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Federal Register / Vol. 71, No.

19 / Monday, January 30, 2006 / Proposed Rules 4839

R–3002G Fort Benning, GA [New] petition submitted by the Center for www.fda.gov/ohrms/dockets/
Boundaries. Beginning at lat. 32°20′15″ N., Science in the Public Interest (CSPI). default.htm and insert the docket
long. 84°58′36″ W.; to lat. 32°15′34″ N., long. With regard to drug products, FDA number(s), found in brackets in the
84°53′11″ W.; to lat. 32°15′32″ N., long. plans to initiate rulemaking to heading of this document, into the
84°54′02″ W.; to lat. 32°15′04″ N., long. implement the Food and Drug ‘‘Search’’ box and follow the prompts
84°55′24″ W.; to lat. 32°14′27″ N., long. Administration Modernization Act of and/or go to the Division of Dockets
84°54′50″ W.; to lat. 32°14′25″ N., long. 1997 (FDAMA) (Pub. L.105–115) Management, 5630 Fishers Lane, rm.
84°56′53″ W.; to lat. 32°14′36″ N., long.
84°56′53″ W.; to lat. 32°14′38″ N., long.
provisions that require declaration of 1061, Rockville, MD 20852.
84°57′56″ W.; to lat. 32°16′36″ N., long. inactive ingredients for drugs. The FOR FURTHER INFORMATION CONTACT:
84°57′58″ W.; to lat. 32°16′36″ N., long. FDAMA provisions have already been Mical E. Honigfort, Center for Food
84°58′35″ W.; to lat. 32°17′39″ N., long. implemented for over-the-counter (OTC) Safety and Applied Nutrition (HFS–
84°58′35″ W.; to lat. 32°17′40″ N., long. drugs. 265), Food and Drug Administration,
84°58′54″ W.; thence to the point of DATES: Submit written or electronic 5100 Paint Branch Pkwy., College Park,
beginning. comments by May 1, 2006. Please see MD 20740, 301–436–1278.
Designated altitudes. Surface to 14,000 feet
section VIII for the effective date of any SUPPLEMENTARY INFORMATION:
Time of designation. Intermittent, 0600– final rule that may publish based on this
Table of Contents
0200 local time daily; other times by NOTAM proposal.
I. Background
6 hours in advance. ADDRESSES: You may submit comments, II. Description of Cochineal Extract and
Controlling agency. FAA, Atlanta identified by Docket No.1998P–0724 Carmine
TRACON. and RIN number 0910–AF12, by any of A. Source and Identity of Cochineal Extract
Using agency. U.S. Army, Commanding the following methods: and Carmine
General, Infantry Center and Fort Benning,
Electronic Submissions B. Uses of Cochineal Extract and Carmine
GA. III. Regulation of Cochineal Extract and
Submit electronic comments in the
* * * * * following ways: Carmine
Issued in Washington, DC on January 24, • Federal eRulemaking Portal: http:// A. The Provisional List of 1960
2006. B. Color Additive Approval of Carmine
www.regulations.gov. Follow the C. Color Additive Approval of Cochineal
Edith V. Parish, instructions for submitting comments. Extract
Manager, Airspace and Rules. • Agency Web site: http:// IV. Allergic Reactions to Cochineal Extract
[FR Doc. E6–1074 Filed 1–27–06; 8:45 am] www.fda.gov/dockets/ecomments. and Carmine
Follow the instructions for submitting A. Descriptions of Allergic Reactions
comments on the agency Web site. B. Adverse Reaction Reports in the
Written Submissions Literature
Submit written submissions in the C. Adverse Reaction Reports in FDA Files
DEPARTMENT OF HEALTH AND following ways: D. CSPI Citizen Petition
HUMAN SERVICES V. FDA Response to the Allergic Reaction
• FAX: 301–827–6870. Reports
• Mail/Hand delivery/Courier [For A. Evaluation of the Allergic Reaction
Food and Drug Administration
paper, disk, or CD–ROM submissions]: Reports
Division of Dockets Management (HFA– B. Options for Action
21 CFR Parts 73 and 101
305), Food and Drug Administration, C. Tentative Conclusions
[Docket No. 1998P–0724, formerly 98P– 5630 Fishers Lane, rm. 1061, Rockville, VI. FDA Response to the CSPI Petition
0724] MD 20852. VII. FDA Proposed Action
To ensure more timely processing of A. Legal Authority
RIN 0910–AF12 B. Food Labeling
comments, FDA is no longer accepting C. Cosmetics Labeling
comments submitted to the agency by e- VIII. Proposed Effective Date
Listing of Color Additives Exempt
mail. FDA encourages you to continue IX. Environmental Impact
From Certification; Food, Drug, and
to submit electronic comments by using X. Analysis of Impacts
Cosmetic Labeling: Cochineal Extract
the Federal eRulemaking Portal or the A. Preliminary Regulatory Impact Analysis
and Carmine Declaration B. Regulatory Alternatives
agency Web site, as described in the
AGENCY: Food and Drug Administration, Electronic Submissions portion of this C. Small Entity Analysis
paragraph. D. Unfunded Mandates
XI. Paperwork Reduction Act of 1995
ACTION: Proposed rule. Instructions: All submissions received
XII. Federalism
must include the agency name and XIII. Comments
SUMMARY: The Food and Drug Docket No(s). and Regulatory XIV. References
Administration (FDA, we) is proposing Information Number (RIN) (if a RIN has
to revise its requirements for cochineal been assigned) for this rulemaking. All I. Background
extract and carmine by requiring their comments received may be posted Cochineal extract is a color additive
declaration on the label of all food and without change to http://www.fda.gov/ that is currently permitted for use in
cosmetic products that contain these ohrms/dockets/default.htm, including foods and drugs in the United States.
color additives. The proposed rule any personal information provided. For The related color additive carmine is
responds to reports of severe allergic detailed instructions on submitting currently permitted for use in foods,
reactions, including anaphylaxis, to comments and additional information drugs, and cosmetics. FDA has listed
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cochineal extract and carmine- on the rulemaking process, see the these color additives, and conditions for
containing food and cosmetics and ‘‘Comments’’ heading of the their safe use, in part 73 of Title 21 of
would allow consumers who are allergic SUPPLEMENTARY INFORMATION section of the Code of Federal Regulations (21 CFR
to these color additives to identify and this document. part 73).
thus avoid products that contain these Docket: For access to the docket to Allergic reactions to cochineal extract
color additives. This proposed action read background documents or and/or carmine in a variety of foods
also responds, in part, to a citizen comments received, go to http:// (grapefruit juice, the alcoholic beverage

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4840 Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules

Campari, a popsicle, candy, yogurt, and protein, and between 5.7 and 6.3 FDA published a provisional list of
artificial crabmeat) and cosmetics (face percent total solid content, and that color additives that included cochineal
blush, eye shadow, eyeliner, and skin carmine contain not less than 50 percent extract in the Federal Register of
products) have been reported in the carminic acid. October 12, 1960 (25 FR 9759). We
scientific and medical literature since Cochineal extract and carmine share provisionally listed cochineal for use in
1961. Since 1994, we have received 11 the same E-number designation in the foods, drugs, and cosmetics on the basis
adverse event reports of allergic European Union, E120. Neither color of prior commercial sale of color
reactions, including anaphylaxis, additive should be confused with the additives which had not been subject to
experienced by individuals after eating unapproved color additive cochineal certification. In the Federal Register of
food or drinking a beverage containing red (E124), a synthetic azo dye that is August 16, 1961 (26 FR 7578) FDA
cochineal extract or carmine, or using sometimes called new coccin, Food Red amended the provisional list to add
cosmetics colored with carmine. We 7, or Ponceau 4R. Carmine also should carmine for use in foods and cosmetics
know of no reports of allergic reaction not be confused with indigo carmine, on the same basis.
to cochineal extract or carmine in drugs. which is certifiable as FD&C Blue No. 2.
B. Color Additive Approval of Carmine
In 1998, we received a citizen petition
B. Uses of Cochineal Extract and
(Docket No. 98P–0724) from CSPI asking On November 9, 1964, we received a
us to take action to protect consumers color additive petition (CAP) that
who are allergic to cochineal extract and Cochineal, carmine, and cochineal requested the permanent listing of
carmine. The CSPI petition, the reports extract have a long history of use. carmine as safe and suitable for use in
from the scientific literature, and the Cochineal originated in Mexico and was or on foods, drugs, and cosmetics. We
voluntarily submitted adverse event used by the ancient Aztecs. It was designated the petition CAP 20 and we
reports provide the factual basis for the discovered there by 16th century published a notice of filing of the
regulatory action we now propose. Spanish explorers, who introduced it to petition in the Federal Register of
Europe and the rest of the world. August 17, 1965 (30 FR 10211).
II. Description of Cochineal Extract and Cochineal was listed in the United
Carmine Permanent listing of carmine for use
States Pharmacopeia from 1831 to 1955 in foods and drugs was supported by
A. Source and Identity of Cochineal and in the National Formulary until safety data and other relevant
Extract and Carmine 1975. information submitted in CAP 20. The
Food uses for carmine include safety data included results of two 90–
Cochineal is a dye made from dried
popsicles, strawberry milk drinks, port day toxicity studies, both in rats. From
and ground female bodies of the scale
wine cheese, artificial crab/lobster these data we calculated an acceptable
insect Dactylopius coccus costa (Coccus
products, cherries in fruit cocktails, and daily intake (ADI) of 25 milligrams per
cacti L.). Powdered cochineal is dark
lumpfish eggs/caviar. Cochineal extract kilogram (mg/kg) or 1,000 parts per
purplish red. The chief coloring
is used in fruit drinks, candy, yogurt, million (ppm) of the daily diet for a
principle in cochineal is carminic acid,
and some processed foods. person, considering a 100–fold safety
a hydroxyanthraquinone linked to a
FDA’s Voluntary Cosmetics factor. The petitioner had reported
glucose unit. Cochineal contains
Registration Program database contains general usage in food products to be
approximately 10 percent carminic acid;
information on the types of cosmetic 0.0025 percent or 25 ppm, and in a few
the remainder consists of insect body
products that contain carmine. selected products as high as 75 to 100
(Cochineal extract is not permitted for ppm. We concluded that if a person’s
Cochineal extract is the concentrated
use as a color additive in cosmetics.) total diet were colored with carmine,
solution obtained after removing the
Carmine has been reported to be used in and if the amounts ingested from drugs,
alcohol from an aqueous-alcoholic
814 formulations including lipsticks, cosmetics, and foods were combined,
extract of cochineal. The chief coloring
blushers, makeup bases, eye shadows, the total ingestion figures would be well
principle in cochineal extract is
eyeliners, nail polishes, hair colors, skin within the margin of safety.
carminic acid. Cochineal extract is
care lotions, bath products, baby CAP 20 also included history-of-use
acidic (pH 5 to 5.5) and varies in color
products, and suntan preparations. information provided in 1965 by several
from orange to red depending on pH.
Carmine is the aluminum or calcium- III. Regulation of Cochineal Extract and companies, both domestic and foreign.
aluminum lake formed by precipitating Carmine These companies either supplied or
carminic acid onto an aluminum used carmine and/or cochineal in food,
hydroxide substrate using aluminum or A. The Provisional List of 1960 drugs, and cosmetics. This history-of-
calcium cation as the precipitant. The The Color Additive Amendments of use information stated that the
carminic acid used to make the lake is 1960 (Public Law 86–618, 74 Stat. 397) companies had received no complaints
obtained by an aqueous extraction of amended the Federal Food, Drug, and during five decades of use. Also, the
cochineal. Carmine is a dark red to Cosmetic Act (the act) to add the companies had received no notification
bright red powder depending on the definition of ‘‘color additive’’ and to of toxicity or allergic reactions from the
amount of carminic acid present. The establish conditions under which color use of the color additives.
lake is only slightly soluble in water, to additives may be safely used. The Color From information in CAP 20, we
which it imparts a red color, and can be Additive Amendments required us to concluded it would not be necessary to
solubilized by strong acids and bases. publish a provisional list of color require the batch certification of
The chemical identity, purity additives that were already in use or carmine. Since carmine is derived from
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specifications, and use restrictions for were certified as color additives prior to a natural source (insects), we concluded
cochineal extract and/or carmine are July 12, 1960. The provisional list was that there would be little likelihood of
provided in § 73.100 (foods), § 73.1100 intended to permit the continued use of contamination with toxic reactants or
(drugs), and § 73.2087 (cosmetics). The the listed color additives for a limited intermediates that would be used in a
regulations require that cochineal time, during which sponsors could synthesis. We also did not set a
extract contain not less than 1.8 percent submit data that established their safety quantitative limitation because we
carminic acid, not more than 2.2 percent and supported their permanent listings. determined that use of the color

