# Permanent Listing of Color Additive Lakes

> Briefs, arguments, decisions, and more.

URL: https://www.frixlaw.com/law-library/documents/fr%3A96-4584

## Record

- **Collection:** Federal Register
- **Document type:** Proposed Rule
- **Published:** March 4, 1996
- **Citation:** 61 FR 8372

## Text

[[Page 8372]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 70, 73, 74, 80, 81, 82, 101, 178, 201, and 701

[Docket Nos. 79N-0043 and 92N-0334]

Permanent Listing of Color Additive Lakes

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA) is proposing to list
certain color additive lakes permanently as suitable and safe for use
in food, drugs, and cosmetics. The agency is proposing to permit the
use of more than one straight color in the preparation of a lake, to
modify the nomenclature for lakes, and to simplify the batch
certification procedure for lakes. As part of these actions, the agency
is proposing to amend its regulations to require the preparation of
lakes from certified batches of straight color; to provide simplified
nomenclature for declaring color additives, including lakes, on
cosmetic products; to require declaration of FD&C Yellow No. 5 and FD&C
Yellow No. 6 on all foods and some drug products containing lakes of
these straight colors; and to terminate the listing of certain straight
colors as components of lakes for drug and cosmetic use and the listing
of calcium salts as components of lakes for food use.
This proposed rule is intended to complete the agency's disposition
of the provisional list of color additives that was established under
the transitional provisions of the Color Additive Amendments of 1960
(the 1960 amendments) and to establish regulations prescribing
conditions under which lakes may be prepared, labeled, and safely used
in food, drugs, and cosmetics.

DATES: Written comments by June 3, 1996, except that comments regarding
information collection should be submitted by April 3, 1996, but not
later than May 3, 1996.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857. Comments regarding information collection to the Office of
Information and Regulatory Affairs, OMB, New Executive Office Building,
rm. 10235, Washington, DC 20503, ATTN: Desk Officer for FDA. Process
descriptions, identity information for anions in precipitants, and
ingredient specifications for substrata (including rosin), and rosin
samples to the Colors Technology Branch (HFS-126), Food and Drug
Administration, 200 C St. SW., Washington, DC 20204.

FOR FURTHER INFORMATION CONTACT:
Regarding proposed certification procedures, including proposed
paperwork requirements, and for proposed product ingredient
declarations:

Julie N. Barrows, Center for Food Safety and Applied Nutrition (HFS-
126), Food and Drug Administration, 200 C St. SW., Washington, DC
20204, 202-205-4662.

Regarding other issues:

Arthur L. Lipman, Center for Food Safety and Applied Nutrition (HFS-
217), Food and Drug Administration, 200 C St. SW., Washington, DC
20204, 202-418-3073.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Identity, Manufacture, and Properties of Lakes
II. Regulatory History and Current Listings of Lakes
A. Regulatory History of Lakes
B. Current Listings of Lakes
C. The 1965 Proposal for Permanent Listing of Lakes and the 1979
Notice of Intent
III. Development of Proposed Actions for Lakes
A. Terminology of Lakes
B. Nomenclature of Lakes
C. Issues Relating to Definition of Lakes and Termination of
Certain Provisional Listings
IV. Safety Review and Proposed Actions for Lakes for Use in Foods
A. Review of Components of Lakes for Use in Foods
B. Specifications for Lakes for Use in Foods
C. Certification Requirement
D. Provisions of Proposed Sec. 74.50 Lakes for Use in Foods
V. Safety Review and Proposed Actions for Lakes for Use in Drugs and
Cosmetics
A. Review of Components of Lakes for Use in Drugs and Cosmetics
B. Specifications for Lakes for Use in Drugs and Cosmetics
C. Certification Requirement
D. Provisions of Proposed Regulations
VI. Other Proposed Actions
A. Removal of Provisional Listings
B. Certification Procedure for Lakes
C. Amendments to Other Regulations
VII. Summary of Information Requested
A. In Situ Manufacturing Processes
B. Identity and Specifications for Rosin
C. Anions in Precipitants
VIII. Effective Date
IX. Inspection of Documents
X. Environmental Impact
XI. Paperwork Reduction Act
XII. Comments
XIII. References

