Labeling Declaration for FD&C Yellow No. 6 and FD&C Yellow No. 5; Amendment of Standard of Identity for Cheese Product

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 74, 133, and 201

[Docket No. 92N-0334]

Labeling Declaration for FD&C Yellow No. 6 and FD&C Yellow No. 5;

Amendment of Standard of Identity for Cheese Product

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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

declaration of FD&C Yellow No. 6 in the ingredient list on the labels

of butter, cheese, and ice cream, and on the labels of drug products

administered to mucous membranes, when the color additive is used in

these products. This proposal is based on reports in the literature of

allergic-type reactions to FD&C Yellow No. 6. This proposed action will

not have any effect on the permanent listing of FD&C Yellow No. 6.

Also, FDA is proposing to amend the standard of identity for cold-pack

and club cheese to make it conform to the requirements for listing FD&C

Yellow No. 5 and FD&C Yellow No. 6 on the labels of food that contains

these color additives. In addition, FDA is proposing to amend the

regulation for FD&C Yellow No. 5 to provide for the use of abbreviated

names for this color additive.

DATES: Written comments by October 4, 1995. The agency is proposing

that any final rule they may issue based upon this proposal become

effective 2 years after its publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Aydin Orstan, Center for Food Safety

and Applied Nutrition (HFS-217), Food and Drug Administration, 200 C

Street, SW., Washington, DC 20204, 202-418-3076.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of November 19, 1986 (51 FR 41765), FDA

published a final rule that permanently listed FD&C Yellow No. 6 for

use generally in food, drugs, and cosmetics. At that time, FDA adopted

a requirement that the labeling of food and drug products that contain

FD&C Yellow No. 6 specifically declare the presence of this color

additive (hereafter referred to as the ``labeling requirement''). The

effective date for this labeling requirement was to be November 19,

1987. The agency adopted the labeling requirement based on evidence in

published reports of a relationship between FD&C Yellow No. 6 and

allergic-type responses in some individuals.

FDA received several objections to the labeling requirement,

including objections to its November 19, 1987, effective date;

objections that questioned the validity of the scientific data that the

agency used in assessing the need for the labeling requirement; and an

objection that asserted that FDA had failed to give adequate notice of

the possibility that it might adopt the labeling requirement. None of

the objections requested a hearing.

In the Federal Register of June 8, 1987 (52 FR 21505), FDA

confirmed the effective date of December 22, 1986, for the permanent

listing of FD&C Yellow No. 6. In that document, the agency reaffirmed

the labeling requirement, responded to the objections that it had

[[Page 37612]]

received on the November 19, 1986, final rule, and modified the rule in

response to some of the objections. The major changes to the final rule

that the agency made included extending the effective date of the

labeling requirement to January 1, 1989, and modifying the language of

the labeling requirement.

On October 5, 1987, the Certified Color Manufacturers Association

(CCMA, now the International Association of Color Manufacturers) filed

a petition in the United States Court of Appeals for the District of

Columbia Circuit challenging that portion of the final rule that

required that food labeling declare the presence of FD&C Yellow No. 6.

The issues raised by CCMA were: (1) Whether FDA provided sufficient

notice under the provisions of the Federal Food, Drug, and Cosmetic Act

(the act), FDA regulations, the Administrative Procedure Act, and the

Due Process Clause of the United States Constitution of its intent to

adopt this requirement; and (2) whether this requirement is supported

by the evidence.

On February 29, 1988, CCMA and FDA presented the Court of Appeals

with a stipulation for the voluntary dismissal of the petition. In the

stipulation, FDA agreed to ``issue a Federal Register notice

withdrawing, as a final rule, the labeling requirement set forth at 52

FR 21505, June 8, 1987, and simultaneously publish as a proposed rule a

labeling requirement for FD&C Yellow No. 6.'' This agreement did not

affect the permanent listing of the color additive.

The agency never published a notice of withdrawal for the labeling

requirement set forth in 1987 (52 FR 21505), but in the Federal

Register of December 6, 1988 (53 FR 49138), the agency published a

notice that stated that the labeling requirements for FD&C Yellow No. 6

would not be enforced until further notice.