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Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules 4841

additive would be economically self- mediated by an antibody, Current testing methods (e.g., skin prick
limiting. immunoglobulin E (IgE). Individuals test (SPT) or in vitro radioallergosorbent
In the Federal Register of April 19, with allergies produce an excess amount test (RAST)) may provide evidence of
1967 (32 FR 6131), FDA published a of IgE antibodies that recognize specific IgE-mediated antibody response to
final rule that permanently listed allergens from food or other substances allergens. However, such testing offers
carmine as a color additive exempt from in the environment. Once formed, these little predictive value for the severity of
certification for use in foods (21 CFR allergen-specific antibodies attach to response. (Ref. 6)
8.317, now § 73.100) and drugs (21 CFR receptors on specialized white blood Most individuals become aware of
8.6009, now § 73.1100). cells (mast cells and basophils), found at their allergy to a specific allergen prior
On June 24, 1977 (42 FR 32228) FDA key interfaces of body contact with to experiencing a severe reaction.
published a regulation permanently foreign substances (e.g., skin, However, once the allergen is identified,
listing carmine as a color additive gastrointestinal and nasorespiratory there are no effective treatment methods
exempt from certification for use in tracts, and blood). The interaction to prevent IgE-mediated reactions from
cosmetics generally, including between an allergen and bound specific occurring. Although treatments are
cosmetics intended for use in the area IgE antibodies at these interfaces available that may limit the severity of
of the eye (§ 73.2087). stimulates these cells to liberate harm from the allergic reaction, they do
histamine and other inflammatory not necessarily eliminate the harm nor,
C. Color Additive Approval of Cochineal mediators involved in the allergic in some cases, stop fatal reactions from
Extract response (Refs. 2 and 3). occurring following exposure to an
On February 14, 1968, we received a Allergic reactions typically manifest allergen (Ref. 6). Fatal reactions have
color additive petition requesting that at the site of allergen contact and vary occurred despite appropriate
we permanently list cochineal extract widely in severity. Signs and symptoms administration of treatment. Thus,
for general use in foods and drugs. We include skin manifestations of flushing, avoidance of the allergen is the only
designated the petition CAP 60 and urticaria (hives), eczema, and method certain to prevent harm and
published a notice of filing in the angioedema (tissue swelling); oral fatal reactions. Reading of labels on
Federal Register of March 15, 1968 (33 manifestations of lip and tongue food, drug, and/or cosmetic products,
FR 4593). swelling and itchiness; gastrointestinal and/or education about potential
Permanent listing of cochineal extract manifestations of stomach cramps, scenarios where contact with allergen-
for use in foods and drugs was nausea, vomiting and/or diarrhea; itchy containing sources could occur, are the
supported by data in CAP 60 which and swollen eye manifestations; cornerstone of risk prevention strategies
showed that cochineal extract was nasorespiratory manifestations of nasal for allergic individuals and their
essentially similar, qualitatively, to congestion and runniness, itchy nose families.
carmine, including the protein fractions. and throat, wheezing, chest tightness Allergens have been identified in
The petition also included information and/or difficulty breathing; and food, drug, and cosmetic products, and
on the long history of use of cochineal cardiovascular manifestations of sensitization (production of IgE
extract and argued that the use of lightheadedness, chest pain, and low antibodies) to allergens may occur
cochineal extract as a color additive in blood pressure. In some cases, a massive through exposure to any or all of these
foods and drugs was comparable to that release of inflammatory mediators can products. Moreover, once sensitized, an
for carmine. lead to a more severe allergic reaction, individual may develop an IgE-
We concluded that the toxicological often termed anaphylaxis, characterized mediated allergic reaction to the
data in CAP 20 could be extrapolated to by multi-organ involvement. allergen by various routes of exposure:
support the safety of cochineal extract. Anaphylaxis can rapidly progress to Topical (in contact with skin or
We further concluded that certification severe respiratory manifestations of mucosa), inhaled, ingested, or
of cochineal extract was not necessary. throat swelling/airway closure or intravenous. Although anaphylaxis can
We also did not set a quantitative cardiovascular collapse/shock that, result from exposure by any route, most
limitation because we determined that without prompt medical management, cases of severe reactions occur when the
use of the color additive would be ultimately result in death. allergen is ingested or injected
economically self-limiting. The allergen type, route of exposure, intravenously. By these routes, allergens
In the Federal Register of December frequency, dose, extent of mediator can be easily absorbed into the systemic
14, 1968 (33 FR 18577), FDA published release, and presence of underlying circulation, leading to life-threatening
illnesses (e.g., asthma) are factors which anaphylaxis in as little as 5 to 15
a final rule that amended the listing
determine the severity of IgE-mediated minutes.
regulation for carmine to include the
allergic reactions (Ref. 4). Based on A range of adverse reactions has been
permanent listing of cochineal extract as
anecdotal reports of food allergic reported to occur from hypersensitivity
a color additive exempt from
reactions and confirmatory oral to foods and cosmetics containing
certification for use in foods (21 CFR
challenge diagnostic studies, minimal carmine or cochineal extract, as well as
8.317, now § 73.100) and drugs (21 CFR
amounts of food allergen can induce from carmine, carminic acid, and
8.6009, now § 73.1100).
allergic reactions in sensitive cochineal extract by themselves. As of
IV. Allergic Reactions to Cochineal individuals (Ref. 5). Although the risk of February 2004, FDA is aware of 35 cases
Extract and Carmine adverse reactions to minimal of hypersensitivity to carmine, carminic
concentrations of allergenic ingredients acid, or cochineal extract published in
A. Descriptions of Allergic Reactions
in drugs and cosmetics would be the scientific and medical literature
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An allergic reaction is characterized expected to be similar to foods, data on and/or reported directly to FDA. Eleven
by an abnormal or exaggerated response the incidence of anaphylaxis resulting of the cases were reported directly to
of the body’s immune system to a from ingestion and/or application of FDA via consumer hotlines, letters, and/
reaction-provoking substance (i.e., drugs and cosmetics is lacking. or MedWatch reports.
allergen), usually a protein (Ref. 1). The There are no tests to predict or Hypersensitivity reactions to carmine,
majority of such responses are determine which allergic individuals carminic acid, or cochineal extract
immediate hypersensitivity reactions are more likely to develop anaphylaxis. include contact dermatitis (4), urticaria/

