' for the purpose of this proposed rule,

means a milky fluid that consists of extremely small particles of

rubber, obtained from the H. brasiliensis (rubber) tree, dispersed in

an aqueous medium. It contains a variety of naturally occurring

substances, including carbohydrates, lipids, phospholipids, proteins,

minerals, small amounts of complex organic material, water, and cis-1,4

polyisoprene, in a colloidal suspension.

The phrase ``natural rubber latex'' refers to the raw material used

in the manufacture of both natural rubber latex products and dry

natural rubber products. These products are formed by two commonly

employed manufacturing processes. One of these is the natural rubber

latex manufacturing process (NRL process), which involves the use of

natural latex in a concentrated liquid form. Products are formed from

NRL processing by dipping, extruding, or coating, and are typically

referred to as containing or made of ``natural rubber latex.'' Examples

of devices manufactured by the NRL process include medical gloves,

catheters, and condoms.

The dry natural rubber manufacturing process (DNR process) involves

the use of coagulated natural latex in dried or milled sheets. Products

are formed from the DNR process 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 rubber.''

Examples of devices or device components containing dry rubber include

syringes with dry rubber plungers, vial stoppers, and intravascular

injection ports.

The phrase, ``contains natural rubber latex,'' as used herein,

encompasses products made by either process, as well as products

described as made of ``synthetic latex'' that include natural rubber

latex in their formulations. This proposed rule would not apply to

products made from synthetic latex, which do not include natural rubber

latex in their formulation.

Since 1988, FDA has noted an increase in the number of reports

submitted to its Medical Device Reporting (MDR) system regarding

sensitivity to natural rubber latex proteins contained in medical

devices. In May of 1990, FDA became aware of deaths associated with

barium enema procedures. Further investigation of the problem revealed

that these deaths were associated with anaphylactic reactions to the

natural latex cuff on the tip of the barium enema catheters. In several

hundred reports of adverse reactions to natural rubber latex that the

agency has received since October 1988, 16 have involved deaths from

anaphylactic shock. Furthermore, several scientific journals have

reported incidents of sensitivity to natural rubber latex proteins in a

wide range of medical devices. (See Refs. 2 through 18.)

Section 701(a) of the Federal Food, Drug, and Cosmetic Act (the

act) (21 U.S.C. 371(a)) authorizes FDA to issue substantive binding

regulations for the efficient enforcement of the act. (Weinberger v.

Hynson, Westcott & Dunning, Inc., 412 U.S. 609 (1973); see also

Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973);

National Ass'n of Pharmaceutical Manufacturers v. FDA, 637 F.2d 877 (2d

Cir. 1981); National Confectioners Ass'n v. Califano, 569 F.2d 690

(D.C. Cir. 1978); National Nutritional Foods Ass'n v. Weinberger, 512

F.2d 688 (2d Cir.), cert. denied, 423 U.S. 825 (1975).)

Section 502(a) of the act (21 U.S.C. 352(a)) provides that a device

is misbranded ``If its labeling is false or misleading in any

particular.'' Section 201(n) of the act (21 U.S.C. 321(n)) provides

that, in determining whether labeling of a regulated article (such as a

device) is misleading

* * * there shall be taken into account * * * not only

representations made or suggested by statement, word, design,

device, or any combination thereof, but also the extent to which the

labeling * * * fails to reveal facts material in light of such

representations * * * with respect to consequences which may result

from the use of the article to which the labeling * * * relates

under the conditions of use prescribed in the labeling or

advertising thereof or under such conditions of use as are customary

or usual.

The courts have upheld FDA's authority to prevent false or

misleading labeling by issuing regulations requiring label warnings and

other affirmative disclosures. (See, e.g., Cosmetic, Toiletry, and

Fragrance Association v. Schmidt, 409 F. Supp. 57 (D.D.C. 1976), aff'd

without opinion, Civil No. 75-1715 (D.C. Cir. August 19, 1977), even in

the absence of a proven cause-and-effect relationship between product

usage and harm; Council for Responsible Nutrition v. Goyan, Civil No.

80-1124 (D.D.C August 1, 1980).)

Section 502(f)(1) of the act provides that a device is also

misbranded unless its labeling bears adequate directions for use.

Adequate directions for use means

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adequate directions under which a layperson can use a device safely and

for the purpose for which it was intended. (See 21 CFR 801.5 and

801.6.)