In November of 1990, Congress passed, and the President signed, the

Nutrition Labeling and Education Act (the 1990 amendments). The 1990

amendments amended section 403(i) of the act (21 U.S.C. 343(i)) to

require the listing by name, as part of the list of ingredients, of

color additives that are subject to certification under section 721(c)

of the act (21 U.S.C. 379e(c)) (section 7 of the 1990 amendments).

However, the 1990 amendments did not change section 403(k) of the act,

which continues to provide that section 403(i) of the act, with respect

to artificial coloring, does not apply in the case of butter, cheese,

or ice cream.

In response to the 1990 amendments, FDA adopted Sec. 101.22(k) (21

CFR 101.22(k)), which became effective on May 8, 1993. Section

101.22(k)(1) requires the label declaration of certifiable color

additives added to foods, while Sec. 101.22(k)(3) states that ``When a

coloring has been added to butter, cheese, or ice cream, it need not be

declared in the ingredient list unless such declaration is required by

a regulation in part 73 or part 74 of this chapter to ensure safe

conditions of use for the color additive.''

Because of literature reports of allergic-type reactions to FD&C

Yellow No. 6, the agency is now proposing to require the declaration of

FD&C Yellow No. 6 on labels for butter, cheese, and ice cream. Because

of these reports, the agency is also proposing to require the

declaration of FD&C Yellow No. 6 as an ingredient when it is used in

drug products that are administered to mucous membranes.

II. Possible Allergic Reactions to FD&C Yellow No. 6

A. Review of Literature

FD&C Yellow No. 6, an azo dye, is defined in Sec. 74.706(a)(1) and

(b) (21 CFR 74.706(a)(1) and (b)). Uncertified FD&C Yellow No. 6 is

commonly known as sunset yellow or sunset yellow FCF. Several published

articles report allergic-type reactions to FD&C Yellow No. 6 (Refs. 1

through 12). One of these, a case study reported by Jenkins et al.

(Ref. 1), was cited as evidence of the allergenic nature of FD&C Yellow

No. 6 in a December 14, 1984, citizen petition concerning provisionally

listed color additives. The agency, in denying that petition, noted

that ``[T]he cited article is an isolated medical case report of an

immunosuppressed, severely ill patient who was observed to experience

gastrointestinal symptoms from sunset yellow powder (presumably

uncertified FD&C Yellow No. 6) taken by mouth.'' The agency stated that

it ``did not consider this single case report to provide a basis for

concluding that FD&C Yellow No. 6 is an allergen.'' This information,

however, together with the structural similarity of FD&C Yellow No. 6

to FD&C Yellow No. 5, which has also been reported to cause allergic-

type reactions, prompted the agency to review all available information

on allergic-type reactions related to the consumption of FD&C Yellow

No. 6.

An early study reported evidence from dermal testing of sensitivity

to FD&C Yellow No. 6 in a patient, but no response was elicited from

administration of the color additive in a double-blind oral challenge

test (Ref. 2). Subsequent studies suggested that patients could develop

urticaria from consumption of azo dyes such as sunset yellow (Refs. 3

and 4). In another study, seven patients with allergic vascular purpura

developed purpura after oral challenge with various azo dyes. One

patient specifically reacted to sunset yellow (Ref. 5). Also, a case

was reported of anaphylactic shock from exposure to FD&C Yellow No. 5

and FD&C Yellow No. 6 in soap used for a cleansing enema. The patient

was reported to be sensitive to both color additives upon subsequent

testing (Ref. 6). However, a double-blind clinical study of 43

asthmatic patients gave negative results for sunset yellow (Ref. 7).

The studies discussed above were questioned by interested parties

in objections to the November 19, 1986, final rule with respect to

their reliability as evidence that would justify label declaration of

FD&C Yellow No. 6. The objections focused on the age of the studies and

the procedures used by the clinicians. However, a more recent

literature search has revealed other studies that were not discussed in

the 1986 final rule.