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4842 Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules

angioedema (9), occupational asthma from 15 minutes to 30 minutes. Two of ingredient list. She also experienced
(10), and systemic anaphylaxis (twelve). the five patients reportedly experienced pruritis and swelling after application of
In more than half of these reports, there ‘‘severe’’ anaphylactic reactions. Of carmine-containing eye shadow. The
is evidence of an IgE-mediated these two, one required hospitalization; second case involved a 42-year-old
diagnostic response (e.g., positive SPT the other was treated with inhalers and woman who experienced multiple
or positive IgE RAST) to carmine and/ intravenous antihistamines. The episodes of facial angioedema and nasal
or its derivatives. In a subset of remaining three experienced congestion after ingestion of crabmeat.
individuals, more specific testing angioedema. She also had severe reactions requiring
identified allergenic proteins in the The five patients demonstrated IgE emergency room visits after ingesting
carmine and/or its derivatives to which sensitization to carmine by SPT and to Campari.
the individuals had been specifically carmine and cochineal extract (provided In 2001, Chung, et al., (Ref. 13)
sensitized. All adverse reactions were by the Campari company) by RAST. described three patients, one with
strongly associated with ingestion, Serum from three patients was also history of anaphylaxis and two with
topical application, or inhalation of tested for specific IgE response to histories of urticaria and/or angioedema
products containing carmine and/or carminic acid. Serum from one of the following ingestion of carmine-
derivatives by the persons making the three (the nonatopic patient) revealed containing foods. The patients’ allergies
reports. Moreover, a subset of sensitized evidence of IgE antibodies directed to carmine were confirmed by
individuals developed adverse reactions against carminic acid. Given their controlled food challenges and SPT to
to a variety of different products previous history of adverse reactions to commercial carmine preparations. Two
containing carmine and/or derivatives. Campari, all five patients refused oral of three patients also had experienced
In addition to the above cases, challenge to carmine. pruritis and erythema after applying
inhalation of carmine and/or derivatives Of particular note in the above study, blush containing carmine.
has been reported to induce an sensitization to carmine was shown to This study also evaluated the protein
immunologic lung disorder, allergic occur in a nonatopic individual. This content of dried pulverized cochineal
extrinsic alveolitis, also known as sensitization was attributed to previous insects and commercial carmine, and
hypersensitivity pneumonitis, in certain use of an eye shadow containing compared and analyzed the specificity
individuals. carmine, from which the patient had of the patients’ sera (reflecting serum
experienced eye itching and skin IgE) to these proteins. Several protein
B. Adverse Reaction Reports in the burning sensation. An SPT result for bands were separated by electrophoresis
Literature this product was positive in the patient. from cochineal insects; none were
The first report of an allergic reaction Thus, this case highlights the separated from commercial carmine.
to carmine was published in 1961 (Ref. probability that an individual, with no Despite the fact that no protein bands
7). The report described a contact previous history of allergy, became were separated from commercial
allergic reaction to a lip salve containing sensitized to carmine from use of carmine, sera from all three patients
carmine, with evidence of positive carmine-containing cosmetics and recognized several protein bands from
patch tests in three affected patients. subsequently experienced a systemic both pulverized cochineal insect extract
Twenty years later an English physician allergic reaction (urticaria and and commercial carmine. Also, using
reported the first case of anaphylactic angioedema) following the ingestion of immunoblotting techniques, addition of
shock from topical exposure to carmine. a food containing carmine. commercial carmine inhibited patients’
In the case of a military recruit involved In 1997, Baldwin, et al., (Ref. 11) sera from recognizing cochineal insect
in a casualty simulation exercise, a reported the case of a 27-year-old proteins. Thus, these results suggest that
makeup stick colored red with carmine woman who experienced anaphylaxis commercial carmine retains
was applied directly to the skin of his within three hours of eating a popsicle proteinaceous material that is
body in the trunk area. Immediately labeled as colored with carmine. The antigenically identical (or similar) to
following application, he went into woman received emergency medical other cochineal insect proteins found in
anaphylactic shock (Ref. 8). care with intravenous fluids, cochineal extract, and that could
Beaudouin, et al., (Ref. 9) published epinephrine and diphenhydramine and potentially induce IgE sensitization or
the first report of anaphylaxis following was briefly hospitalized. Her past response in sensitive individuals.
ingestion of carmine. A 35-year-old medical history included allergic Although one or more such proteins
woman was seen with generalized rhinitis. The woman recalled that her were recognized by the patients’ sera, no
urticaria, angioedema, and asthma that only other known exposure to carmine single protein was recognized by all
began two hours after eating yogurt was when she used a carmine- three patients, making determination of
containing an estimated 1.3 mg of containing face blush. Use of this blush a single allergenic component in
carmine. The woman had positive SPT caused an immediate, pruritic, carmine-derived products not possible
for carmine powder and carmine erythematous eruption when she used it at this time.
colored yogurt. directly on her facial skin but not when Although potentially inconsequential
A 1997 article (Ref. 10) describes she applied it over a face foundation. to regulatory decisions regarding foods,
allergic reactions (including When she was later tested, she exhibited drugs, and cosmetics, carmine has been
anaphylaxis) experienced by five highly positive SPT to the popsicle and noted in reactions associated with
patients after ingesting the alcoholic carmine, but had negative responses to inhalational exposure. Carmine has
beverage Campari, which contains the other components of the popsicle. A been implicated in occupational asthma
carmine. All five patients were women; passive transfer test (which indicates among workers in factories where the
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three had a history of allergic transfer of IgE sensitization) to carmine dye is manufactured or added to
respiratory disease, one had only non- was also positive. products (Refs. 14, 15, and 16) and in
clinical sensitivity to mugwort, and one In 1999, DiCello, et al., (Ref. 12) extrinsic allergic alveolitis (Refs. 17 and
was nonatopic (had no history of described two cases of allergic reaction 18). With regards to occupational
allergy). The time period between to carmine. A 27-year-old woman asthma secondary to inhalation of
ingestion and onset of allergic reaction developed anaphylaxis after ingestion of carmine powder, the first report was
was given for four patients and varied yogurt which listed carmine on the published in 1979 (Ref. 15) in the case

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Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules 4843

of a 54-year-old man who had worked containing carmine and to carmine petitioner specifically requested that we
as a blender of cosmetics. Five years itself. do the following:
after carmine was introduced as a 4. On May 16, 1998, a 50-year-old 1. Immediately require that cochineal
coloring agent, he developed attacks of woman reported having a severe allergic extract and/or carmine be listed by
breathlessness at work, which would reaction within 15 minutes of drinking name in the ingredient lists of all foods,
start within 20 minutes of exposure to a 16 ounce bottle of fruit drink, which drugs, and cosmetics to help protect
the coloring agent. Bronchial was labeled as containing extracts of individuals who know they are sensitive
provocation testing established that cochineal. She experienced swelling in to the colorings;
carmine was responsible for his the area of her eyes and tightness in her 2. Immediately require labeling of
wheezing attacks. He was also tested throat. She was treated and hospitalized animal (insect) origin of cochineal
with an extract of cochineal insects overnight. extract and carmine;
prepared in Coca’s solution; inhalation 5. A 49-year-old woman who had no 3. Undertake or require scientific
of this provoked his asthma. Although other allergies and mild hypertension reviews or studies to determine the
a lung function test suggested pre- reported on August 30, 2000, that she specific allergenic component of
existing emphysema, his attacks were made two visits to an emergency room cochineal extract and carmine and
reproducible when exposed to carmine for treatment of severe anaphylactic whether it could be eliminated from the
powder. A second report of reaction after eating small amounts of coloring, as well as to determine the
occupational asthma secondary to food colored with carmine: Crab soup, prevalence and maximum severity of
inhalation of carmine powder was yogurt, candy, ruby red grapefruit juice, allergic reactions;
published in 1987 (Ref. 16). A 1994 and pasta salad with artificial crabmeat. 4. If necessary, prohibit the use of
study (Ref. 14) demonstrated the She subsequently had a positive SPT to cochineal extract and carmine entirely.
formation of specific IgE antibodies carmine. In support of its requested actions,
against carmine and cochineal extract in 6. An atopic woman around the age of CSPI provided six articles from the
a worker who had developed 50 called to report having experienced scientific and medical literature
occupational asthma. recurrent episodes of swollen eyelids describing adverse reactions to
after consuming jelly or gelatin dessert cochineal extract and/or carmine after
C. Adverse Reaction Reports in FDA containing carmine. At the time of her inhalation of the color additive,
Files call, she had not had an allergic workup ingestion of foods and beverages
Since 1994, we have received 11 regarding her reactions. containing the color additive, or topical
voluntarily submitted reports of allergic 7. A woman reported experiencing an application of products containing the
reactions, including anaphylaxis, allergic reaction she attributed to eating color additive. These articles are
experienced by individuals after eating a custard-style yogurt containing discussed in section IV.B of this
food or drinking a beverage containing carmine. Shortly after eating the yogurt, document.
cochineal extract or carmine or using she experienced an anaphylactic
reaction, with trouble swallowing, V. FDA Response to the Allergic
cosmetics colored with carmine. Reaction Reports
1. On June 20, 1995, a 27-year-old hives, itching, and swelling of the
woman experienced anaphylaxis within eyelids. She was treated by an allergist. A. Evaluation of the Allergic Reaction
3 hours of eating a popsicle labeled as She also reported past sensitivity to eye Reports
colored with carmine. A report of this shadows and other cosmetics which she
The data show that a person may
case was also published in the medical thought contained carmine.
8. A letter from a law firm informed become sensitized and reactive to
literature as described previously (Ref. carmine and cochineal extract from
us of the experience of one of their
11). ingestion, inhalation, or topical
clients indicating that carmine might be
2. On April 22, 1997, a 30-year-old exposure to the color additives.
implicated in allergic reactions. The
woman experienced urticaria, Evidence for this is provided by
firm did not provide any clinical details
angioedema, and respiratory distress published case reports of allergic
but enclosed a copy of a publication on
after consuming ruby red grapefruit reactions to foods containing carmine
carmine allergenicity from the journal
juice with carmine. She had and cochineal extract (Refs. 10, 11, and
experienced similar reactions after 9. On May 2, 2000, a woman reported 12), occupational asthma from exposure
eating purple candy colored with anaphylactic shock from carmine in to carmine (Refs. 15, 16, and 17), and
carmine. She also reported having a skin foods and cosmetics applied to her skin allergic reactions to topically applied
rash after using a purple eye shadow and stated that she carries an injectable cosmetics containing carmine (Refs. 9,
containing carmine. SPT to ruby red medication for treatment when needed. 13, and 14). The data in the published
grapefruit juice, purple candy, purple 10. On September 21, 2000, a woman reports establish that the allergic
eye shadow, and carmine dye were all reported an allergic reaction by her eyes reactions result from IgE-mediated
positive. to an eyeliner containing carmine. antibody response to carmine or
3. A 26-year-old woman experienced 11. In a letter dated March 26, 1999, cochineal extract. The data also
anaphylaxis on July 22, 1997, with a physician reported treating a patient establish that individuals may become
generalized pruritus, urticaria, and who experienced an anaphylactic sensitized and reactive to carmine from
angioedema, after eating custard-style reaction after eating yogurt containing use of cosmetics containing that color
strawberry-banana yogurt containing carmine and had a positive SPT to additive. These same individuals have
carmine. During the episode, she was diluted carmine. been shown to subsequently experience
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found to have an elevated serum more severe allergic reactions, including

tryptase level of 18 (upper limit of D. CSPI Citizen Petition life-threatening IgE-mediated
normal is 13.5), which is indicative of CSPI submitted a citizen petition anaphylaxis, following the ingestion of
massive activation/release of mast cells. (Docket No. 98P–0724), dated August carmine or cochineal extract in foods.
Following the episode, she 24, 1998, requesting that we take action Further evidence is provided in the 11
demonstrated positive SPT to both to protect consumers who are allergic to voluntarily submitted adverse reaction
custard-style strawberry-banana yogurt carmine and cochineal extract. The reports we have received that describe

