Listing of Color Additives Exempt From Certification; Food, Drug, and Cosmetic Labeling: Cochineal Extract and Carmine Declaration, 4839-4851 [E6-1104]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 19 (Monday, January 30, 2006)]
[Proposed Rules]
[Pages 4839-4851]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-1104]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 73 and 101

[Docket No. 1998P-0724, formerly 98P-0724]
RIN 0910-AF12


Listing of Color Additives Exempt From Certification; Food, Drug, 
and Cosmetic Labeling: Cochineal Extract and Carmine Declaration

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, we) is proposing to 
revise its requirements for cochineal extract and carmine by requiring 
their declaration on the label of all food and cosmetic products that 
contain these color additives. The proposed rule responds to reports of 
severe allergic reactions, including anaphylaxis, to cochineal extract 
and carmine-containing food and cosmetics and would allow consumers who 
are allergic to these color additives to identify and thus avoid 
products that contain these color additives. This proposed action also 
responds, in part, to a citizen petition submitted by the Center for 
Science in the Public Interest (CSPI).
    With regard to drug products, FDA plans to initiate rulemaking to 
implement the Food and Drug Administration Modernization Act of 1997 
(FDAMA) (Pub. L.105-115) provisions that require declaration of 
inactive ingredients for drugs. The FDAMA provisions have already been 
implemented for over-the-counter (OTC) drugs.

DATES: Submit written or electronic comments by May 1, 2006. Please see 
section VIII for the effective date of any final rule that may publish 
based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No.1998P-0724 
and RIN number 0910-AF12, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN has 
been assigned) for this rulemaking. All comments received may be posted 
without change to https://www.fda.gov/ohrms/dockets/default.htm, 
including any personal information provided. For detailed instructions 
on submitting comments and additional information on the rulemaking 
process, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Mical E. Honigfort, Center for Food 
Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1278.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Description of Cochineal Extract and Carmine
    A. Source and Identity of Cochineal Extract and Carmine
    B. Uses of Cochineal Extract and Carmine
III. Regulation of Cochineal Extract and Carmine
    A. The Provisional List of 1960
    B. Color Additive Approval of Carmine
    C. Color Additive Approval of Cochineal Extract
IV. Allergic Reactions to Cochineal Extract and Carmine
    A. Descriptions of Allergic Reactions
    B. Adverse Reaction Reports in the Literature
    C. Adverse Reaction Reports in FDA Files
    D. CSPI Citizen Petition
V. FDA Response to the Allergic Reaction Reports
    A. Evaluation of the Allergic Reaction Reports
    B. Options for Action
    C. Tentative Conclusions
VI. FDA Response to the CSPI Petition
VII. FDA Proposed Action
    A. Legal Authority
    B. Food Labeling
    C. Cosmetics Labeling
VIII. Proposed Effective Date
IX. Environmental Impact
X. Analysis of Impacts
    A. Preliminary Regulatory Impact Analysis
    B. Regulatory Alternatives
    C. Small Entity Analysis
    D. Unfunded Mandates
XI. Paperwork Reduction Act of 1995
XII. Federalism
XIII. Comments
XIV. References

I. Background

    Cochineal extract is a color additive that is currently permitted 
for use in foods and drugs in the United States. The related color 
additive carmine is currently permitted for use in foods, drugs, and 
cosmetics. FDA has listed these color additives, and conditions for 
their safe use, in part 73 of Title 21 of the Code of Federal 
Regulations (21 CFR part 73).
    Allergic reactions to cochineal extract and/or carmine in a variety 
of foods (grapefruit juice, the alcoholic beverage

[[Page 4840]]

Campari, a popsicle, candy, yogurt, and artificial crabmeat) and 
cosmetics (face blush, eye shadow, eyeliner, and skin products) have 
been reported in the scientific and medical literature since 1961. 
Since 1994, we have received 11 adverse event reports of allergic 
reactions, including anaphylaxis, experienced by individuals after 
eating food or drinking a beverage containing cochineal extract or 
carmine, or using cosmetics colored with carmine. We know of no reports 
of allergic reaction to cochineal extract or carmine in drugs.
    In 1998, we received a citizen petition (Docket No. 98P-0724) from 
CSPI asking us to take action to protect consumers who are allergic to 
cochineal extract and carmine. The CSPI petition, the reports from the 
scientific literature, and the voluntarily submitted adverse event 
reports provide the factual basis for the regulatory action we now 
propose.