In 1982, Ibero et al. (Ref. 8) published a study performed on 25

children with food allergy histories. To determine a cause for their

symptoms, they were put through exhaustive tests, including: Case

histories; cutaneous tests; determination of peripheral eosinophilia;

determination of plasma immunoglobulins A, M, and G; determination of

secretory immunoglobulin A in saliva; determination of total and

specific immunoglobulin E against various food antigens; and being fed

diets from which suspected food products were excluded. When these

tests gave negative results, the patients were subjected to oral

provocation with different food additives, including tartrazine and

sunset yellow FCF after 48 hours of exclusion from their diets of dyes,

benzoates, and salicylates. A lactose placebo was used in the study,

but it is not clear whether the study was double-blinded.

Eight out of the 25 children challenged with sunset yellow reacted

positively. Five of these had immediate positive reactions, and three

had ``semi-retarded'' or ``retarded positive'' reactions (terminology

used in the report). The agency is not considering the reported ``semi-

retarded'' or ``retarded positive'' reactions as positive to sunset

yellow because it is unclear what is meant by this terminology.

Although 5 positive reactions out of 25 patients is a large percentage,

the agency

[[Page 37613]]

considers this study to offer only limited evidence of the

allergenicity of FD&C Yellow No. 6 because the report does not give

complete details of the design of the study.

Sweatman et al. in 1986, published a case report of an 8-year-old

girl with oro-facial granulomatosis (Ref. 9). This disease consists of

swelling of the lips and face, frequently with vertical fissures in the

lips and oral mucosal abnormalities. Oro-facial granulomatosis has been

associated with sarcoidosis and Crohn's disease, but these diseases

were ruled out in this case by clinical pathology tests. However, a

double-blind challenge test produced a severe reaction to sunset yellow

and carmoisine, another azo dye. The authors concluded that while these

additives were clearly a cause of her condition, it was likely that

other foods were also involved.

A 1986 study by Supramaniam and Warner focused on food additive

intolerance in a group of children with a history of angioedema or

urticaria (Ref. 10). The children underwent double-blind, placebo-

controlled challenge testing with several food and color additives

including sunset yellow. The additives or placebo were given in 4-hour

intervals, and examinations for skin reactions, temperature changes,

pulse and respiration rates, and peak expiratory flow rate were done at

15-minute intervals. A reaction was judged positive if either urticaria

or angioedema occurred. Of the 36 children who were challenged with

sunset yellow, 10 reacted positively. Although limited information is

given in this paper, the study appears to have been well-conducted and

provides support for the existence of hypersensitivity to FD&C Yellow

No. 6 based on the percentages of children who reacted to sunset

yellow. The investigators did not specify the amounts of the additives

used in the testing protocol, only that smaller quantities of the

additives were used than might be ingested in an estimated maximum

daily intake.

In 1987, Murdoch et al. studied 24 patients with urticaria who were

in remission on an additive-free diet by subjecting them to placebo-

controlled, double-blind outpatient challenge testing with encapsulated

food additives (Ref. 11). Three of the subjects gave positive responses

to at least two separate challenges to azo dyes, with negative

responses after placebo. These three subjects then underwent single-

blind challenge testing in a hospital. One of the three subjects

reacted to sunset yellow both in outpatient and hospital challenge

tests. The subject experienced erythema and pruritus, with significant

increases in plasma histamine levels in the hospital testing. The

agency concludes that this study offers only limited evidence of the

allergenicity of FD&C Yellow No. 6 because the hospital testing was

only single-blinded and not placebo-controlled.

In 1989, Gross et al. reported the case of a physician who

experienced severe abdominal pain and urticaria which required four

hospitalizations within a 2-year period (Ref. 12). Small intestinal

biopsies revealed chronic inflammation and eosinophils. FD&C Yellow No.