II. Latex Labeling

FDA is proposing that medical devices containing natural rubber

latex that may directly or indirectly contact living human tissue be

labeled with a statement identifying the product as one which contains

natural rubber latex, which may cause allergic reactions. Direct

contact with living human tissue occurs when a natural rubber latex-

containing medical device touches the skin, mucous, or serosal

surfaces. Examples of indirect contact with living human tissue by a

natural rubber latex-containing medical device include, but are not

limited to, the following: Contact with natural rubber latex proteins

that have become suspended in liquid, which can occur when injections

are given through a natural rubber latex-containing injection port or a

syringe with a natural rubber latex-containing plunger; contact with

natural rubber latex protein that is airborne, often in conjunction

with the use of glove dusting powder; and contact with natural latex

residues that have been transferred to nonrubber latex-containing

medical devices, or other objects or surfaces. Devices affected by this

proposed rule would be required to be labeled with one of the following

statements: ``This product contains natural rubber latex which may

cause allergic reactions in some individuals''; ``This product has

components that contain natural rubber latex which may cause allergic

reactions in some individuals''; or ``This product is made from natural

rubber latex which may cause allergic reactions in some individuals''.

The agency has provided three labeling options so that

manufacturers may choose the language most appropriate for their

products. The agency invites comments regarding whether FDA should

require a single, uniform, labeling statement for all natural latex-

containing medical devices, and the agency will consider comments

recommending alternative language for the proposed labeling statements.

Representative examples of natural rubber latex-containing medical

devices which would require such labels include, but are not limited to

the following: Cuffed-barium enema tips and enteroclysis catheters;

contraceptive devices such as condoms with or without spermicidal

lubricant, cervical caps, diaphragms and accessories, and therapeutic

douche apparati; airway and respiratory devices such as oxygen

cannulas, nasopharyngeal airways, tracheal tubes and inflatable cuffs,

tracheobronchial suction catheters, breathing bags and mouthpieces;

dental and surgical equipment such as dental dams, orthodontic

appliances and headgear, anaesthetic gas masks, epistaxis balloons, and

endotracheal tubes; and frequently used hospital equipment such as

urinary catheters and accessories, blood pressure cuffs, intravascular

equipment with latex injection ports, electrode pads, tourniquets,

enema bags, hot or cold water bottles, rubber sheets, stomach and

intestinal tubes, hemodialysis equipment, wound drains, adhesive tape,

elastic bandages, and medical gloves.

Medical gloves include surgeon's gloves, as classified at 21 CFR

878.4460, and patient examination gloves, as classified at 21 CFR

880.6250. Some medical gloves are made of materials that may not

contain natural rubber latex in their formulations and, therefore,

would not be subject to this proposal. It should be further noted that

the term ``medical gloves'' is used to distinguish them from nonmedical

gloves that are not regulated by FDA. Nonmedical gloves, commonly

referred to as utility, industrial, protective, or general purpose

gloves, are not medical devices if they are not intended and/or labeled

for a medical purpose, such as prevention of disease. Such products

would not be subject to this proposed rule.

This rule is being proposed because medical devices that are

composed of natural rubber latex, or which contain components

formulated from natural latex, pose a significant health risk to some

health care consumers and providers. A statement on the label of

medical devices identifying the presence of natural latex, and its

risks, is considered to be necessary for the safe and effective use of

such devices. The primary purpose of such a statement is to inform

health care professionals and consumers about the presence and risks of

natural rubber latex, and to ensure a safe medical environment for

persons who have been identified as sensitive to natural rubber latex.

The agency believes that a statement on the labeling of the devices

stating that the product contains natural rubber latex, and that the

presence of natural rubber latex may cause allergic reactions, is

essential. The omission of such information from the labeling of such a

device would constitute an omission of a material fact, and would

render the device misbranded within the meaning of section 502(a) of

the act (21 U.S.C. 352(a)). Moreover, because users need to be aware of

safety problems that may be caused by natural rubber latex, FDA

believes that a device containing natural rubber latex, which is not

labeled with information regarding the presence of natural rubber latex

and its potential risks, fails to bear adequate directions for use, and

is, therefore, also misbranded under section 502(f)(1) of the act.

Section 502(c) of the act provides that a device is misbranded

``[i]f any word, statement, or other information required by or under

authority of this Act to appear on the label or labeling is not

prominently placed thereon with such conspicuousness (as compared with

other words, statements, designs, or devices, in the labeling) and in

such terms as to render it likely to be read and understood by the

ordinary individual under customary conditions of purchase and use.''

Accordingly, the proposed regulation would require the rubber latex

sensitivity statement to be displayed prominently and conspicuously on

the device labeling. If the labeling statement is not prominently

displayed, the product would be deemed misbranded under section 502(c)

of the act.