II. Description of Cochineal Extract and Carmine

A. Source and Identity of Cochineal Extract and Carmine

    Cochineal is a dye made from dried and ground female bodies of the 
scale insect Dactylopius coccus costa (Coccus cacti L.). Powdered 
cochineal is dark purplish red. The chief coloring principle in 
cochineal is carminic acid, a hydroxyanthraquinone linked to a glucose 
unit. Cochineal contains approximately 10 percent carminic acid; the 
remainder consists of insect body fragments.
    Cochineal extract is the concentrated solution obtained after 
removing the alcohol from an aqueous-alcoholic extract of cochineal. 
The chief coloring principle in cochineal extract is carminic acid. 
Cochineal extract is acidic (pH 5 to 5.5) and varies in color from 
orange to red depending on pH.
    Carmine is the aluminum or calcium-aluminum lake formed by 
precipitating carminic acid onto an aluminum hydroxide substrate using 
aluminum or calcium cation as the precipitant. The carminic acid used 
to make the lake is obtained by an aqueous extraction of cochineal. 
Carmine is a dark red to bright red powder depending on the amount of 
carminic acid present. The lake is only slightly soluble in water, to 
which it imparts a red color, and can be solubilized by strong acids 
and bases.
    The chemical identity, purity specifications, and use restrictions 
for cochineal extract and/or carmine are provided in Sec.  73.100 
(foods), Sec.  73.1100 (drugs), and Sec.  73.2087 (cosmetics). The 
regulations require that cochineal extract contain not less than 1.8 
percent carminic acid, not more than 2.2 percent protein, and between 
5.7 and 6.3 percent total solid content, and that carmine contain not 
less than 50 percent carminic acid.
    Cochineal extract and carmine share the same E-number designation 
in the European Union, E120. Neither color additive should be confused 
with the unapproved color additive cochineal red (E124), a synthetic 
azo dye that is sometimes called new coccin, Food Red 7, or Ponceau 4R. 
Carmine also should not be confused with indigo carmine, which is 
certifiable as FD&C Blue No. 2.

B. Uses of Cochineal Extract and Carmine

    Cochineal, carmine, and cochineal extract have a long history of 
use. Cochineal originated in Mexico and was used by the ancient Aztecs. 
It was discovered there by 16th century Spanish explorers, who 
introduced it to Europe and the rest of the world. Cochineal was listed 
in the United States Pharmacopeia from 1831 to 1955 and in the National 
Formulary until 1975.
    Food uses for carmine include popsicles, strawberry milk drinks, 
port wine cheese, artificial crab/lobster products, cherries in fruit 
cocktails, and lumpfish eggs/caviar. Cochineal extract is used in fruit 
drinks, candy, yogurt, and some processed foods.
    FDA's Voluntary Cosmetics Registration Program database contains 
information on the types of cosmetic products that contain carmine. 
(Cochineal extract is not permitted for use as a color additive in 
cosmetics.) Carmine has been reported to be used in 814 formulations 
including lipsticks, blushers, makeup bases, eye shadows, eyeliners, 
nail polishes, hair colors, skin care lotions, bath products, baby 
products, and suntan preparations.

III. Regulation of Cochineal Extract and Carmine

A. The Provisional List of 1960

    The Color Additive Amendments of 1960 (Public Law 86-618, 74 Stat. 
397) amended the Federal Food, Drug, and Cosmetic Act (the act) to add 
the definition of ``color additive'' and to establish conditions under 
which color additives may be safely used. The Color Additive Amendments 
required us to publish a provisional list of color additives that were 
already in use or were certified as color additives prior to July 12, 
1960. The provisional list was intended to permit the continued use of 
the listed color additives for a limited time, during which sponsors 
could submit data that established their safety and supported their 
permanent listings.
    FDA published a provisional list of color additives that included 
cochineal extract in the Federal Register of October 12, 1960 (25 FR 
9759). We provisionally listed cochineal for use in foods, drugs, and 
cosmetics on the basis of prior commercial sale of color additives 
which had not been subject to certification. In the Federal Register of 
August 16, 1961 (26 FR 7578) FDA amended the provisional list to add 
carmine for use in foods and cosmetics on the same basis.

B. Color Additive Approval of Carmine

    On November 9, 1964, we received a color additive petition (CAP) 
that requested the permanent listing of carmine as safe and suitable 
for use in or on foods, drugs, and cosmetics. We designated the 
petition CAP 20 and we published a notice of filing of the petition in 
the Federal Register of August 17, 1965 (30 FR 10211).
    Permanent listing of carmine for use in foods and drugs was 
supported by safety data and other relevant information submitted in 
CAP 20. The safety data included results of two 90-day toxicity 
studies, both in rats. From these data we calculated an acceptable 
daily intake (ADI) of 25 milligrams per kilogram (mg/kg) or 1,000 parts 
per million (ppm) of the daily diet for a person, considering a 100-
fold safety factor. The petitioner had reported general usage in food 
products to be 0.0025 percent or 25 ppm, and in a few selected products 
as high as 75 to 100 ppm. We concluded that if a person's total diet 
were colored with carmine, and if the amounts ingested from drugs, 
cosmetics, and foods were combined, the total ingestion figures would 
be well within the margin of safety.
    CAP 20 also included history-of-use information provided in 1965 by 
several companies, both domestic and foreign. These companies either 
supplied or used carmine and/or cochineal in food, drugs, and 
cosmetics. This history-of-use information stated that the companies 
had received no complaints during five decades of use. Also, the 
companies had received no notification of toxicity or allergic 
reactions from the use of the color additives.
    From information in CAP 20, we concluded it would not be necessary 
to require the batch certification of carmine. Since carmine is derived 
from a natural source (insects), we concluded that there would be 
little likelihood of contamination with toxic reactants or 
intermediates that would be used in a synthesis. We also did not set a 
quantitative limitation because we determined that use of the color

[[Page 4841]]

additive would be economically self-limiting.
    In the Federal Register of April 19, 1967 (32 FR 6131), FDA 
published a final rule that permanently listed carmine as a color 
additive exempt from certification for use in foods (21 CFR 8.317, now 
Sec.  73.100) and drugs (21 CFR 8.6009, now Sec.  73.1100).
    On June 24, 1977 (42 FR 32228) FDA published a regulation 
permanently listing carmine as a color additive exempt from 
certification for use in cosmetics generally, including cosmetics 
intended for use in the area of the eye (Sec.  73.2087).

