[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