Accordingly, under the proposed rule, any natural rubber latex-

containing medical device that is not labeled as required, and that is

initially introduced or initially delivered for introduction into

interstate commerce after the effective date of the final rule, would

be misbranded under sections 201(n) and 502(a), (c), and (f)(1) of the

act.

FDA believes that it is also necessary to prohibit certain labeling

statements on devices that contain natural rubber latex. FDA has

received reports of sensitivity to medical gloves labeled as

``hypoallergenic.'' FDA believes that this term, traditionally used

with cosmetics, erroneously implies that the user of products labeled

as hypoallergenic is assured that the risk of an allergic reaction to

the chemicals or other materials in the products would be minimal. In

the past, use of the ``hypoallergenic'' label has been based on 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 accurately detect the presence or absence of natural

latex protein levels. Furthermore, current manufacturing processes

cannot remove from devices the natural latex proteins below the level

to which some individuals may be sensitive. Thus the risk of allergic

reaction remains.

Therefore, the agency believes that the presence of the term

``hypoallergenic''

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on the labeling of a natural rubber latex-containing device is false

and misleading because it incorrectly implies that the product labeled

as ``hypoallergenic'' may be used safely by latex sensitive persons.

FDA also believes that products with such labeling fail to bear

adequate directions for use because they do not state that rubber

latex-containing products labeled as hypoallergenic may still cause

allergic reactions. For these reasons, FDA is proposing that the

hypoallergenic claim be removed from the labeling of natural rubber

latex-containing medical devices. Accordingly, under the proposed rule,

FDA would consider natural rubber latex-containing medical devices

labeled as hypoallergenic that are initially introduced or delivered

for introduction after the effective date of the final rule, to be

misbranded under section 502(a) and (f)(1) of the act. Although

manufacturers would no longer be permitted to label their rubber latex-

containing devices as ``hypoallergenic,'' persons wishing to make

claims regarding the sensitizing potential of manufacturing chemical

residues (MTB's, thiurams, and carbamates) in finished latex products

should contact the Division of Small Manufacturers Assistance (1-800-

638-2041) and request a copy of the guidance document entitled

``Testing for Skin Sensitization to Chemicals in Latex Products.''

FDA does not intend to require a new submission under section

510(k) of the act (21 U.S.C. 360) (510(k) submission) based upon

labeling changes made to comply with this proposed regulation, provided

that no other changes requiring a new 510(k) submission under 21 CFR

807.81 are made to the device. FDA does not intend to require

manufacturers of devices subject to an approved premarket approval

(PMA) application to submit a PMA supplement under 21 CFR 814.39(d),

for any change to the product labeling that would be required by this

regulation. FDA intends, instead, to require manufacturers to submit an

annual report under 21 CFR 814.39(e) for such changes.

III. Request for Comments

FDA recognizes that this regulation applies to an array of devices

that vary widely in their manufacture and use. FDA welcomes comments on

all aspects of the regulation, but particularly invites comments on the

following areas:

1. Some of the devices to which this regulation applies may be sold

in bulk packages which are then divided up and used individually. How

can FDA best ensure that the message that the regulation is intended to

convey reaches the ultimate user?

2. It has been suggested that the message could be conveyed by

using a symbol, especially on smaller devices. FDA invites comments on

whether using a symbol would be useful, and, if so, what would be an

appropriate symbol?

IV. Exemptions and Variances

Affected persons may request an exemption or variance from the

requirements of this regulation, if they believe that full compliance

with the regulation is not necessary for the safe and effective use of

the device. Requests for exemption or variance must be submitted in

accordance with the requirements for a citizen petition set forth in 21

CFR 10.30.

V. Environmental Impact

The agency has determined under 21 CFR 25.24(e)(2) 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 proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

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 agency believes that

this rule is consistent with the regulatory philosophy and principles

identified in the Executive Order. In addition, the proposed rule is

not a significant regulatory action as defined by the Executive Order

and so is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. This proposed rule primarily requires a labeling

change which would not have a significant economic impact on small

entities, because the 180 days before the final rule based upon this

proposal would become effective will allow most manufacturers to

exhaust their existing supply of labels. Therefore, under the

Regulatory Flexibility Act, no further analysis is required.

VII. Paperwork Reduction Act of 1995

FDA tentatively concludes that the labeling requirements in this

proposed rule are not subject to review by the Office of Management and

Budget because they do not constitute a ``collection of information''

under the Paperwork Reduction Act of 1995 (Pub. L. 104-13). Rather, the

proposed warning statements 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)).