I. Identity, Manufacture, and Properties of Lakes

Color additives may be added to food, drugs, cosmetics, and certain
medical devices for the purpose of imparting color. The three
categories of color additives are: (1) ``Straight colors'' (color
additives that have not been mixed or chemically reacted with any other
substance); (2) lakes (color additives formed by chemically reacting a
straight color with water-insoluble substances); and (3) mixtures
(color additives formed by mixing a color additive with one or more
other color additives or noncolored substances, without chemical
reaction.)
A lake is a water-insoluble pigment composed of a water-soluble
straight color strongly adsorbed onto an insoluble substratum through
use of a precipitant. The regulations in part 82 (21 CFR part 82),
where lakes are provisionally listed, use the term ``basic radical'' to
denote a precipitant. As more fully described in section III.A.6. of
this document, the agency is proposing to replace the term ``basic
radical'' with the more scientifically accurate term ``precipitant.''
The proposed terminology will be used throughout the rest of this
document.
The first step in manufacturing a lake is the preparation of an
aqueous slurry of the substratum (e.g., alumina). This aqueous slurry
is mixed with an aqueous solution of a straight color to produce a
partially precipitated (or laked) product. The laking process is
completed by the addition of a precipitant (e.g., aluminum chloride),
which results in the production of the salt (e.g., aluminum salt) of
the straight color and the adsorption of the salt onto the substratum.
The resulting lake is washed, dried, and finely ground before
marketing.
The literature reports several variations of the basic laking
process (Refs. 1 through 5). Some substrata are synthesized in situ;
i.e., the components used to prepare the substratum, rather than the
preformed substratum, are added during the laking procedure. For
example, alumina slurries may be prepared by precipitation of hydrated
alumina from an aluminum sulfate solution with a sodium carbonate or
sodium hydroxide solution. These slurries are used directly in the
synthesis of lakes, without isolation of the precipitated substratum.
Some lakes are themselves prepared in situ. In this process, the
chemical precursors for the straight color are mixed directly with the
substratum and the precipitant during the laking procedure. The lake is
produced as the

[[Page 8373]]
straight color is synthesized, without isolation of the straight color
as a discrete batch.
The chemical association between the components of a lake may
involve various types of interactions, including ionic bonds, hydrogen
bonds, and van der Waals forces (Refs. 4 through 9). Lakes generally
contain 10 to 40 percent by weight of the straight color. They also
contain approximately 1 to 4 percent of the weight of the lake as the
cationic precipitant. The remaining 56 to 89 percent, by weight, of
lakes consists primarily of substrata. The color content of a lake
depends on the desired color intensity and shade of the lake.
Lakes offer many technical advantages over water-soluble straight
colors. The chemical bonding of the color with substrata generally
promotes light and heat stability. Furthermore, because lakes are not
water-soluble, the use of lakes in aqueous foods reduces color
migration.
The agency's current regulations for lakes in part 82 were issued
under section 203 of the Color Additive Amendments of 1960 (Pub. L. 86-
618), which provided for the temporary, provisional listing of
commercially established colors. The regulations provide that before a
lake may be used in a food, drug, or cosmetic product, each batch of
the lake must be certified by FDA. When requesting certification of a
batch of a lake, the requester submits a sample from the batch to the
agency for analysis. If the agency finds that the concentrations of
impurities in the sample are within the levels specified, and the batch
otherwise appears to comply with the applicable regulations, the agency
certifies the batch by issuing the requester a certificate showing the
certification lot number assigned to that batch of lake.
Lakes represent approximately 25 percent of the total poundage of
color additives certified by FDA. Approximately 80 percent of the lakes
certified are FD&C (food, drugs, and cosmetics) lakes and the remaining
20 percent are D&C (drugs and cosmetics) lakes. (See section II.A. of
this document for an explanation of the terms ``FD&C'' and ``D&C''.)