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4844 Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules

allergic reactions, including extract on the labels of all foods and part 73, FDA also proposes to amend
anaphylaxis, experienced by individuals cosmetics that contain them. We plan to § 101.22(k)(2) to provide that
after eating food or drinking a beverage address prescription drugs in a separate certification-exempt color additives
containing cochineal extract or carmine rulemaking. This labeling requirement need not be declared on the labels of
or using cosmetics colored with will enable sensitized individuals to foods unless such declaration is
carmine. Because events were reported recognize that a product contains required by a regulation in part 73. We
from a population of unknown size, carmine or cochineal extract by reading do not propose to amend § 101.22(k)(3)
estimates of overall frequency of allergy a product’s labeling, and will thereby to require the declaration of cochineal
to these color additives cannot be made. enable those individuals to avoid extract or carmine on the labels of
products that contain the color butter, cheese, and ice cream because
B. Options for Action
additives. This labeling requirement that declaration would be required by
Individuals with known sensitivity to will also enable consumers and health reference to proposed new
carmine or cochineal extract need to care professionals to more quickly § 73.100(d)(2).
avoid products that contain these color identify sensitivities to these color
additives in order to prevent potentially 2. Drugs
life-threatening allergic reactions. There With respect to OTC drugs,
are several possible ways to accomplish 1. Foods § 201.66(c)(8) (21 CFR 201.66(c)(8))
this. One way is to prohibit use of There is currently no requirement that requires the outside container or
carmine and cochineal extract in all the presence of cochineal extract or wrapper of the retail package, or the
foods, drugs, and cosmetics. A second carmine be declared in food labeling. immediate container label if there is no
way is to identify and eliminate the Section 403(i) of the act (21 U.S.C. outside container or wrapper, to contain
allergenic component of carmine and 343(i)) requires that a food label declare a listing of the established name of each
cochineal extract. If an allergen is a the ingredients in the food, using the inactive ingredient. If the OTC drug
contaminant of the color additive, rather common or usual name of the product is also a cosmetic, then the
than the coloring principle, then FDA ingredient. However, this section allows inactive ingredients must be listed in
can set additional limiting the food label to designate certification- accordance with specific provisions of
specifications in the regulations for the exempt color additives as coloring §§ 701.3(a) or (f) (21 CFR 701.3(a) or (f))
color additives and, if necessary, require without naming the additives. The and 21 CFR 720.8, as applicable.
certification for each batch of carmine implementing regulation, § 101.22(k)(2) Therefore, whether the OTC drug is or
and cochineal extract to ensure (21 CFR 101.22(k)(2)), permits label is not also a cosmetic, there is a
compliance with these specifications. A declaration of a certification-exempt preexisting regulatory requirement for
third way is to require declaration of the color additive with a general phrase declaration of inactive ingredients,
presence of these color additives on the such as ‘‘Artificial Color,’’ ‘‘Color including carmine and cochineal extract
labels of all foods, drugs, and cosmetics. Added,’’ or some other equally under § 201.66(c)(8). Failure to comply
informative term that makes it clear that with this regulation would render an
C. Tentative Conclusions a color additive has been used in the OTC drug misbranded and subject to
We have tentatively concluded that it food. enforcement action under section 502(c)
is unnecessary to prohibit the use of Section 403(k) of the act requires that of the act (21 U.S.C. 352(c)).
carmine and cochineal extract in all a food that bears or contains any Furthermore, section 412 of FDAMA
foods, drugs, and cosmetics. Although artificial coloring must bear labeling amended the misbranding provisions in
the color additives have been shown to stating that fact, but states that the section 502(e) of the act to require
produce allergic responses in certain provisions of this section and of section declaration of inactive ingredients for
sensitized individuals, there is no 403(i) described previously do not apply drugs, including prescription drugs. We
evidence of a significant hazard to the to butter, cheese, or ice cream. Section plan to initiate a separate rulemaking to
general population when the color 101.22(k)(3) states that color additives implement these FDAMA provisions.1
additives are used as specified by the need not be declared on the labels of
3. Cosmetics
color additive regulations in part 73. butter, cheese, and ice cream unless
We have also tentatively concluded such declaration is required by a Cosmetics that are offered for retail
that requiring additional testing to regulation in part 73 or 21 CFR part 74. sale are subject to the labeling
identify and remove the allergenic We have reviewed published and requirements of § 701.3. Section 701.3(a)
component in carmine and cochineal submitted reports describing allergic requires that the labels of cosmetics
extract would do little to protect the responses to food products containing offered for retail sale bear a declaration
health of individuals sensitive to those cochineal extract or carmine. These of the name of each ingredient in
additives because: (1) Given evidence reports are sufficient to demonstrate a descending order of predominance,
that different people appear to react to hazard to the health of consumers who except that the individual ingredients of
different components of the color are sensitive to the color additives. fragrances and flavors are not required
additives, it may not be technically or Therefore, we tentatively conclude that to be listed and may be identified
economically feasible to identify and the labels of all foods containing together as ‘‘fragrance’’ or ‘‘flavor.’’
reduce the allergenic component of cochineal extract or carmine should However, § 701.3(f) permits color
carmine and cochineal extract to a low declare the presence of those color additives to be declared as a group at
enough level so that it would no longer additives in the ingredient statements as
1 These provisions of FDAMA have already been
induce an allergic response in sensitized a condition of safe use. To that end, we
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implemented for OTC drugs as described in the

individuals; and (2) additional testing propose the following amendments. preceding paragraph. See 64 FR 13254, 13263
and the rulemaking required to FDA proposes to amend § 73.100(d) (March 17, 1999). Note also that current 21 CFR
implement the results of the testing by adding new paragraph (d)(2) to 200.100(b)(5) requires the label of a prescription
would delay our resolution of the issue require the declaration of cochineal drug that is not for oral use (such as a topical or
injectable drug) to bear the names of inactive
for sensitive individuals. extract and carmine on the labels of all ingredients, but permits certain color components
Instead, FDA proposes to require foods. Because § 101.22(k)(2) does not to be designated as ‘‘coloring’’ rather than being
declaration of carmine or cochineal refer to any labeling requirements in specifically named.

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Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules 4845