VIII. Comments

Interested persons may submit written comments regarding this

proposed rule, by September 23, 1996, to the Dockets Management Branch

(address above). Two copies of any comments are to be submitted, except

that individuals may submit one copy. Comments are to be identified

with the docket number found in brackets in the heading of this

document. Received comments may be seen in the office above between 9

a.m. and 4 p.m., Monday through Friday.

IX. References

The following references have been placed on display in the Dockets

Management Branch (address above) 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 edition, 1987.

2. Turjanmaa, K., ``Incidence of Immediate Allergy to Latex

Gloves in Hospital Personnel,'' Contact Dermatitis, 17: 27-275,

1987.

3. 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.

4. Turjanmaa, K. and T. Reunala, ``Condoms as a Source of Latex

Allergen and Cause of Contact Urticaria,'' Contact Dermatitis, 20:

360-364, 1989.

5. FDA medical alert--allergenic reactions to latex-containing

medical devices, March 29, 1991.

6. 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.

7. 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.

8. Tomazic, V., T. Withrow, B. Fisher, and S. Dillard, ``Short

Analytical Review-Latex-

[[Page 32621]]

Associated Allergies and Anaphylactic Reactions,'' Clinical

Immunology and Immunopathology, 64: 89-97, 1992.

9. Slater, J. and S. Chhabra, ``Latex Antigens,'' Journal of

Allergy and Clinical Immunology, 89: 673-678, 1992.

10. 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.

11. 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.

12. Berky, Z., J. Luciano, and W. James, ``Latex Glove Allergy--

A Survey of the US Army Dental Corps,'' Journal of the American

Medical Association, 268: 2695-2697, 1992.

13. Gonzalez, E., ``Latex Hypersensitivity: A New and Unexpected

Problem,'' Hospital Practice, pp. 137-151, February 15, 1996.

14. Stehlin, D., ``Latex Allergies: When Rubber Rubs the Wrong

Way,'' FDA Consumer, pp. 16-21, September 1992.

15. ACAI (American College of Allergy & Immunology), Interim

Recommendations to Health Professionals & Organizations Regarding

Latex Allergy Precautions, March, 1992.

16. Young, M., M. Meyers, L. McCulloch, and L. Brown, ``Latex

Allergy-A guideline for perioperative nurses,'' AORN Journal, 56:

488-502, 1992.

17. Hamann, C. P., ``Natural Rubber Latex Protein Sensitivity in

Review,'' American Journal of Contact Dermatitis, 4:1. March 1993,

4-21.

18. 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.

19. USDHHS/PHS/FDA/CDRH, Regulatory Requirements for Medical

Gloves--A Workshop Manual, FDA 93-4257, as amended May, 1993.

List of Subjects in 21 CFR Part 801

Labeling, Medical devices, and 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. New Sec. 801.437 is added to subpart H to read as follows:

Sec. 801.437 User labeling for rubber latex-containing medical

devices.

(a) This section applies to all medical device products composed of

or containing, or having components which are composed of or contain,

natural rubber latex that may directly or indirectly contact living

human tissue. The term ``natural rubber latex'' includes natural rubber

latex, dry rubber, and synthetic latex which contains natural rubber

latex in its formulation.

(b) Data in the Medical Device Reporting System and scientific

literature indicate that some individuals may be at risk of a severe

anaphylactic reaction to natural rubber latex proteins. In order to

protect the public health and minimize the risk to rubber latex

sensitive individuals, medical devices containing natural rubber latex

shall be labeled as set forth in paragraphs (c) and (d) of this

section.

(c) Natural rubber latex-containing medical devices shall

prominently and legibly bear one of the following statements on the

device labeling, in conformance with section 502(c) of the act: ``This

product contains natural rubber latex which may cause allergic

reactions in some individuals''; ``This product has components that

contain natural rubber latex which may cause allergic reactions in some

individuals''; or ``This product is made from natural rubber latex

which may cause allergic reactions in some individuals''.

(d) Because the natural rubber latex proteins to which some

individuals are sensitive cannot be completely removed from latex

gloves, the term ``hypoallergenic'' is inappropriate. Therefore, rubber

latex gloves and other natural rubber latex-containing medical devices

shall not contain the term ``hypoallergenic'' on their labeling.

(e) 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.

(f) Any device subject to this section that is not labeled in

accordance with paragraphs (c) and (d) of this section, and that is

initially introduced or initially delivered for introduction into

interstate commerce after the effective date of this final regulation,

is misbranded under sections 201(n) and 502(a) and (f)(1) of the act.

Any such device that is not labeled in accordance with paragraph (c) of

this section, is also misbranded under section 502(c) of the act.

Dated: June 17, 1996.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 96-15990 Filed 6-21-96; 8:45 am]

BILLING CODE 4160-01-F