II. Regulatory History and Current Listings of Lakes

A. Regulatory History of Lakes

Section 7 of the Food and Drugs Act of 1906 (Pub. L. 59-384)
prohibited the use of poisonous or deleterious colors in confectionery
and the coloring or staining of food to conceal damage or inferiority.
In 1907, the agency, then part of the Department of Agriculture, issued
Food Inspection Decision 76 (Ref. 10), which contains a list of seven
straight colors approved for use in food. Between 1907 and 1939, the
agency expanded the list of straight colors approved for use in food
from 7 to 15. These colors were known as ``coal tar colors'' because
they were synthesized mainly from substances obtained from coal tar.
However, prior to 1939, the agency's list of acceptable colors did not
include lakes of coal tar colors because such lakes were not used in
food. Also, prior to 1938, the government program for batch analysis
and certification of colors was voluntary.
The Federal Food, Drug, and Cosmetic Act of 1938 (21 U.S.C. 301 et
seq. (the act)) (Pub. L. 75-717) required FDA to list coal tar colors
``harmless and suitable'' for use in foods, drugs, and cosmetics, and
to certify all batches of listed colors, including lakes. The agency
issued regulations under the act listing lakes for food use, as well as
for drug and cosmetic use, and establishing conditions for
certification of batches of lakes (4 FR 1922, May 9, 1939; 4 FR 3931,
September 16, 1939; and 5 FR 1138, March 23, 1940). The agency issued
the first certificate for a lake under the act on May 11, 1939 (Ref.
11).
The initial listing of lakes for food use under the act restricted
their use to coloring shell eggs (egg dyeing) (5 FR 1138). In 1959, at
the request of industry, the agency expanded the uses of lakes prepared
from FD&C straight colors to encompass general use in foods (24 FR
3818, May 13, 1959; and 24 FR 5302, June 30, 1959).
The 1960 amendments amended the act by defining the term ``color
additive'' (section 201(t) (21 U.S.C. 321(t))) for the first time and
restricting the use of color additives in or on food, drugs, cosmetics,
or the human body to those listed in FDA regulations. (The Medical
Device Amendments of 1976 (Pub. L. 94-295) extended these restrictions
to the use of color additives in certain medical devices.) As amended,
the act provides that a food (section 402(c) (21 U.S.C. 342(c))), drug
or device (section 501(a)(4) (21 U.S.C. 351(a)(4))), or cosmetic, other
than a coal tar hair dye (section 601(e) (21 U.S.C. 361(e))), is
adulterated if it is, bears, or contains an unsafe color additive.
Section 721 (formerly section 706) of the amended act (21 U.S.C. 379e)
provides for the listing of safe and suitable color additives for use
in foods, drugs, cosmetics, and medical devices; it prohibits the
listing of a color additive for a proposed use unless data establish
that such use will be safe. Section 721 of the act also continues the
requirement for certification of batches of color additives, with or
without diluents, to determine whether each batch conforms to the
purity and identity specifications in the applicable listing
regulation. However, the amendments allow FDA to exempt color additives
from batch certification if certification is unnecessary to protect the
public health.
Section 203 of the 1960 amendments also provided for the
provisional listing of color additives that were commercially
established when the 1960 amendments were enacted, pending completion
of scientific investigations necessary to determine their safety under
the new standard established by the 1960 amendments. The purpose of
section 203 was to allow the use of such color additives on an interim
basis, to the extent consistent with the public health. Section 203
directed the agency to recognize as provisionally listed the following
color additives: (1) Any color additive which, on the day preceding the
enactment date, was listed and certifiable for any use or uses and for
which a batch or batches had been certified for such use or uses prior
to the enactment date; (2) any color additive which was commercially
used or sold prior to the enactment date for any use or uses on any
food, drug, or cosmetic, but was not required to be listed under the
act; (3) synthetic beta carotene. The provisional listing was to apply
only to the use or uses to which the certification applied, or for
which the color additive had been commercially used or sold.
Under the authority of the 1960 amendments, in the Federal Register
of October 12, 1960 (25 FR 9759), the agency provisionally listed those
color additives, including lakes, covered by section 203. This listing,
originally codified as 21 CFR 8.501 and later recodified as Sec. 81.1
(21 CFR 81.1) (42 FR 15665, March 22, 1977) included many of the coal
tar colors (including lakes) that had been previously listed.
In the Federal Register of December 27, 1963 (28 FR 14311), the
agency determined that batch certification was unnecessary to ensure
the safety of most color additives derived from plant, animal, or
mineral sources, and designated these color additives as exempt from
certification. However, the agency determined that batch certification
was necessary to ensure the safety of most color additives, including
lakes, derived principally from coal and petroleum sources, and
designated those colors as subject to certification. Currently, the
color additives exempt from batch certification and the permanently
listed color additives