the end of the ingredient statement, 1. CSPI requested that FDA unnecessary to ensure the safe use of
without respect to order of immediately require that cochineal cochineal extract and carmine in foods,
predominance. extract and carmine be listed by name drugs, and cosmetics for the majority of
Cosmetics that are manufactured and in the ingredient lists of all foods, drugs, consumers in the general public. Thus,
sold for use only by professionals, and cosmetics. we have not undertaken and we do not
called ‘‘professional-use-only’’ products, We believe that requiring the propose to require the requested
are not subject to the requirements of declaration of cochineal extract and scientific reviews or studies.
§ 701.3 and thus need not bear carmine would provide sensitized 4. CSPI requested that, if necessary,
ingredient labeling. Cosmetic products consumers with the information needed FDA prohibit the use of cochineal
that are gifts or free samples also need to avoid products that contain those extract and carmine entirely.
not bear ingredient labeling. color additives. For the reasons stated in As noted previously, we have
Professional-use-only products section V of this document, FDA tentatively concluded that it is
include: (1) The makeup used in proposes to require the declaration of unnecessary to prohibit the use of
photography studios and by makeup carmine and cochineal extract on the cochineal extract and carmine in foods,
artists for television, movie, and theater labels of all foods and cosmetics, and drugs, and cosmetics. Although the
actors/actresses, (2) products intended plans to address drugs in a separate color additives have been shown to
for use only by professionals in beauty rulemaking. produce allergic responses in certain
salons, skin care clinics, and massage 2. CSPI requested that FDA sensitized individuals, there is no
therapy shops, and (3) camouflage immediately require labeling of animal evidence of a significant hazard to the
makeup dispensed by physicians and (insect) origin of cochineal extract and general population when the color
aestheticians to clients with skin carmine. additives are used as specified by the
conditions such as scarring. We do not believe requiring the color additive regulations in part 73.
Cosmetics that are gifts or free declaration of animal (insect) origin of Requiring declaration of carmine and
samples need not bear ingredient cochineal extract and carmine in the cochineal extract on the labels of all
labeling because they are not intended labeling of products containing these foods and cosmetics will enable
for retail sale as consumer commodities. color additives is necessary. FDA has sensitized individuals to inform
However, in the case of a gift that is tentatively concluded that the proposed themselves of the presence of the color
actually a ‘‘gift-with-purchase,’’ we have labeling requirement will provide additives by reading a product’s label
stated in our trade correspondence (Ref. sensitized consumers sufficient and will thereby enable the individuals
19) that the ‘‘gift’’ is not considered a information to avoid products to avoid those products that contain
free gift per se, because it can only be containing these color additives. carmine or cochineal extract. Thus, we
obtained by consumers who purchase Furthermore, information on the
do not propose to prohibit the use of
the product to which the gift is attached. origin of these color additives is readily
cochineal extract and carmine.
Therefore, such a ‘‘gift’’ must currently available to those consumers who want
bear a complete ingredient declaration it. This information is provided in VII. FDA Proposed Action
on the label of the package in standard dictionaries under the
A. Legal Authority
accordance with the requirements of definitions for the words ‘‘cochineal’’
§ 701.3. and ‘‘carmine.’’ This information is also The legal authority for the regulations
We have reviewed published and provided in the color additive prescribing the safe use of color
submitted reports of allergic responses, regulation governing use of cochineal additives in foods, drugs, and cosmetics
including anaphylaxis, to cosmetic extract and carmine in foods ( § 73.100). comes from section 721(b) of the act (21
products that contain carmine. Thus, we do not propose to require U.S.C. 379e(b)). Under section 721(b),
Furthermore, we have discussed the labeling of animal (insect) origin of FDA has the authority to prescribe
possibility that consumers sensitized to cochineal extract and carmine. conditions, including labeling
carmine from use of cosmetics 3. CSPI requested that FDA undertake requirements, under which a color
containing that color additive may or require scientific reviews or studies additive may be safely used. Products
subsequently experience more severe to determine the specific allergenic containing color additives that are not
allergic reactions, including component of cochineal extract and used in compliance with the color
anaphylaxis, from ingestion of carmine carmine, and whether it could be additive regulations are adulterated
or cochineal extract in foods. We have eliminated from the color additives, as under sections 402(c) (foods), 501(a)(4)
tentatively concluded that all cosmetic well as to determine the prevalence and (drugs), or 601(e) (cosmetics) of the act
products should declare the presence of maximum severity of allergic reactions. (21 U.S.C. 342(c), 351(a)(4), and 361(e),
carmine in their labeling. Therefore, We could not identify the specific respectively). We have concluded that
FDA proposes to amend § 73.2087 to allergenic component in carmine and cochineal extract and carmine may
require declaration of carmine on the cochineal extract from our review of the cause potentially severe allergic
labels of cosmetics that are not subject published literature, except to state that responses in humans. Thus, we believe
to the requirements of § 701.3. The it is likely to be of insect origin. One label information about the presence of
amended regulation will require that the study we reviewed found that no these color additives in all foods and
cosmetics specifically declare the universal protein was recognized by cosmetics is necessary to ensure their
presence of carmine prominently and patients known to be allergic to carmine safe use. We note that, with respect to
conspicuously at least once in the and that it remains unclear whether the OTC drugs, declaration of inactive
labeling and will provide the following allergenic component consists of ingredients is already required under
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statement as an example: ‘‘Contains proteins from the cochineal insects or a § 201.66(c)(8), and we plan to initiate a
carmine as a color additive.’’ protein-carminic acid complex. We rulemaking to implement the FDAMA
believe that additional scientific reviews provisions that require declaration of
VI. FDA Response to the CSPI Petition or studies to determine the specific inactive ingredients for drugs, including
FDA’s response to the actions allergenic components of cochineal prescription drugs.
requested in the CSPI petition is as extract and carmine may be helpful if Additional legal authority for
follows: successful; however, they would be requiring disclosure of a coloring that is,

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4846 Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules

or that bears or contains, a food allergen cumulatively have a significant effect on the additives as ingredients in their
comes from section 403(x) of the act. the human environment. Therefore, products. In the case of cosmetics, the
Under that section, a coloring neither an environmental assessment proposal would require firms to declare
determined by regulation to be, or to nor an environmental impact statement the presence of carmine on products not
bear or contain, a food allergen must be is required. subject to the requirements of § 701.3
disclosed in a manner specified by (e.g., professional-use-only products or
X. Analysis of Impacts
regulation. free gifts). Cosmetics which are
A. Preliminary Regulatory Impact consumer commodities and subject to
B. Food Labeling Analysis the requirements of § 701.3 are already
FDA proposes to amend the color We have examined the economic required to list carmine as an ingredient.
additive regulation (§ 73.100) that implications of this proposed rule as Although we discuss these costs as
permits the use of cochineal extract or required by Executive Order 12866. though they accrued to the affected
carmine in foods by adding new Executive Order 12866 directs agencies firms, these costs are actually social
paragraph (d)(2) to require that all food to assess all costs and benefits of costs that firms may pass on to
(including butter, cheese, and ice cream) available regulatory alternatives and, consumers via higher product prices,
that contains cochineal extract or when regulation is necessary, to select depending on market conditions. The
carmine specifically declare the regulatory approaches that maximize costs would be greatest for firms
presence of the color additive by its net benefits (including potential currently producing products
respective common or usual name, economic, environmental, public health containing these additives and for firms
‘‘cochineal extract’’ or ‘‘carmine,’’ in the and safety, and other advantages; that begin using these additives in
ingredient statement of the food label. distributive impacts; and equity). existing products after the final rule
Failure to adhere to this requirement Executive Order 12866 classifies a rule based on this proposal has taken effect
would make any food that bears or as significant if it meets any one of a but before their next regularly
contains cochineal extract or carmine number of specified conditions, scheduled label change. Costs would be
adulterated under section 402(c) of the including having an annual effect on the greatest for these firms because they
act. economy of $100 million, adversely would need to change labels before their
FDA also proposes to amend affecting a sector of the economy in a next regularly scheduled label redesign,
§ 101.22(k)(2) of the food labeling material way, adversely affecting and they may lose some inventory of
regulations to disallow generic competition, or adversely affecting jobs. already printed labels. The costs would
declaration of color additives for which A regulation is also considered a be much smaller for firms that begin
individual declaration is required by significant regulatory action if it raises using these color additives in new
applicable regulations in part 73. novel legal or policy issues. We have products that are introduced after the
Currently, that paragraph allows any determined that this proposed rule is final rule based on this proposal has
certification-exempt color additive to be not an economically significant taken effect and for firms that begin
declared in a generic way as ‘‘Artificial regulatory action as defined by using these additives in existing
Color’’ or ‘‘Artificial Color Added,’’ Executive Order 12866. products after their next regularly
rather than by its specific common or scheduled label redesign after the final
usual name. B. Regulatory Alternatives rule based on this proposal has taken
We considered the following effect. Costs would be much smaller for
C. Cosmetics Labeling these firms because they could
regulatory alternatives in this analysis.
FDA proposes to amend the color We request comments on these and any incorporate the requirements of this rule
additive regulation (§ 73.2087) other plausible alternatives: (1) Take no in their label design during their label
permitting the use of carmine in action; (2) take the proposed action; (3) design phase, and they would not lose
cosmetics to require that cosmetics take the proposed action, but make the label inventory. The costs for these
containing carmine that are not subject effective date later; (4) take the proposed firms would be the loss of otherwise free
to the requirements of § 701.3 action, but make the effective date label space. These costs would be
specifically declare the presence of sooner; or (5) ban carmine and minimal because this rule requires the
carmine prominently and conspicuously cochineal extract. use of only a small portion of the total
at least once in the label or labeling. The available label space.
amended regulation will provide the 1. Option One: Take No Action Firms would respond in one of two
following statement as an example: We treat the option of taking no action ways to the increased costs of using
‘‘Contains carmine as a color additive.’’ as generating neither costs nor benefits. carmine and cochineal extract. First,
Including this requirement in the color We use this option as the baseline in firms might use these additives and
additive regulations will make any comparison with which we determine label products containing these
cosmetic that contains carmine and that the cost and benefits of the other additives as required by the final rule
does not declare its presence on the options. Any favorable or unfavorable based on this proposal. Second, firms
label adulterated under section 601(e) of results from taking no action will be might decide not to use these additives
the act. captured in the costs and benefits of the or to delay using them until after their
other options. next regularly scheduled label change.
VIII. Proposed Effective Date Firms would decide which action to
2. Option Two: Take the Proposed take based on estimated profits, which
The proposed effective date for any
Action would vary with changes in consumer
final rule that may issue based on this
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proposal is 2 years after its date of a. Costs. This proposed rule would demand for the relabeled or
publication in the Federal Register. increase the cost of using cochineal reformulated products, the costs of
extract and carmine in foods and some relabeling or reformulating, and changes
IX. Environmental Impact cosmetics because it would require in consumer demand resulting from
The agency has determined under 21 firms using these substances to list them changes in product prices. We assume
CFR 25.30(k) that this action is of a type on product labels. In the case of foods, in this analysis that the required
that does not individually or the proposal would require firms to list labeling would not significantly reduce