6 was the one common additive in all the foods and drugs that were

suspected of causing the problem. The patient was challenged with FD&C

Yellow No. 6 (using 8 milligram capsules) and encapsulated brown sugar

as the placebo in a single-blind test. One capsule was given twice a

day for 4 days. The patient developed abdominal cramps, hives, and

nervousness following the administration of the FD&C Yellow No. 6,

which was given first, but not after placebo. The patient subsequently

underwent a placebo-controlled, double-blind challenge with the

capsules given twice a day for 5 days. Placebo was administered first

with no effect. However, severe abdominal cramps and marked fatigue

occurred when FD&C Yellow No. 6 was administered. The authors concluded

that the patient was suffering from allergic gastroenteritis from FD&C

Yellow No. 6. This study was adequately conducted, and the results

clearly document a case of adverse reaction to FD&C Yellow No. 6.

B. FDA's Tentative Conclusion Concerning Allergenicity of FD&C Yellow

No. 6

In evaluating the reports described above, the agency recognizes

that there are deficiencies in the conduct of some of the clinical

studies (Ref. 13). However, in spite of the limitations of the studies,

the agency tentatively concludes that the available evidence supports

an association of FD&C Yellow No. 6 with allergic-type responses in

susceptible individuals who may be exposed to this color additive in

food, drugs, and cosmetics containing it. Therefore, under section

721(b)(3) of the act, the agency tentatively concludes that the label

declaration of FD&C Yellow No. 6 is necessary as a condition of use to

ensure a reasonable certainty of no harm from the prescribed use of the

color additive for those susceptible individuals.

As discussed previously, Sec. 101.22(k)(1) requires the label

declaration of certifiable color additives, including FD&C Yellow No.

6, added to foods, while Sec. 101.22(k)(3) exempts butter, cheese, or

ice cream from this requirement unless the label declaration is

required for safe conditions of use under part 73 or 74 (21 CFR part 73

or 74). Therefore, the agency is proposing to require that the labels

of butter, cheese, and ice cream disclose when FD&C Yellow No. 6 is

present in the food. Furthermore, the agency is proposing that drug

products administered to mucous membranes that contain this color

additive declare its presence in their labeling. This labeling

requirement, if adopted, will serve to inform the public of the

presence of FD&C Yellow No. 6 in these food and drug products and thus

enable susceptible individuals to avoid it. The knowledge acquired

through labeling of consumer products may also be of assistance when

susceptible individuals patronize places, such as restaurants, where

foods would not ordinarily be labeled.

Label declaration of specific color additives in cosmetics has been

required since May 31, 1976. Thus, no action is required for cosmetics.

III. Label Declaration

A. Food

Section 721(b)(3) of the act provides that regulations for the

listing of a color additive shall ``prescribe the conditions under

which such additive may be safely employed for such use or uses

(including but not limited to,* * * and directions or other labeling or

packaging requirements for such additive).'' As reviewed above in this

document, FD&C Yellow No. 6 has been reported to be associated with

allergic-type responses in humans. Thus, the agency tentatively finds

that the requirement for label declaration of the color additive in

butter, cheese, or ice cream, which are currently exempt from such

declaration under section 403(k) of the act, is justified.

Consumers who may be allergic to FD&C Yellow No. 6 are likely to be

selective of the types of foods that they use and to read ingredient

listings on food labels to avoid the allergic-type reactions to the

color additive. The label declaration of FD&C Yellow No. 6 in human

foods, except butter, cheese, and ice cream, is already required under

Sec. 101.22(k)(1). Accordingly, a label declaration of the presence of

FD&C Yellow No. 6 in butter, cheese, and ice cream, whether added as

the straight color additive, a mixture, or a lake, will enable persons

who may be sensitive to FD&C Yellow No. 6 to avoid unwitting

[[Page 37614]]

exposure to this color additive. Therefore, the agency proposes to

amend Sec. 74.706 to require that the labeling of butter, cheese, and

ice cream that contain FD&C Yellow No. 6 include a declaration of the

presence of this color additive in the list of ingredients.

To minimize the economic impact of imposing this requirement, the

agency is proposing that any final rule that may issue based upon this

proposal become effective 2 years after its publication in the Federal

Register. However, the agency solicits comments on whether a different

effective date is appropriate.