C. Color Additive Approval of Cochineal Extract

    On February 14, 1968, we received a color additive petition 
requesting that we permanently list cochineal extract for general use 
in foods and drugs. We designated the petition CAP 60 and published a 
notice of filing in the Federal Register of March 15, 1968 (33 FR 
4593).
    Permanent listing of cochineal extract for use in foods and drugs 
was supported by data in CAP 60 which showed that cochineal extract was 
essentially similar, qualitatively, to carmine, including the protein 
fractions. The petition also included information on the long history 
of use of cochineal extract and argued that the use of cochineal 
extract as a color additive in foods and drugs was comparable to that 
for carmine.
    We concluded that the toxicological data in CAP 20 could be 
extrapolated to support the safety of cochineal extract. We further 
concluded that certification of cochineal extract was not necessary. We 
also did not set a quantitative limitation because we determined that 
use of the color additive would be economically self-limiting.
    In the Federal Register of December 14, 1968 (33 FR 18577), FDA 
published a final rule that amended the listing regulation for carmine 
to include the permanent listing of cochineal extract as a color 
additive exempt from certification for use in foods (21 CFR 8.317, now 
Sec.  73.100) and drugs (21 CFR 8.6009, now Sec.  73.1100).

IV. Allergic Reactions to Cochineal Extract and Carmine

A. Descriptions of Allergic Reactions

    An allergic reaction is characterized by an abnormal or exaggerated 
response of the body's immune system to a reaction-provoking substance 
(i.e., allergen), usually a protein (Ref. 1). The majority of such 
responses are immediate hypersensitivity reactions mediated by an 
antibody, immunoglobulin E (IgE). Individuals with allergies produce an 
excess amount of IgE antibodies that recognize specific allergens from 
food or other substances in the environment. Once formed, these 
allergen-specific antibodies attach to receptors on specialized white 
blood cells (mast cells and basophils), found at key interfaces of body 
contact with foreign substances (e.g., skin, gastrointestinal and 
nasorespiratory tracts, and blood). The interaction between an allergen 
and bound specific IgE antibodies at these interfaces stimulates these 
cells to liberate histamine and other inflammatory mediators involved 
in the allergic response (Refs. 2 and 3).
    Allergic reactions typically manifest at the site of allergen 
contact and vary widely in severity. Signs and symptoms include skin 
manifestations of flushing, urticaria (hives), eczema, and angioedema 
(tissue swelling); oral manifestations of lip and tongue swelling and 
itchiness; gastrointestinal manifestations of stomach cramps, nausea, 
vomiting and/or diarrhea; itchy and swollen eye manifestations; 
nasorespiratory manifestations of nasal congestion and runniness, itchy 
nose and throat, wheezing, chest tightness and/or difficulty breathing; 
and cardiovascular manifestations of lightheadedness, chest pain, and 
low blood pressure. In some cases, a massive release of inflammatory 
mediators can lead to a more severe allergic reaction, often termed 
anaphylaxis, characterized by multi-organ involvement. Anaphylaxis can 
rapidly progress to severe respiratory manifestations of throat 
swelling/airway closure or cardiovascular collapse/shock that, without 
prompt medical management, ultimately result in death.
    The allergen type, route of exposure, frequency, dose, extent of 
mediator release, and presence of underlying illnesses (e.g., asthma) 
are factors which determine the severity of IgE-mediated allergic 
reactions (Ref. 4). Based on anecdotal reports of food allergic 
reactions and confirmatory oral challenge diagnostic studies, minimal 
amounts of food allergen can induce allergic reactions in sensitive 
individuals (Ref. 5). Although the risk of adverse reactions to minimal 
concentrations of allergenic ingredients in drugs and cosmetics would 
be expected to be similar to foods, data on the incidence of 
anaphylaxis resulting from ingestion and/or application of drugs and 
cosmetics is lacking.
    There are no tests to predict or determine which allergic 
individuals are more likely to develop anaphylaxis. Current testing 
methods (e.g., skin prick test (SPT) or in vitro radioallergosorbent 
test (RAST)) may provide evidence of IgE-mediated antibody response to 
allergens. However, such testing offers little predictive value for the 
severity of response. (Ref. 6)
    Most individuals become aware of their allergy to a specific 
allergen prior to experiencing a severe reaction. However, once the 
allergen is identified, there are no effective treatment methods to 
prevent IgE-mediated reactions from occurring. Although treatments are 
available that may limit the severity of harm from the allergic 
reaction, they do not necessarily eliminate the harm nor, in some 
cases, stop fatal reactions from occurring following exposure to an 
allergen (Ref. 6). Fatal reactions have occurred despite appropriate 
administration of treatment. Thus, avoidance of the allergen is the 
only method certain to prevent harm and fatal reactions. Reading of 
labels on food, drug, and/or cosmetic products, and/or education about 
potential scenarios where contact with allergen-containing sources 
could occur, are the cornerstone of risk prevention strategies for 
allergic individuals and their families.
    Allergens have been identified in food, drug, and cosmetic 
products, and sensitization (production of IgE antibodies) to allergens 
may occur through exposure to any or all of these products. Moreover, 
once sensitized, an individual may develop an IgE-mediated allergic 
reaction to the allergen by various routes of exposure: Topical (in 
contact with skin or mucosa), inhaled, ingested, or intravenous. 
Although anaphylaxis can result from exposure by any route, most cases 
of severe reactions occur when the allergen is ingested or injected 
intravenously. By these routes, allergens can be easily absorbed into 
the systemic circulation, leading to life-threatening anaphylaxis in as 
little as 5 to 15 minutes.
    A range of adverse reactions has been reported to occur from 
hypersensitivity to foods and cosmetics containing carmine or cochineal 
extract, as well as from carmine, carminic acid, and cochineal extract 
by themselves. As of February 2004, FDA is aware of 35 cases of 
hypersensitivity to carmine, carminic acid, or cochineal extract 
published in the scientific and medical literature and/or reported 
directly to FDA. Eleven of the cases were reported directly to FDA via 
consumer hotlines, letters, and/or MedWatch reports.
    Hypersensitivity reactions to carmine, carminic acid, or cochineal 
extract include contact dermatitis (4), urticaria/