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demand because relatively few cosmetics which are not subject to the We used the average labeling costs of
consumers are sensitive to these color requirements of § 701.3: (1) the other NAICS categories to estimate
additives. (If the required labeling did Professional-use only products, the costs for the NAICS categories that
significantly reduce demand, then we including, makeup used in photography did not appear in the labeling cost
would need to distinguish the costs of studies and television, movies, and program.
firm activity that result from changes in theater; makeup used by professionals We then reduced the estimated
the costs of using carmine and cochineal in beauty salons, skin care clinics, and labeling costs for some of the NAICS
extract from the costs of firm activity massage therapy shops; and camouflage categories based on information from
that result from changes in product makeup given by physicians and U.S. Census Bureau industry reports
demand. The former would represent estheticians to clients with skin based on the 1997 economic census. We
social costs; the latter would represent conditions such as scarring; (2) free made these corrections only on those
distributive effects.) In addition, we samples or gifts, if not linked to a NAICS categories for which we were
assume that all firms would relabel purchase. We already require all other unable to limit the product categories to
rather than reformulate because cosmetics to declare the presence of the most relevant products using the
relabeling is generally much less costly color additives on the label. product categories provided in the label
than reformulating. Based on this list of products, the cost model.
For foods and cosmetics, we For Seafood Canning (311711), we
most relevant product categories and
estimated relabeling costs using a model assumed that the primary type of
NAICS codes appearing in the labeling
developed by Research Triangle product that might contain carmine or
cost program are as follows: Fluid Milk
Institute (RTI) under contract to FDA. cochineal extract is surimi (imitation
(311511), yogurt and flavored milk
This model estimates labeling costs crab). This product comprised about 9
portion only; Ice Cream and Frozen percent of the total value of shipments
based on the length of the compliance
Dessert Manufacturing (311520); for this NAICS code (Ref. 20). Therefore,
period (that is, the length of time we
Commercial Bakeries (311812) bakery we estimated that the labeling costs
give firms to comply with the
snacks, pies, and cakes only; Frozen would be 9 percent of the estimated
requirements of the final rule upon
Cakes, Pies, and Other Pastries costs for the entire NAICS code.
publication of the final rule), the parts
Manufacturing (311813); Cookies and We made a similar correction to the
of the label that are affected, and the
Cracker Manufacturing (311821), cost estimates for Fresh and Frozen
North American Industry Classification
cookies only; Flour Mixes and Dough Seafood Manufacturing (311712). The
System (NAICS) codes or descriptions of
the type of products. The label cost Manufacturing from Purchased Flour Census report did not provide the value
model does not cover cosmetics, so we (311822), baking mixes only; Chocolate of shipment figures for fresh surimi
estimated relabeling costs for cosmetics and Confectionery Manufacturing from products in order to avoid disclosing
by extrapolating from the data on food. Cacao Beans (311320); Nonchocolate data on individual companies. However,
The proposed effective date for this Confectionery Manufacturing (311340); the report included the data in higher
rule will be 24 months following the Fruit and Vegetable Canning (311421) level totals. Therefore, we estimated an
publication of the final rule. The rule juices, jams/jellies/preserves, fruit, and upper bound on the size of the value of
will affect only the ingredient list for tomato products only; Specialty shipments for fresh surimi products by
most affected products. We estimated Canning (311422) entrees, side dishes, subtracting off from the total value of
the labeling costs for cosmetic products and soup only; Dried and Dehydrated shipments all of the value of shipments
based on the costs of changing the Foods (311423), soup only; Spice and of the categories for which the report
ingredient lists for the relevant product Extract Manufacturing (311942), spices provided data. We did not need to use
types that appeared in the label cost and seasonings only; Other Snack Food this approach for frozen surimi products
model. We do not know the number of Manufacturing (311919) except because the report provided data on
food products or cosmetics that contain unpopped popcorn; Seafood Canning those products. Using these figures, we
carmine or cochineal extract. According (311711); Fresh and Frozen Seafood estimated that surimi products
to industry literature, these additives are Manufacturing (311712); Frozen comprised a maximum of 8 percent of
technically suitable for use in a wide Specialty Food Manufacturing (311412); the total value of shipments for this
variety of food including dairy products Mayonnaise, Dressing, and Other NAICS code (Ref. 21).
such as ice cream and yogurt; popsicles; Prepared Sauce Manufacturing For Meat Processed from Carcasses
baked goods including doughnuts, (311941), vinegar only; Frozen Fruit, (311612), we assumed that the primary
bakery mixes, cones, and fruitcake; Juice, and Vegetable Manufacturing types of products that might contain
confections and candy including (311411), juice concentrate only; and carmine or cochineal extract are canned
chewing gum base, hard candies, soft- Soft Drink Manufacturing (312111) meat and sausage. These products
toffee/caramel, and gum types/jellies; carbonated beverages and non-fruit comprised about 34 percent of the total
fruit fillings and puddings, jellies, and drinks only; and All Other value of shipments for this NAICS code
gelatin dessert; canned cherries; Miscellaneous Food Manufacturing (Ref. 22).
seasonings; snacks; canned meat (311999) baking ingredients, drink For Distilleries (312140), we assumed
products; pork sausage; surimi (artificial mixes, desert toppings, gelatin that the primary types of product that
crabmeat); soup and soup mixes; tomato puddings, syrups, and side dishes only. might contain carmine or cochineal
products; vinegar; beverages and fruit- In addition, the following relevant extract are bottled cordials and liqueurs.
based drinks; fruit-based liquors; and NAICS codes do not appear in the These products comprised about 13
syrups. All of the food products featured labeling cost program: Retail Bakeries percent of the total value of shipments
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in the adverse event reports that we (311811); Confectionery Manufacturing for this NAICS code (Ref. 23).
discussed previously in this preamble from Purchased Chocolate (311330); For Toilet Preparation Manufacturing
fall into one of these categories. Carmine Flavoring Syrup and Concentrate (325620), we assumed that the primary
is also suitable for use in a variety of Manufacturing (311930); Meat types of product that might contain
cosmetics, including lipsticks, blushes, Processed from Carcasses (311612); carmine or cochineal extract is
and eye shadows. However, this rule Distilleries (312140); and Toilet cosmetics (lip, eye, and blushers). These
affects the following categories of Preparation Manufacturing (325620). products comprised about 11 percent of

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the total value of shipments for this involving adverse events in the United responses in general. In a study done
NAICS code (Ref. 24). States involving carmine or cochineal under contract to FDA, RTI estimated
For Retail Bakeries (311811), we extract in food or cosmetics that we the value of avoiding a severe allergic
assumed that the primary product types identified in the literature and in our response to be approximately $58,000
product that might contain carmine or FDA files. The other 11 cases did not (Ref. 29). This estimate was based on a
cochineal extract are cakes, cookies, contain information on the labeling of quality adjusted life year of
doughnuts, pies, and other sweet goods the product that caused the reaction or approximately $200,000. We have
(sweet rolls, coffeecake, pastries, involved products that were already revised our estimate of a quality
Danishes, muffins, etc.). These products labeled as containing carmine or adjusted life year to a range of $100,000
comprised about 32 percent of the total cochineal extract. to $500,000 (68 FR 41489, July 11,
value of shipments for this NAICS code The first of these events occurred in 2003). Therefore, we have adjusted the
(Ref. 25). May 1994. The last of these events estimate of the value of avoiding a
We do not have information on the occurred in 2001. However, our severe allergic response to a range of
proportion of those products that are literature search covered the period up between $26,000 and $132,000. This
suitable to contain carmine or cochineal to February 2004. estimate accounted for the probability of
extract that actually contain those color Passive reporting systems generally death or coma due to a severe allergic
additives and that do not already list capture only a small fraction of adverse response; however, it did not account
them on the ingredient list. However, events. The actual fraction of adverse for medical costs. Severe reactions
the proportion of products that contain events captured by those systems is involve anaphylaxis and typically
these additives is probably only a small difficult to estimate because it depends require hospitalization and often
portion of the total number of suitable on a number of factors, including public emergency room care. These
products. Therefore, we assumed that and physician awareness of a problem, hospitalizations typically last 48 hours
between 1 percent and 10 percent of the the timing of press releases and other to 72 hours. One nationwide study
products in the most relevant product actions, the degree to which the adverse found the mean cost of a hospital stay
categories actually contain carmine and events are considered unusual or for a severe allergic reaction involving
cochineal extract and do not already notable, and the severity of the adverse respiratory symptoms to be
voluntarily list these substances in the events. Estimates of reporting rates for approximately $6,500 (Ref. 30).
ingredient list. Under these particular type of problems under these Therefore, we estimate the average total
assumptions, we estimate the one-time types of systems tend to range from cost of a severe allergic reaction to
labeling costs to be approximately $0 about 10 percent to less than 1 percent carmine or cochineal extract to be
million to $3 million. (Refs. 26, 27, and 28). The reporting rate approximately $33,000 to $139,000. We
b. Benefits. This rule would generate for adverse events involving allergic have two estimates of the value of
health benefits by reducing the number responses to products containing avoiding a mild allergic response $54
of adverse events involving cochineal unlabeled carmine would be probably and $437 (Ref. 29). The average of these
extract and carmine via two potential be toward the low end of the scale two estimates is about $250.
pathways: (1) Consumers who know because it would be difficult for Six of 14, or 43 percent, of the adverse
they are sensitive to these color consumers or physicians to relate the events reports involving food and
additives would be better able to avoid problem to carmine or cochineal extract cosmetics involved severe adverse
products containing these color if those substances were not listed on events that required emergency
additives, and (2) consumers and health the product package. Therefore, we treatment or hospitalization. We assume
care professionals would be able to assume that we are aware of only about that the same proportion of unreported
more quickly identify sensitivities to 1 percent of the adverse events adverse events would be severe. Under
these color additives. In addition to the involving these products. Under this the assumption that about 43 percent of
health benefits, this rule would allow assumption, we estimate that 300 adverse event are severe, and based on
consumers who know they are sensitive adverse events involving these the estimated number of adverse events
to these color additives to consume substances may have occurred between eliminated by this rule and the
products that they may otherwise avoid May 1994 and February 2004 (a estimated value of avoiding severe and
because of uncertainty over whether the reporting period of 9 years and 9 mild allergic reactions, we estimate the
products contain these color additives. months) involving products covered by potential annual health benefits of this
We have identified three adverse this rule, containing these additives, rule to be between $0 million and $2
events from the FDA files and the and not already listing these additives million. The total discounted value of
literature that involved products on the ingredient list. This corresponds this stream of health benefits at a
containing carmine or cochineal extract to an annual rate of 31 adverse events. discount rate of seven percent is
in which those color additives did not We do not have sufficient information between $1 million and $26 million. We
or probably did not appear on the to estimate the percentage of these are unable to quantify the non-health
ingredient list. All three cases involved adverse events that this rule would benefits of this rule for consumers who
crabmeat. In one case, we know that eliminate. However, the reports know they are sensitive to these
these additives did not appear on the involving products that already list substances and who would be able to
product label. In the other two cases, we these ingredients on the ingredient list consume some products that they might
do not have information on whether the suggest that this type of labeling will not currently avoid because of uncertainty
additives appeared on the labels or not. eliminate all of these adverse events. over whether the products contain these
However, our experience is that Therefore, we assume that this rule additives.
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crabmeat containing carmine or would eliminate between 10 percent

cochineal extract rarely indicates these and 90 percent of these cases. 3. Option Three: Take the Proposed
additives in the ingredient list. Although we do not have estimates of Action, but Make the Effective Date
Therefore, we assumed that these the value of avoiding severe and non- Later
additives did not appear on the product severe allergic reactions to carmine and Increasing the compliance period to
label in these two cases. These three cochineal extract, we do have estimates 36 months would reduce the cost of
cases are part of a group of 14 cases of avoiding severe and mild allergic revising labels because more firms could

