32618 Federal Register / Vol. 61, No. 122 / Monday, June 24, 1996 / Proposed Rules

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.

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
Federal Register / Vol. 61, No. 122 / Monday, June 24, 1996 / Proposed Rules 32619

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 latexcontaining medical device touches the

skin, mucous, or serosal surfaces.

Examples of indirect contact with living

human tissue by a natural rubber latexcontaining 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 latexcontaining 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 latexcontaining 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’’
32620 Federal Register / Vol. 61, No. 122 / Monday, June 24, 1996 / Proposed Rules

on the labeling of a natural rubber latexcontaining 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 latexcontaining 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. MakinenKiljunen, 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-Associated
Federal Register / Vol. 61, No. 122 / Monday, June 24, 1996 / Proposed Rules 32621

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 § 801.437 is added to subpart

H to read as follows:

§ 801.437 User labeling for rubber latexcontaining 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 § 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