B. Drugs

The use of color additives in drugs for human use is an old,

accepted practice in the pharmaceutical industry. The use of color

additives in drugs serves a necessary public health function because it

permits drugs of identical size and shape to be distinguished. The

distinguishing characteristic provided by the use of color additives is

an important quality control tool in dispensing drugs to prevent mixups

among otherwise similarly appearing products. The ability to

distinguish among products is also important to persons taking more

than one drug, especially to the patient who may think in terms of

taking a drug of a particular color rather than by name of the drug.

Color additives in drugs also assist in the identification of a drug in

cases of accidental overdose.

Because yellow is a primary color, yellow color additives are

widely used in coloring drug products. A substantial number of drug

products would have to be reformulated if FD&C Yellow No. 6 were

prohibited in drugs for human use. If prohibition of FD&C Yellow No. 6

from use in drugs were found to be necessary to protect the public

health, the considerable time and effort necessary to reformulate drugs

and the loss of product identification would be unimportant. However,

on the basis of the available information concerning the nature and

extent of possible intolerance to FD&C Yellow No. 6, the agency

tentatively concludes that prohibiting all drug uses of FD&C Yellow No.

6 is not necessary, and that requiring labeling similar to that for

foods will ensure the protection of patients who may be intolerant of

FD&C Yellow No. 6.

Therefore, the agency is proposing to require label declaration of

FD&C Yellow No. 6 when the color additive is present in prescription

and over-the-counter (OTC) drug products administered orally, nasally,

rectally, or vaginally. Other modes of exposure are not expected to

trigger an allergic response. As discussed in section III.A. of this

document, authority for this action is provided by section 721(b)(3) of

the act, which states that the regulations for the listing of a color

additive shall prescribe the conditions, including directions or other

labeling or packaging requirements, under which the color additive may

be safely used.

In the Federal Register of November 19, 1986 (51 FR 41765) and June

8, 1987 (52 FR 21505), FDA established Secs. 74.1706(c)(2) and

201.20(c) (21 CFR 74.1706(c)(2) and 201.20(c)). These regulations

provided requirements for the label declaration of FD&C Yellow No. 6 in

certain drug products. As discussed in Section I of this document, in

the Federal Register of December 6, 1988 (53 FR 49138), the agency

issued a final rule that suspended Secs. 74.706(d)(2), 74.1706(c)(2),

and 201.20(c) pending further agency action. The agency is now

proposing to adopt these regulations.

Under the proposed Secs. 74.1706(c)(2) and 201.20(c), prescription

and over-the-counter (OTC) drug products administered orally, nasally,

rectally, or vaginally will be required to declare the presence of FD&C

Yellow No. 6 by listing the color additive using the name FD&C Yellow

No. 6. Topical or other externally applied drug products are not

subject to these proposed regulations. If these proposed regulations

are adopted, holders of approved applications for drug products

containing FD&C Yellow No. 6 will be required to describe a labeling

change to comply with the rule in accordance with Sec. 314.70(d)(2) (21

CFR 314.70(d)(2)).

The agency is proposing that any final rule that may issue based

upon this proposal become effective 2 years after its publication in

the Federal Register, the same effective date proposed previously for

labels of butter, cheese, and ice cream containing FD&C Yellow No. 6.

Any drug product that is initially introduced or initially delivered

for introduction into interstate commerce after the effective date

would be misbranded under section 502 of the act (21 U.S.C. 352) if not

in compliance with this proposed rule. However, the agency solicits

comments on whether a different effective date is appropriate.

IV. Conforming Amendments

In the Federal Register of January 6, 1993 (58 FR 2891), the agency

amended the cheese standards in part 133 (21 CFR part 133) to bring

them into conformity with the requirements of the 1990 amendments. For

the declaration of color additives, the amended cheese standards refer

to the applicable sections of 21 CFR parts 101 and 130. However, in

that document, the agency overlooked a provision in the standard of

identity for cold-pack and club cheese (Sec. 133.123) that ``Artificial

coloring need not be declared.'' The agency notes that this provision

is redundant because Sec. 101.22(k)(3) provides that artificial

coloring added to butter, cheese, or ice cream need not be declared

unless such declaration is required by a regulation in 21 CFR part 73

or 74. Furthermore, this provision may create confusion, because, under

Sec. 74.705(d)(2), FD&C Yellow No. 5 is required to be declared in the

ingredient list on the labels of butter, cheese, and ice cream when the

color additive is used in these products, and now the agency is

proposing the same requirement for FD&C Yellow No. 6. Therefore, the

agency is proposing to amend the standard of identity for cold-pack and

club cheese in Sec. 133.123 by removing paragraph (f)(1), that provides

that artificial color need not be declared. With the removal of this

provision, all of the cheese standards will be subject to the labeling

provisions of Sec. 130.3(e) and thus, the requirements of Sec. 101.22

(c) and (k). Moreover, the agency notes that Sec. 133.123(f)(2)