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Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules 4849

time the revisions to coincide with another substance, that one could best b. Benefits. Banning these additives
regularly scheduled label changes. We describe carmine or cochineal extract as would generate health benefits by
estimated that the cost of revising labels a non-critical minor ingredient, that eliminating the possibility that sensitive
under Option 2 would be $0 million to firms would find that discrimination consumers would ingest these
$3 million under a 24-month testing was sufficient to gauge consumer substances. These health benefits would
compliance period. Therefore, the cost acceptance of the new formulations, and be greater than the health benefits of
of revising labels under a 36-month that firms would not need to perform Option Two because they would
compliance period would be $0 million any analytical or consumer sampling include all of the adverse events
to some amount less than $3 million. tests. We estimated reformulation costs eliminated under Option Two as well as
However, delaying the effective date using the same approach that we used some additional adverse events
would also reduce benefits. For to estimate labeling costs, except that involving people who do not yet realize
example, if we set the effective date to we were unable to estimate they are sensitive to these additives or
36 months, then we would eliminate the reformulation costs for Commercial who realize they are sensitive to these
$0 million to $2 million in benefits that Bakeries (311812) bakery snacks, pies, additives but fail to read the ingredient
would have taken place in months 24 to and cakes only using the reformulation list. In particular, this option would
36 under Option Two. The ranges of cost model. Therefore, we based our eliminate cases of the type captured in
estimated cost and benefit reductions estimate of the reformulation costs for the 11 adverse event reports discussed
overlap. Thus, we have insufficient that product category on the average previously that involved food or
information to determine if this option reformulation cost for the product type cosmetics containing carmine or
would generate higher or lower net categories that appeared in the cochineal extract in which these color
benefits than Option Two. reformulation cost model. The estimated additives probably appeared on the
one-time total reformulation cost was $3 product label. The reporting rate for
4. Option Four: Take the Proposed
million to $1,390 million. adverse events involving products that
Action, but Make the Effective Date In addition to the one-time are labeled as containing carmine or
Sooner reformulation costs, this option may cochineal extract should be significantly
Decreasing the compliance period also increase the costs of producing higher than reports rates for adverse
would increase the cost of revising affected products or reduce the value events involving products that are not
labels because fewer firms could time that consumers place on those products. so labeled. Therefore, we assumed that
the revisions to coincide with regularly However, one cannot infer that these the reporting rate for labeled products is
scheduled label changes. For example, results would necessarily occur based approximately 10 percent. Based on this
based on the labeling cost model that we on the current use of these additives assumption, this option would prevent
discussed under Option Two, we because the one-time costs of 42 annual adverse events and generate
estimate that the costs of this rule under reformulation might have led firms to annual health benefits of approximately
a compliance period of 12 months continue using these additives even $1 million to $3 million. The total
would be approximately $3 million to though substitutes existed that were discounted value of this stream of
$55 million. The estimated costs under equally costly and did not reduce the health benefits at a discount rate of 7
Option Two were $0 million to $3 value that consumers placed on those percent is $9 million to $36 million.
million. Therefore, moving up the products. If these results—increased In addition to health benefits, banning
effective date by 12 months would production costs or reduced consumer these additives would also generate
increase costs by $3 million to $52 valuation—were to occur, they would benefits by allowing consumers who
million. However, moving up the not be one-time costs but recurring know they are sensitive to these
compliance date would also increase costs. However, extrapolating such costs additives to consume some products
benefits relative to Option Two by to infinity would not be reasonable that they might otherwise avoid. We do
providing benefits during months 12 to because technical improvements in not have sufficient information to
24 after the publication date of the final substitutes for carmine and cochineal quantify this benefit. However, this
rule. These benefits would amount to extract could eventually eliminate such benefit would probably be greater than
approximately $0 million to $2 million. costs. Nevertheless, these costs could be the comparable benefit under Option
Thus, this option would reduce net much greater than the corresponding Two because, under this option,
benefits by $1 million to $52 million recurring costs under Option Two, consumers would not have to read
relative to Option Two. which were generated by the permanent product labels to determine whether
loss of a small amount of otherwise free they could consume particular products.
5. Option Five: Ban Carmine or
label space.
Cochineal Extract 6. Summary of Costs and Benefits.
This option would also generate
a. Costs. Banning carmine or significant distributive effects by We do not have good information on
cochineal extract would require firms reducing the profits of firms that the current usage of carmine and
currently using these additives in produce, import, or process carmine and cochineal extract or the current number
products covered by this rule to cochineal extract and by increasing the of adverse events associated with those
reformulate all such products. Although profits of firms that produce, import, or additives. However, under the
a number of potential substitutes exist, process substitutes. In some cases, the assumptions we used in this analysis,
each of these substitutes has technical same firms that handle cochineal extract we estimate that taking the proposed
and functional characteristics that differ and carmine may handle substitutes for action would generate one-time
from those of cochineal extract and these additives. The distributive effects relabeling costs of between $0 million
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carmine. We estimated reformulation generated by this option would probably and $3 million and some small but
costs using a model developed by RTI be much greater than the distributive permanently recurring costs associated
under contract to FDA. For purposes of effects generated by Option Two with the loss of otherwise free label
providing the necessary inputs for the because under Option Two most firms space. We also estimate that taking the
reformulation cost model, we assumed using carmine or cochineal extract proposed action would generate
that firms would probably replace would probably continue to use these permanently recurring annual health
carmine or cochineal extract with additives. benefits of between $0 million and $2

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4850 Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules

million, with a total discounted value in the preceding cost benefit analysis. businesses that manufacture, import, or
under a 7 percent discount rate of For most of the relevant NAICS codes, process these color additives and do not
between $1 million and $26 million. In SBA defines a small business as a also handle substitutes. These
addition, taking the proposed action business with 500 or fewer employees. distributive effects would also be
would generate recurring benefits for The exceptions are NAICS codes 311821 considered costs from the perspective of
consumers who are sensitive to these and 312140, for which the cutoff is 750 the affected small businesses. Other
substances and who would be able to employees, and 311422, for which the firms, including small firms, would
consume some products that they might cutoff is 1,000 employees. We used the benefit from these distributive effects.
otherwise have avoided. Based on these 1997 Economic Census to check the However, we are unable to consider
estimates, taking the proposed action number of firms that would be classified positive effects on small businesses for
has the potential to produce significant as small businesses under the SBA purposes of this analysis.
net benefits but also has some potential definitions. We found that virtually all
to produce small net costs. We estimate (98 percent) of the firms in the relevant D. Unfunded Mandates
that delaying the compliance date to 36 NAICS code categories are small The Unfunded Mandates Reform Act
months after publication of the final businesses according to the SBA of 1995 (Public Law 104–4), requiring
rule rather than 24 months after definitions. cost-benefit and other analyses, in
publication of the final rule, as Total costs potentially incurred by section 1531(a) defines a significant rule
proposed, would reduce the one-time small businesses will be virtually equal as ‘‘a Federal mandate that may result
reformulation costs to between $0 to the social costs estimated in the cost in the expenditure by State, local, and
million and some amount less than $3 benefit analysis because the vast tribal governments in the aggregate, or
million and reduce health benefits by majority of the affected firms discussed by the private sector, of $100,000,000
between $0 million and $2 million. in the cost benefit analysis are small (adjusted annually for inflation) in any
Thus, we cannot determine if delaying businesses. These costs may or may not 1 year.’’ FDA has determined that this
the effective date to 36 months after the be borne by small businesses because rule does not constitute a significant
publication of the final rule would firms may be able to pass on some or all rule under the Unfunded Mandates
increase net benefits. We also estimate of these costs to consumers in the form Reform Act.
that moving up the compliance date to of higher prices, depending on market
12 months after publication of the final conditions. If the total costs accruing to XI. Paperwork Reduction Act of 1995
rule would increase the one-time small businesses are proportional to the
This proposed rule contains
reformulation costs by $3 million to $52 number of affected food and cosmetic
information collections that are subject
million and increase benefits by firms that are small businesses, and if
to review by the Office of Management
approximately $0 million to $2 million. these firms are unable to pass on any
and Budget (OMB) under the Paperwork
Thus, moving up the effective date to 12 costs to consumers, then we estimate
Reduction Act of 1995 (PRA) (44 U.S.C.
months after the publication of the final that the one-time costs accruing to small
3501–3520). The labeling requirements
rule would decrease net benefits. businesses from taking the proposed
action would be $0 million to $3 in this proposed rule cross-reference
Banning carmine and cochineal extract
million, plus some small but labeling requirements in other
would generate a one-time
permanently recurring costs associated regulations; therefore, FDA is not
reformulation cost of $3 million to
with the loss of otherwise free label estimating the burden of this proposed
$1,390 million, plus possible recurring
space. rule separately. The burden hours for 21
costs from increased production costs
All of the regulatory alternatives CFR 70.25 cross-referenced in
caused by the use of substitutes or from
discussed in the cost benefit analysis §§ 73.100(d)(1) and 73.2087(c)(1) have
reduced consumer valuation of the
reformulated products. A ban would would change the potential impact of been estimated and approved under
generate benefits of approximately $1 this rule on small businesses. Taking no OMB control number 0910–0016. The
million to $3 million per year, with a action would eliminate all potential burden hours for 21 CFR 101.4 cross-
total discounted value under a 7 percent impacts on small businesses. Taking the referenced in § 73.100(d)(2) have been
discount rate of $9 million to $36 proposed action but increasing the estimated and approved under OMB
million. Therefore, we estimate that a compliance period from 24 months to control number 0910–0381. The burden
ban would generate potentially large net 36 months would reduce the potential hours for § 73.2087(c)(2) will be
social costs. impact on small businesses to between submitted for OMB review and approval
$0 million and some amount less than in a future submission for § 701.3.
C. Small Entity Analysis $3 million. However, as discussed in the XII. Federalism
We have examined the economic cost benefit analysis, extending the
implications of this proposed rule as compliance period from 24 months to We have examined this proposal
required by the Regulatory Flexibility 36 months would also reduce benefits following the principles of Executive
Act (5 U.S.C. 601–612). If a rule has a by the amount that would otherwise Order 13132, ‘‘Federalism.’’ We have
significant economic impact on a have been generated in the first 12 determined that a final rule based on
substantial number of small entities, the months. Taking the proposed action but this proposal would not contain policies
Regulatory Flexibility Act requires decreasing the compliance period from that have substantial direct effects on
agencies to analyze regulatory options 24 months to 12 months would the States, on the relationship between
that would lessen the economic effect of substantially increase the potential the National Government and the States,
the rule on small entities. We find that impact on small businesses to between or on the distribution of power and
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this proposed rule would have a $3 million and $55 million. Banning responsibilities among the different
significant economic impact on a carmine and cochineal extract would levels of government. We have therefore
substantial number of small entities. significantly increase the potential costs concluded that, because it does not have
The Small Business Administration for small food and cosmetic firms to implications for federalism as defined in
(SBA) publishes definitions of small between $3 million and $1,390 million. the Executive order, this proposal does
businesses by NAICS code. We In addition, a ban would also generate not need a summary impact statement
presented a list of relevant NAICS codes significant distributive effects on small on federalism.