[[Page 4842]]

angioedema (9), occupational asthma (10), and systemic anaphylaxis 
(twelve). In more than half of these reports, there is evidence of an 
IgE-mediated diagnostic response (e.g., positive SPT or positive IgE 
RAST) to carmine and/or its derivatives. In a subset of individuals, 
more specific testing identified allergenic proteins in the carmine 
and/or its derivatives to which the individuals had been specifically 
sensitized. All adverse reactions were strongly associated with 
ingestion, topical application, or inhalation of products containing 
carmine and/or derivatives by the persons making the reports. Moreover, 
a subset of sensitized individuals developed adverse reactions to a 
variety of different products containing carmine and/or derivatives. In 
addition to the above cases, inhalation of carmine and/or derivatives 
has been reported to induce an immunologic lung disorder, allergic 
extrinsic alveolitis, also known as hypersensitivity pneumonitis, in 
certain individuals.

B. Adverse Reaction Reports in the Literature

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

[[Page 4843]]

of a 54-year-old man who had worked as a blender of cosmetics. Five 
years after carmine was introduced as a coloring agent, he developed 
attacks of breathlessness at work, which would start within 20 minutes 
of exposure to the coloring agent. Bronchial provocation testing 
established that carmine was responsible for his wheezing attacks. He 
was also tested with an extract of cochineal insects prepared in Coca's 
solution; inhalation of this provoked his asthma. Although a lung 
function test suggested pre-existing emphysema, his attacks were 
reproducible when exposed to carmine powder. A second report of 
occupational asthma secondary to inhalation of carmine powder was 
published in 1987 (Ref. 16). A 1994 study (Ref. 14) demonstrated the 
formation of specific IgE antibodies against carmine and cochineal 
extract in a worker who had developed occupational asthma.

C. Adverse Reaction Reports in FDA Files

    Since 1994, we have received 11 voluntarily submitted reports of 
allergic reactions, including anaphylaxis, experienced by individuals 
after eating food or drinking a beverage containing cochineal extract 
or carmine or using cosmetics colored with carmine.
    1. On June 20, 1995, a 27-year-old woman experienced anaphylaxis 
within 3 hours of eating a popsicle labeled as colored with carmine. A 
report of this case was also published in the medical literature as 
described previously (Ref. 11).
    2. On April 22, 1997, a 30-year-old woman experienced urticaria, 
angioedema, and respiratory distress after consuming ruby red 
grapefruit juice with carmine. She had experienced similar reactions 
after eating purple candy colored with carmine. She also reported 
having a skin rash after using a purple eye shadow containing carmine. 
SPT to ruby red grapefruit juice, purple candy, purple eye shadow, and 
carmine dye were all positive.
    3. A 26-year-old woman experienced anaphylaxis on July 22, 1997, 
with generalized pruritus, urticaria, and angioedema, after eating 
custard-style strawberry-banana yogurt containing carmine. During the 
episode, she was found to have an elevated serum tryptase level of 18 
(upper limit of normal is 13.5), which is indicative of massive 
activation/release of mast cells. Following the episode, she 
demonstrated positive SPT to both custard-style strawberry-banana 
yogurt containing carmine and to carmine itself.
    4. On May 16, 1998, a 50-year-old woman reported having a severe 
allergic reaction within 15 minutes of drinking a 16 ounce bottle of 
fruit drink, which was labeled as containing extracts of cochineal. She 
experienced swelling in the area of her eyes and tightness in her 
throat. She was treated and hospitalized overnight.
    5. A 49-year-old woman who had no other allergies and mild 
hypertension reported on August 30, 2000, that she made two visits to 
an emergency room for treatment of severe anaphylactic reaction after 
eating small amounts of food colored with carmine: Crab soup, yogurt, 
candy, ruby red grapefruit juice, and pasta salad with artificial 
crabmeat. She subsequently had a positive SPT to carmine.
    6. An atopic woman around the age of 50 called to report having 
experienced recurrent episodes of swollen eyelids after consuming jelly 
or gelatin dessert containing carmine. At the time of her call, she had 
not had an allergic workup regarding her reactions.
    7. A woman reported experiencing an allergic reaction she 
attributed to eating a custard-style yogurt containing carmine. Shortly 
after eating the yogurt, she experienced an anaphylactic reaction, with 
trouble swallowing, hives, itching, and swelling of the eyelids. She 
was treated by an allergist. She also reported past sensitivity to eye 
shadows and other cosmetics which she thought contained carmine.
    8. A letter from a law firm informed us of the experience of one of 
their clients indicating that carmine might be implicated in allergic 
reactions. The firm did not provide any clinical details but enclosed a 
copy of a publication on carmine allergenicity from the journal Lancet.
    9. On May 2, 2000, a woman reported anaphylactic shock from carmine 
in foods and cosmetics applied to her skin and stated that she carries 
an injectable medication for treatment when needed.
    10. On September 21, 2000, a woman reported an allergic reaction by 
her eyes to an eyeliner containing carmine.
    11. In a letter dated March 26, 1999, a physician reported treating 
a patient who experienced an anaphylactic reaction after eating yogurt 
containing carmine and had a positive SPT to diluted carmine.