unnecessarily repeats part of the first sentence of Sec. 133.123(f).

Therefore, to make this cheese standard consistent with the other

cheese standards in part 133 and to eliminate this redundancy, the

agency is also proposing to remove Sec. 133.123(f)(2).

Also, the agency is proposing to revise the current labeling

requirement for FD&C Yellow No. 5, which requires that foods that

contain FD&C Yellow No. 5, including butter, cheese, and ice cream,

declare the color additive as ``FD&C Yellow No. 5'' (21 CFR

74.705(d)(2)). The agency's new labeling requirements in

Sec. 101.22(k)(1) allow for the use of abbreviated names of certified

color additives on food labels. For example, FD&C Yellow No. 5 may be

declared either by its full name as ``FD&C Yellow No. 5'' or by an

appropriate abbreviation, such as ``Yellow 5.'' Therefore, to prevent

any confusion over label declaration of FD&C Yellow No. 5, the agency

is proposing to revise Sec. 74.705(d)(2) to state that the labels of

butter, cheese, and ice cream that contain FD&C Yellow No. 5 shall

declare the color additive in accordance with Sec. 101.22(k)(1). The

agency is also proposing to remove the statement ``Foods for human

use'' in the current Sec. 74.705(d)(2), because the 1990 amendments

made it mandatory to declare the certified color additives on labels of

foods for human use, other than butter, cheese, and ice cream, and

[[Page 37615]]

this requirement is already codified in Sec. 101.22(k).

V. Conclusion

FDA has reviewed literature reports providing evidence that FD&C

Yellow No. 6 may cause allergic-type responses in some individuals.

Based on this evidence, the agency tentatively concludes that a label

declaration of the color additive is necessary to ensure that its use

is safe in butter, cheese, and ice cream and in drugs administered to

mucous membranes. Accordingly, the agency is proposing to amend its

regulations by adding Secs. 74.706(d)(2), 74.1706(c)(2), and 201.20(c).

In addition, the agency is proposing to amend the standard of identity

for cold-pack and club cheese (Sec. 133.123) to make it conform to the

requirement that FD&C Yellow No. 5 and FD&C Yellow No. 6 be declared on

the label of this product. Also, the agency is proposing to amend the

regulation for FD&C Yellow No. 5 (Sec. 74.705(d)(2)) to provide for the

use of abbreviated names for this color additive.

VI. References

The following references have been placed on display at 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. Jenkins, P., R. Michelson, and P. A. Emerson, ``Adverse Drug

Reaction to Sunset Yellow in Rifampicin/Isoniazid Tablet,'' Lancet,

385, 1982.

2. Chaffee, F.H., and G.A. Settipane, ``Asthma Caused by FD&C

Approved Dyes,'' Journal of Allergy, 40:65-71, 1967.

3. Michaelsson, G., and L. Juhlin, ``Urticaria Induced by

Preservatives and Dye Additives in Food and Drugs,'' British Journal

of Dermatology, 88:525-532, 1973.

4. Thune, P., and A. Granholt, ``Provocation Tests with

Antiphlogistica and Food Additives in Recurrent Urticaria,''

Dermatologica, 151:360-367, 1975.

5. Michaelsson, G., L. Pattersson, and L. Juhlin, ``Purpura

Caused by Food and Drug Additives,'' Archives of Dermatology,

109:49-52, 1974.

6. Trautlein, J., and W.J. Mann, ``Anaphylactic Shock Caused by

Yellow Dye (FD&C No. 5 and FD&C No. 6) in an Enema (Case Report),''

Annals of Allergy, 41:28-29, 1978.

