[Federal Register Volume 60, Number 140 (Friday, July 21, 1995)]
[Proposed Rules]
[Pages 37611-37616]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-17831]



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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.

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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