D. CSPI Citizen Petition

    CSPI submitted a citizen petition (Docket No. 98P-0724), dated 
August 24, 1998, requesting that we take action to protect consumers 
who are allergic to carmine and cochineal extract. The petitioner 
specifically requested that we do the following:
    1. Immediately require that cochineal extract and/or carmine be 
listed by name in the ingredient lists of all foods, drugs, and 
cosmetics to help protect individuals who know they are sensitive to 
the colorings;
    2. Immediately require labeling of animal (insect) origin of 
cochineal extract and carmine;
    3. Undertake or require scientific reviews or studies to determine 
the specific allergenic component of cochineal extract and carmine and 
whether it could be eliminated from the coloring, as well as to 
determine the prevalence and maximum severity of allergic reactions;
    4. If necessary, prohibit the use of cochineal extract and carmine 
entirely.
    In support of its requested actions, CSPI provided six articles 
from the scientific and medical literature describing adverse reactions 
to cochineal extract and/or carmine after inhalation of the color 
additive, ingestion of foods and beverages containing the color 
additive, or topical application of products containing the color 
additive. These articles are discussed in section IV.B of this 
document.

V. FDA Response to the Allergic Reaction Reports

A. Evaluation of the Allergic Reaction Reports

    The data show that a person may become sensitized and reactive to 
carmine and cochineal extract from ingestion, inhalation, or topical 
exposure to the color additives. Evidence for this is provided by 
published case reports of allergic reactions to foods containing 
carmine and cochineal extract (Refs. 10, 11, and 12), occupational 
asthma from exposure to carmine (Refs. 15, 16, and 17), and allergic 
reactions to topically applied cosmetics containing carmine (Refs. 9, 
13, and 14). The data in the published reports establish that the 
allergic reactions result from IgE-mediated antibody response to 
carmine or cochineal extract. The data also establish that individuals 
may become sensitized and reactive to carmine from use of cosmetics 
containing that color additive. These same individuals have been shown 
to subsequently experience more severe allergic reactions, including 
life-threatening IgE-mediated anaphylaxis, following the ingestion of 
carmine or cochineal extract in foods.
    Further evidence is provided in the 11 voluntarily submitted 
adverse reaction reports we have received that describe

[[Page 4844]]

allergic reactions, including anaphylaxis, experienced by individuals 
after eating food or drinking a beverage containing cochineal extract 
or carmine or using cosmetics colored with carmine. Because events were 
reported from a population of unknown size, estimates of overall 
frequency of allergy to these color additives cannot be made.

B. Options for Action

    Individuals with known sensitivity to carmine or cochineal extract 
need to avoid products that contain these color additives in order to 
prevent potentially life-threatening allergic reactions. There are 
several possible ways to accomplish this. One way is to prohibit use of 
carmine and cochineal extract in all foods, drugs, and cosmetics. A 
second way is to identify and eliminate the allergenic component of 
carmine and cochineal extract. If an allergen is a contaminant of the 
color additive, rather than the coloring principle, then FDA can set 
additional limiting specifications in the regulations for the color 
additives and, if necessary, require certification for each batch of 
carmine and cochineal extract to ensure compliance with these 
specifications. A third way is to require declaration of the presence 
of these color additives on the labels of all foods, drugs, and 
cosmetics.