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Federal Register / Vol. 71, No. 19 / Monday, January 30, 2006 / Proposed Rules 4851

XIII. Comments 20. U.S. Census Bureau (http:// contain cochineal extract or carmine
www.census.gov/prod/ec97/97m3117a.pdf) shall specifically declare the presence of
Interested persons may submit to the 21. U.S. Census Bureau (http:// the color additive by listing its
Division of Dockets Management (see www.census.gov/prod/ec97/97m3117b.pdf) respective common or usual name,
ADDRESSES) written or electronic 22. U.S. Census Bureau http://
‘‘cochineal extract’’ or ‘‘carmine,’’ in the
comments regarding this document. statement of ingredients in accordance
23. U.S. Census Bureau (http://
Submit a single copy of electronic with § 101.4 of this chapter.
comments or two paper copies of any 24. U.S. Census Bureau (http:// * * * * *
mailed comments, except that www.census.gov/prod/ec97/97m3256d.pdf)
individuals may submit one paper copy. 25. U.S. Census Bureau (http:// 3. Section 73.2087 is amended by
Identify comments with the docket www.census.gov/prod/ec97/97m3118a.pdf) revising paragraph (c) to read as follows:
number found in brackets in the 26. Goldman, S. A., D. L. Kennedy, D. J.
§ 73.2087 Carmine.
heading of this document. Received Graham, et al., ‘‘The Clinical Impact of
comments may be seen in the Division Adverse Event Reporting,’’ MedWatch * * * * *
of Dockets Management between 9 a.m. Continuing Education Article, pp. 1–11, (c) Labeling. (1) The color additive
1996. and any mixture prepared therefrom
and 4 p.m., Monday through Friday.
27. Chyka, P. A. and S. W. McCommon,
Drug Safety, vol. 23, pp. 87–93, 2000.
intended solely or in part for coloring
XIV. References purposes shall bear, in addition to any
28. Rawlins, M. D. Journal of the Royal
1. Sampson, H. A., The Journal of Allergy College of Physicians of London, vol. 29, No. information required by law, labeling in
and Clinical Immunology, vol. 103, number 1, January/February 1995. accordance with the provisions of
5, part 1, pp. 717–728, 1999. 29. Research Triangle Institute, ‘‘Estimating § 70.25 of this chapter.
2. Lucas, C. D. and J. B. Hallagan, the Value of Consumers’ Loss From Foods
Advances in Food and Nutrition Research, (2) Cosmetics containing carmine that
Violating the FD&C Act, vol. II,’’ Final
vol. 43, pp. 195–216, 2001. Report, pp. G–11, G–22, September 1998.
are not subject to the requirements of
3. Sampson, H. A., Allergy, vol. 53, pp. 30. Weighted National Estimates From § 701.3 shall specifically declare the
125–130, 1998. HCUP Nationwide Inpatient Sample (NIS), presence of carmine prominently and
4. Sampson, H. A., Pediatrics, vol. 111, pp. 1997, Agency for Healthcare Research and conspicuously at least once in the
1601–1608, 2003. Quality (AHRQ), based on data collected by labeling. For example: ‘‘Contains
5. Taylor, S. L., S. L. Hefle, C. Bindslev- individual States and provided to AHRQ by carmine as a color additive.’’
Jensen, et al., The Journal of Allergy and the States, estimates found on HCUPnet at
Clinical Immunology, vol. 109(1), pp. 24–30, * * * * *
6. Sicherer S. H., E. H. Morrow, H. A. List of Subjects PART 101—FOOD LABELING
Sampson, Journal of Allergy and Clinical
Immunology, vol. 105(3), pp. 582–586, 2000. 21 CFR Part 73 5. The authority citation for 21 CFR
7. Sarkany, I., R. H. Meara, and J. Everall, Color additives, Cosmetics, Drugs, part 101 continues to read as follows:
Transactions and Annual Report of the St. Medical devices. Authority: 15 U.S.C. 1453, 1454, 1455; 21
John’s Hospital Dermatological Society, vol. U.S.C. 321, 331, 342, 343, 348, 371; 42 U.S.C.
46, p. 39, 1961. 21 CFR Part 101
243, 264, 271.
8. Park, G. R., Journal of the Royal Army Food labeling, Nutrition, Reporting
Medical Corps (London), vol. 127, pp. 85–86, 6. Section 101.22 is amended by
and recordkeeping requirements. revising paragraph (k)(2) to read as
9. Beaudouin, E., G. Kanny, H. Lambert, et Therefore, under the Federal Food,
al., Annals of Allergy, Asthma, & Drug, and Cosmetic Act and under
Immunology, vol. 74, pp. 427–430, 1995. authority delegated to the Commissioner § 101.22 Foods; labeling of spices,
10. Wuthrich, B., M. K. Kagi, and W. of Food and Drugs, 21 CFR parts 73 and flavorings, colorings and chemical
Stucker, Allergy, vol. 52, pp. 1133–1137, 101 are proposed to be amended as preservatives.
1997. follows: * * * * *
11. Baldwin, J. L., A. H. Chou, and W. R.
Solomon, Annals of Allergy, Asthma, & PART 73—LISTING OF COLOR (k)(2) Color additives not subject to
Immunology, vol. 79, pp. 415–419, 1997. ADDITIVES EXEMPT FROM certification, and not otherwise required
12. DiCello, M. C., A. Myc, J. R. Baker, and CERTIFICATION by applicable regulations in part 73 of
J. L. Baldwin, Allergy and Asthma this chapter to be declared by their
Proceedings, vol. 20, pp. 377–382, 1999. 1. The authority citation for 21 CFR respective common or usual names, may
13. Chung, K., J. R. Baker, Jr., J. L. Baldwin, part 73 continues to read as follows: be declared as ‘‘Artificial Color,’’
et al., Allergy, vol. 56, pp. 73–77, 2001. ‘‘Artificial Color Added,’’ or ‘‘Color
14. Quirce, S., M. Cuevas, J. M. Olaguibel, Authority: 21 U.S.C. 321, 341, 342, 343,
348, 351, 352, 355, 361, 362, 371, 379e. Added’’ (or by an equally informative
et al., Journal of Allergy and Clinical
Immunology, vol. 93, pp. 44–52, 1994. 2. Section 73.100 is amended by term that makes clear that a color
15. Burge, P. S., I. M. O’Brien, M. G. Harris, revising paragraph (d) to read as additive has been used in the food).
et al., Clinical Allergy, vol. 9, pp. 185–189, follows: Alternatively, such color additives may
1979. be declared as ‘‘Colored with ______’’ or
16. Durham, S. R., B. J. Graneek, R. § 73.100 Cochineal extract; carmine. ‘‘______color,’’ the blank to be filled in
Hawkins, et al., Journal of Allergy and * * * * * with the name of the color additive
Clinical Immunology, vol. 79, pp. 398–406, (d) Labeling requirements. (1) The listed in the applicable regulation in
1987. label of the color additives and any part 73 of this chapter.
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17. Christiansen, M. L., G. Ahlbom, W. mixtures intended solely or in part for

Frank, et al., European Journal of Respiratory * * * * *
coloring purposes prepared therefrom
Diseases, vol. 62 (suppl. 113), pp. 82–83, Dated: October 25, 2005.
1981. shall conform to the requirements of
§ 70.25 of this chapter. Jeffrey Shuren,
18. Dietemann-Molard, A., J. J. Braun, B.
(2) The label of food products Assistant Commissioner for Policy.
Sohier, et al., Lancet, vol. 338, pp. 460, 1991.
19. Letter from A. Halper, FDA to N. Bravo, intended for human use, including [FR Doc. E6–1104 Filed 1–27–06; 8:45 am]
Elf Sanofi, Inc., October 27, 1993. butter, cheese, and ice cream, that BILLING CODE 4160–01–S

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