7. Weber, R.W., M. Hoffman, D.A. Raine, and H. S. Nelson,

``Incidence of Bronchoconstriction Due to Aspirin, Azo Dyes, Non-Azo

Dyes, and Preservatives in a Population of Perennial Asthmatics,''

Journal of Allergy and Clinical Immunology, 64:32-37, 1979.

8. Ibero, M., J.L. Eseverri, C. Barroso, and J. Botey, ``Dyes,

Preservatives and Salicylates in the Induction of Food Intolerance

and/or Hypersensitivity in Children,'' Allergologia et

Immunopathologia, 10:263-268, 1982.

9. Sweatman, M.C., R. Tasker, J.O. Warner, M.M. Ferguson, and

D.N. Mitchell, ``Oro-Facial Granulomatosis. Response to Elemental

Diet and Provocation by Food Additives,'' Clinical Allergy, 16:331-

338, 1986.

10. Supramaniam, G., and J.O. Warner, ``Artificial Food Additive

Intolerance in Patients with Angio-oedema and Urticaria,'' Lancet,

907-909, 1986.

11. Murdoch, R.D., I. Pollock, E. Young, and M.H. Lessof, ``Food

Additive-Induced Urticaria: Studies of Mediator Release During

Provocation Tests,'' Journal of the Royal College of Physicians of

London, 4:262-266, 1987.

12. Gross, P.A., K. Lance, R.J. Whitlock, and R.S. Blume,

``Additive Allergy: Allergic Gastroenteritis Due to Yellow DyeNo.

6,'' Annals of Internal Medicine, 111:87-88, 1989.

13. Center for Drug Evaluation and Research and Center for Food

Safety and Applied Nutrition evaluations of the cited references.

VII. Environmental Impact Determination

The agency has determined under Sec. 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.

VIII. 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 proposed 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 definedby 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. Because of the proposed 2-year compliance period,

the incremental cost of this proposed regulation to manufacturers will

be negligible. Therefore, the agency certifies that the proposed 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.

A. Options Considered

1. No Action

Do not require label declaration of FD&C Yellow No. 6 in butter,

cheese, and ice cream (i.e., maintain the status quo). FD&C Yellow No.

6, however, has been reported to be associated with allergic-type

responses in some individuals. Thus, this option is not considered

viable.

2. Require Label Declaration

The 1990 amendments mandated the inclusion of certified color

additives in the ingredient list on the labels of foods. However,

butter, cheese, and ice cream are exempt from this requirement under

section 403(k) of the act. A substantial number of these products

contain the color additive. To enable susceptible individuals to avoid

possible allergic-type responses to FD&C Yellow No. 6 by alerting these

individuals to the presence of the color additive in these products,

the agency tentatively concludes that label declaration is necessary.

3. Delisting the Color Additive

The benefits of delisting the color additive would not warrant the

costs. The color additive does not pose a significant health hazard to

the general population but does cause allergic-type responses in

certain susceptible individuals.

B. Economic Impact

1. Costs

a. Costs to food industry. The methodology for determining the

costs of food labeling was described in detail in the regulatory impact

analysis of the proposed rules to amend the food labeling regulations

that published in the Federal Register of November 27, 1991 (56 FR

60856). However, the only food manufacturers affected by this

regulation are those who produce butter, cheese, or ice cream, and who

use FD&C Yellow No. 6 as an ingredient in one of these foods. The

proposed effective date of this regulation is 2 years after its

publication in the Federal Register. A 2-year compliance period

generally provides sufficient time to permit use of current stocks of

labeling thus minimizing inventory disposal costs. Also, most

manufacturers of food products typically redesign labels within a 2-

year period. Thus, food manufacturers will be able to incorporate

mandated label changes with regularly scheduled revisions. Therefore,

the incremental cost to food

[[Page 37616]]

manufacturers of this proposed regulation is expected to be negligible.