C. Tentative Conclusions

    We have tentatively concluded that it is unnecessary to prohibit 
the use of carmine and cochineal extract in all foods, drugs, and 
cosmetics. Although the color additives have been shown to produce 
allergic responses in certain sensitized individuals, there is no 
evidence of a significant hazard to the general population when the 
color additives are used as specified by the color additive regulations 
in part 73.
    We have also tentatively concluded that requiring additional 
testing to identify and remove the allergenic component in carmine and 
cochineal extract would do little to protect the health of individuals 
sensitive to those additives because: (1) Given evidence that different 
people appear to react to different components of the color additives, 
it may not be technically or economically feasible to identify and 
reduce the allergenic component of carmine and cochineal extract to a 
low enough level so that it would no longer induce an allergic response 
in sensitized individuals; and (2) additional testing and the 
rulemaking required to implement the results of the testing would delay 
our resolution of the issue for sensitive individuals.
    Instead, FDA proposes to require declaration of carmine or 
cochineal extract on the labels of all foods and cosmetics that contain 
them. We plan to address prescription drugs in a separate rulemaking. 
This labeling requirement will enable sensitized individuals to 
recognize that a product contains carmine or cochineal extract by 
reading a product's labeling, and will thereby enable those individuals 
to avoid products that contain the color additives. This labeling 
requirement will also enable consumers and health care professionals to 
more quickly identify sensitivities to these color additives.
1. Foods
    There is currently no requirement that the presence of cochineal 
extract or carmine be declared in food labeling. Section 403(i) of the 
act (21 U.S.C. 343(i)) requires that a food label declare the 
ingredients in the food, using the common or usual name of the 
ingredient. However, this section allows the food label to designate 
certification-exempt color additives as coloring without naming the 
additives. The implementing regulation, Sec.  101.22(k)(2) (21 CFR 
101.22(k)(2)), permits label declaration of a certification-exempt 
color additive with a general phrase such as ``Artificial Color,'' 
``Color Added,'' or some other equally informative term that makes it 
clear that a color additive has been used in the food.
    Section 403(k) of the act requires that a food that bears or 
contains any artificial coloring must bear labeling stating that fact, 
but states that the provisions of this section and of section 403(i) 
described previously do not apply to butter, cheese, or ice cream. 
Section 101.22(k)(3) states that color additives need not be declared 
on the labels of butter, cheese, and ice cream unless such declaration 
is required by a regulation in part 73 or 21 CFR part 74. We have 
reviewed published and submitted reports describing allergic responses 
to food products containing cochineal extract or carmine. These reports 
are sufficient to demonstrate a hazard to the health of consumers who 
are sensitive to the color additives. Therefore, we tentatively 
conclude that the labels of all foods containing cochineal extract or 
carmine should declare the presence of those color additives in the 
ingredient statements as a condition of safe use. To that end, we 
propose the following amendments.
    FDA proposes to amend Sec.  73.100(d) by adding new paragraph 
(d)(2) to require the declaration of cochineal extract and carmine on 
the labels of all foods. Because Sec.  101.22(k)(2) does not refer to 
any labeling requirements in part 73, FDA also proposes to amend Sec.  
101.22(k)(2) to provide that certification-exempt color additives need 
not be declared on the labels of foods unless such declaration is 
required by a regulation in part 73. We do not propose to amend Sec.  
101.22(k)(3) to require the declaration of cochineal extract or carmine 
on the labels of butter, cheese, and ice cream because that declaration 
would be required by reference to proposed new Sec.  73.100(d)(2).
2. Drugs
    With respect to OTC drugs, Sec.  201.66(c)(8) (21 CFR 201.66(c)(8)) 
requires the outside container or wrapper of the retail package, or the 
immediate container label if there is no outside container or wrapper, 
to contain a listing of the established name of each inactive 
ingredient. If the OTC drug product is also a cosmetic, then the 
inactive ingredients must be listed in accordance with specific 
provisions of Sec. Sec.  701.3(a) or (f) (21 CFR 701.3(a) or (f)) and 
21 CFR 720.8, as applicable. Therefore, whether the OTC drug is or is 
not also a cosmetic, there is a preexisting regulatory requirement for 
declaration of inactive ingredients, including carmine and cochineal 
extract under Sec.  201.66(c)(8). Failure to comply with this 
regulation would render an OTC drug misbranded and subject to 
enforcement action under section 502(c) of the act (21 U.S.C. 352(c)).
    Furthermore, section 412 of FDAMA amended the misbranding 
provisions in section 502(e) of the act to require declaration of 
inactive ingredients for drugs, including prescription drugs. We plan 
to initiate a separate rulemaking to implement these FDAMA 
provisions.\1\
---------------------------------------------------------------------------

    \1\ These provisions of FDAMA have already been implemented for 
OTC drugs as described in the preceding paragraph. See 64 FR 13254, 
13263 (March 17, 1999). Note also that current 21 CFR 200.100(b)(5) 
requires the label of a prescription drug that is not for oral use 
(such as a topical or injectable drug) to bear the names of inactive 
ingredients, but permits certain color components to be designated 
as ``coloring'' rather than being specifically named.
---------------------------------------------------------------------------

3. Cosmetics
    Cosmetics that are offered for retail sale are subject to the 
labeling requirements of Sec.  701.3. Section 701.3(a) requires that 
the labels of cosmetics offered for retail sale bear a declaration of 
the name of each ingredient in descending order of predominance, except 
that the individual ingredients of fragrances and flavors are not 
required to be listed and may be identified together as ``fragrance'' 
or ``flavor.'' However, Sec.  701.3(f) permits color additives to be 
declared as a group at

[[Page 4845]]

the end of the ingredient statement, without respect to order of 
predominance.
    Cosmetics that are manufactured and sold for use only by 
professionals, called ``professional-use-only'' products, are not 
subject to the requirements of Sec.  701.3 and thus need not bear 
ingredient labeling. Cosmetic products that are gifts or free samples 
also need not bear ingredient labeling.
    Professional-use-only products include: (1) The makeup used in 
photography studios and by makeup artists for television, movie, and 
theater actors/actresses, (2) products intended for use only by 
professionals in beauty salons, skin care clinics, and massage therapy 
shops, and (3) camouflage makeup dispensed by physicians and 
aestheticians to clients with skin conditions such as scarring.
    Cosmetics that are gifts or free samples need not bear ingredient 
labeling because they are not intended for retail sale as consumer 
commodities. However, in the case of a gift that is actually a ``gift-
with-purchase,'' we have stated in our trade correspondence (Ref. 19) 
that the ``gift'' is not considered a free gift per se, because it can 
only be obtained by consumers who purchase the product to which the 
gift is attached. Therefore, such a ``gift'' must currently bear a 
complete ingredient declaration on the label of the package in 
accordance with the requirements of Sec.  701.3.
    We have reviewed published and submitted reports of allergic 
responses, including anaphylaxis, to cosmetic products that contain 
carmine. Furthermore, we have discussed the possibility that consumers 
sensitized to carmine from use of cosmetics containing that color 
additive may subsequently experience more severe allergic reactions, 
including anaphylaxis, from ingestion of carmine or cochineal extract 
in foods. We have tentatively concluded that all cosmetic products 
should declare the presence of carmine in their labeling. Therefore, 
FDA proposes to amend Sec.  73.2087 to require declaration of carmine 
on the labels of cosmetics that are not subject to the requirements of 
Sec.  701.3. The amended regulation will require that the cosmetics 
specifically declare the presence of carmine prominently and 
conspicuously at least once in the labeling and will provide the 
following statement as an example: ``Contains carmine as a color 
additive.''

VI. FDA Response to the CSPI Petition

    FDA's response to the actions requested in the CSPI petition is as 
follows:
    1. CSPI requested that FDA immediately require that cochineal 
extract and carmine be listed by name in the ingredient lists of all 
foods, drugs, and cosmetics.
    We believe that requiring the declaration of cochineal extract and 
carmine would provide sensitized consumers with the information needed 
to avoid products that contain those color additives. For the reasons 
stated in section V of this document, FDA proposes to require the 
declaration of carmine and cochineal extract on the labels of all foods 
and cosmetics, and plans to address drugs in a separate rulemaking.
    2. CSPI requested that FDA immediately require labeling of animal 
(insect) origin of cochineal extract and carmine.
    We do not believe requiring the declaration of animal (insect) 
origin of cochineal extract and carmine in the labeling of products 
containing these color additives is necessary. FDA has tentatively 
concluded that the proposed labeling requirement will provide 
sensitized consumers sufficient information to avoid products 
containing these color additives.
    Furthermore, information on the origin of these color additives is 
readily available to those consumers who want it. This information is 
provided in standard dictionaries under the definitions for the words 
``cochineal'' and ``carmine.'' This information is also provided in the 
color additive regulation governing use of cochineal extract and 
carmine in foods ( Sec.  73.100). Thus, we do not propose to require 
labeling of animal (insect) origin of cochineal extract and carmine.
    3. CSPI requested that FDA undertake or require scientific reviews 
or studies to determine the specific allergenic component of cochineal 
extract and carmine, and whether it could be eliminated from the color 
additives, as well as to determine the prevalence and maximum severity 
of allergic reactions.
    We could not identify the specific allergenic component in carmine 
and cochineal extract from our review of the published literature, 
except to state that it is likely to be of insect origin. One study we 
reviewed found that no universal protein was recognized by patients 
known to be allergic to carmine and that it remains unclear whether the 
allergenic component consists of proteins from the cochineal insects or 
a protein-carminic acid complex. We believe that additional scientific 
reviews or studies to determine the specific allergenic components of 
cochineal extract and carmine may be helpful if successful; however, 
they would be unnecessary to ensure the safe use of cochineal extract 
and carmine in foods, drugs, and cosmetics for the majority of 
consumers in the general public. Thus, we have not undertaken and we do 
not propose to require the requested scientific reviews or studies.
    4. CSPI requested that, if necessary, FDA prohibit the use of 
cochineal extract and carmine entirely.
    As noted previously, we have tentatively concluded that it is 
unnecessary to prohibit the use of cochineal extract and carmine in 
foods, drugs, and cosmetics. Although the color additives have been 
shown to produce allergic responses in certain sensitized individuals, 
there is no evidence of a significant hazard to the general population 
when the color additives are used as specified by the color additive 
regulations in part 73. Requiring declaration of carmine and cochineal 
extract on the labels of all foods and cosmetics will enable sensitized 
individuals to inform themselves of the presence of the color additives 
by reading a product's label and will thereby enable the individuals to 
avoid those products that contain carmine or cochineal extract. Thus, 
we do not propose to prohibit the use of cochineal extract and carmine.

VII. FDA Proposed Action

A. Legal Authority

    The legal authority for the regulations prescribing the safe use of 
color additives in foods, drugs, and cosmetics comes from section 
721(b) of the act (21 U.S.C. 379e(b)). Under section 721(b), FDA has 
the authority to prescribe conditions, including labeling requirements, 
under which a color additive may be safely used. Products containing 
color additives that are not used in compliance with the color additive 
regulations are adulterated under sections 402(c) (foods), 501(a)(4) 
(drugs), or 601(e) (cosmetics) of the act (21 U.S.C. 342(c), 351(a)(4), 
and 361(e), respectively). We have concluded that cochineal extract and 
carmine may cause potentially severe allergic responses in humans. 
Thus, we believe label information about the presence of these color 
additives in all foods and cosmetics is necessary to ensure their safe 
use. We note that, with respect to OTC drugs, declaration of inactive 
ingredients is already required under Sec.  201.66(c)(8), and we plan 
to initiate a rulemaking to implement the FDAMA provisions that require 
declaration of inactive ingredients for drugs, including prescription 
drugs.
    Additional legal authority for requiring disclosure of a coloring 
that is,

[[Page 4846]]

or that bears or contains, a food allergen comes from section 403(x) of 
the act. Under that section, a coloring determined by regulation to be, 
or to bear or contain, a food allergen must be disclosed in a manner 
specified by regulation.