Manufacturers could, of course, revise their labeling before the

effective date of the regulation, and the agency encourages them to do

so.

b. Costs to the drug industry. There are 815 currently marketed

prescription and OTC drug products that are administered to mucous

membranes (through oral, nasal, rectal or vaginal routes) and that

contain FD&C Yellow No. 6. The cost of printing a drug label is

estimated to be $258 per label. Therefore, the printing cost associated

with this proposed regulation is estimated to be $210,270. FDA assumes

that almost all existing label stocks for drug products will be

depleted by the proposed effective date. Therefore, this proposed

regulation will result in little or no inventory disposal costs.

Administrative costs are estimated to be approximately $850 per firm.

FDA estimates that approximately 113 firms will be affected by this

regulation. Therefore, the administrative costs are estimated to be

$96,050. The total one-time cost to the drug industry of declaring FD&C

Yellow No. 6 on the label is $306,320.

2. Benefits

The benefit of requiring the labeling of FD&C Yellow No. 6 on

butter, cheese, ice cream, and drug products administered to mucous

membranes is ultimately the reduction of allergic-type reactions. FDA

does not have information to quantify the benefits of this proposed

regulation.

C. Summary

FDA has determined that this proposed rule is not a significant

rule as defined by Executive Order 12866. The requirement to include

FD&C Yellow No. 6 on the labels of butter, cheese, ice cream, and drug

products administered to mucous membranes would result in a one-time

cost of about $306,000.

IX. Comments

Interested persons may, on or before October 4, 1995, submit to the

Dockets Management Branch (address above) written comments regarding

this proposal. 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.

List of Subjects

21 CFR Part 74

Color additives, Cosmetics, Drugs.

21 CFR Part 133

Cheese, Food grades and standards, Food labeling.

21 CFR Part 201

Drugs, Labeling, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that the suspension of the effective date of 21 CFR 201.20(c)

at 53 FR 49138, December 6, 1988, be removed and 21 CFR parts 74 and

133 be amended as follows:

PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION

1. The authority citation for 21 CFR part 74 continues to read as

follows:

Authority: Secs. 201, 401, 402, 403, 409, 501, 502, 505, 601,

602, 701, 721 of the Federal, Food, Drug, and Cosmetic Act (21

U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 371, 379e).

2. Section 74.705 is amended by revising paragraph (d)(2) to read

as follows:

Sec. 74.705 FD&C Yellow No. 5.

* * * * *

(d) * * *

(2) Butter, cheese, and ice cream that contain FD&C Yellow No. 5

shall be labeled in accordance with Sec. 101.22(k)(1) of this chapter.

* * * * *

3. Section 74.706 is amended by adding paragraph (d)(2) to read as

follows:

Sec. 74.706 FD&C Yellow No. 6.

* * * * *

(d) * * *

(2) Butter, cheese, and ice cream that contain FD&C Yellow No. 6

shall be labeled in accordance with Sec. 101.22(k)(1) of this chapter.

* * * * *

4. Section 74.1706 is amended by adding paragraph (c)(2) to read as

follows:

Sec. 74.1706 FD&C Yellow No. 6.

* * * * *

(c) * * *

(2) The label of over-the-counter (OTC) and prescription drug

products intended for human use and administered orally, nasally,

rectally, or vaginally containing FD&C Yellow No. 6 shall specifically

declare the presence of FD&C Yellow No. 6 by listing the color additive

using the name FD&C Yellow No. 6. The labels of certain drug products

subject to this labeling requirement that are also cosmetics, such as

antibacterial mouthwashes and fluoride toothpastes, need not comply

with this requirement provided they comply with the requirements of

Sec. 701.3 of this chapter.

* * * * *

PART 133--CHEESES AND RELATED CHEESE PRODUCTS

5. The authority citation for 21 CFR part 133 continues to read as

follows:

Authority: Secs. 201, 401, 403, 409, 701, 721 of the Federal,

Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 343, 348, 371,

379e).

Sec. 133.123 [Amended]

6. Section 133.123 Cold-pack and club cheese is amended by removing

paragraphs (f)(1) and (f)(2).

Dated: July 6, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95-17831 Filed 7-20-95; 8:45 am]

BILLING CODE 4160-01-P