B. Food Labeling

    FDA proposes to amend the color additive regulation (Sec.  73.100) 
that permits the use of cochineal extract or carmine in foods by adding 
new paragraph (d)(2) to require that all food (including butter, 
cheese, and ice cream) that contains cochineal extract or carmine 
specifically declare the presence of the color additive by its 
respective common or usual name, ``cochineal extract'' or ``carmine,'' 
in the ingredient statement of the food label. Failure to adhere to 
this requirement would make any food that bears or contains cochineal 
extract or carmine adulterated under section 402(c) of the act.
    FDA also proposes to amend Sec.  101.22(k)(2) of the food labeling 
regulations to disallow generic declaration of color additives for 
which individual declaration is required by applicable regulations in 
part 73. Currently, that paragraph allows any certification-exempt 
color additive to be declared in a generic way as ``Artificial Color'' 
or ``Artificial Color Added,'' rather than by its specific common or 
usual name.

C. Cosmetics Labeling

    FDA proposes to amend the color additive regulation (Sec.  73.2087) 
permitting the use of carmine in cosmetics to require that cosmetics 
containing carmine that are not subject to the requirements of Sec.  
701.3 specifically declare the presence of carmine prominently and 
conspicuously at least once in the label or labeling. The amended 
regulation will provide the following statement as an example: 
``Contains carmine as a color additive.'' Including this requirement in 
the color additive regulations will make any cosmetic that contains 
carmine and that does not declare its presence on the label adulterated 
under section 601(e) of the act.

VIII. Proposed Effective Date

    The proposed effective date for any final rule that may issue based 
on this proposal is 2 years after its date of publication in the 
Federal Register.

IX. Environmental Impact

    The agency has determined under 21 CFR 25.30(k) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

X. Analysis of Impacts

A. Preliminary Regulatory Impact Analysis

    We have examined the economic implications of this proposed rule as 
required by Executive Order 12866. Executive Order 12866 directs 
agencies to assess all costs and benefits of available regulatory 
alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). Executive Order 12866 classifies a 
rule as significant if it meets any one of a number of specified 
conditions, including having an annual effect on the economy of $100 
million, adversely affecting a sector of the economy in a material way, 
adversely affecting competition, or adversely affecting jobs. A 
regulation is also considered a significant regulatory action if it 
raises novel legal or policy issues. We have determined that this 
proposed rule is not an economically significant regulatory action as 
defined by Executive Order 12866.

B. Regulatory Alternatives

    We considered the following regulatory alternatives in this 
analysis. We request comments on these and any other plausible 
alternatives: (1) Take no action; (2) take the proposed action; (3) 
take the proposed action, but make the effective date later; (4) take 
the proposed action, but make the effective date sooner; or (5) ban 
carmine and cochineal extract.
1. Option One: Take No Action
    We treat the option of taking no action as generating neither costs 
nor benefits. We use this option as the baseline in comparison with 
which we determine the cost and benefits of the other options. Any 
favorable or unfavorable results from taking no action will be captured 
in the costs and benefits of the other options.
2. Option Two: Take the Proposed Action
    a. Costs. This proposed rule would increase the cost of using 
cochineal extract and carmine in foods and some cosmetics because it 
would require firms using these substances to list them on product 
labels. In the case of foods, the proposal would require firms to list 
the additives as ingredients in their products. In the case of 
cosmetics, the proposal would require firms to declare the presence of 
carmine on products not subject to the requirements of Sec.  701.3 
(e.g., professional-use-only products or free gifts). Cosmetics which 
are consumer commodities and subject to the requirements of Sec.  701.3 
are already required to list carmine as an ingredient.
    Although we discuss these costs as though they accrued to the 
affected firms, these costs are actually social costs that firms may 
pass on to consumers via higher product prices, depending on market 
conditions. The costs would be greatest for firms currently producing 
products containing these additives and for firms that begin using 
these additives in existing products after the final rule based on this 
proposal has taken effect but before their next regularly scheduled 
label change. Costs would be greatest for these firms because they 
would need to change labels before their next regularly scheduled label 
redesign, and they may lose some inventory of already printed labels. 
The costs would be much smaller for firms that begin using these color 
additives in new products that are introduced after the final rule 
based on this proposal has taken effect and for firms that begin using 
these additives in existing products after their next regularly 
scheduled label redesign after the final rule based on this proposal 
has taken effect. Costs would be much smaller for these firms because 
they could incorporate the requirements of this rule in their label 
design during their label design phase, and they would not lose label 
inventory. The costs for these firms would be the loss of otherwise 
free label space. These costs would be minimal because this rule 
requires the use of only a small portion of the total available label 
space.
    Firms would respond in one of two ways to the increased costs of 
using carmine and cochineal extract. First, firms might use these 
additives and label products containing these additives as required by 
the final rule based on this proposal. Second, firms might decide not 
to use these additives or to delay using them until after their next 
regularly scheduled label change. Firms would decide which action to 
take based on estimated profits, which would vary with changes in 
consumer demand for the relabeled or reformulated products, the costs 
of relabeling or reformulating, and changes in consumer demand 
resulting from changes in product prices. We assume in this analysis 
that the required labeling would not significantly reduce

[[Page 4847]]

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