[[Page 8374]]
subject to batch certification are listed in parts 73 and 74 (21 CFR
parts 73 and 74), respectively.
Since the establishment of the provisional list in 1960, the agency
has gradually removed color additives from the list either by permanent
listing or by termination of listing due to lack of interest by
industry or due to safety concerns prompted by the agency's reviews. At
this time, only lakes remain provisionally listed in parts 81 and 82.
After the enactment of the act in 1938, FDA established the
designation ``FD&C'' to identify color additives listed for use in
foods, drugs, and cosmetics; the designation ``D&C'' to identify color
additives listed for general use in drugs and cosmetics, but not foods;
and the designation ``Ext. D&C'' to identify color additives listed for
use only in externally applied drugs and cosmetics (4 FR 1922 at 1923).
These designations are still part of the names of certified color
additives. However, the uses of some straight colors (and consequently
also of their lakes) were restricted when they were permanently listed,
based on the safety reviews conducted by the agency under the 1960
amendments. Consequently, the designations ``FD&C'' or ``D&C'' in the
name of a certified color additive can no longer be relied upon to
accurately describe the approved uses of the color additive.

B. Current Listings of Lakes

1. Provisional Listing and General Provisions for Lakes
Section 81.1 identifies the provisionally listed color additives.
The only color additives remaining on the provisional list are lakes
(Sec. 81.1(a), (b), and (c)).
Part 82, subpart A, prescribes the general provisions applicable to
provisionally listed color additives. Section 82.3 contains definitions
of terms such as ``alumina'' and ``blanc fixe.'' Section 82.5
prescribes general specifications, including specifications for levels
of lead, arsenic, and heavy metals other than lead and arsenic, that
are applicable to lakes listed in the other subparts of part 82. It
also provides a specification for the level of soluble barium
applicable to lakes listed in subpart C or D of part 82 that contain a
barium salt.
2. Provisional Listing of Lakes for Use in Foods, Drugs, and Cosmetics
Part 82, subpart B, identifies the lakes that are provisionally
listed for use in foods, drugs, and cosmetics. Section 82.50 prescribes
the certification requirements for these lakes.
Section 82.51 specifies that lakes for use in foods, drugs, and
cosmetics are made by extending, on a substratum of alumina, a salt of
one of the following certified water-soluble straight colors with the
cation precipitant aluminum or calcium: FD&C Blue No. 1 (Sec. 82.101);
FD&C Blue No. 2 (Sec. 82.102); FD&C Green No. 3 (Sec. 82.203); FD&C
Yellow No. 5 (Sec. 82.705); and FD&C Yellow No. 6 (Sec. 82.706). Only
previously certified batches of the straight color may be used. Section
82.51 also provides specifications for soluble chlorides and sulfates
and for inorganic matter insoluble in hydrochloric acid (HCl) and
prescribes rules for naming the lakes that are listed for use in foods,
drugs, and cosmetics.
3. Provisional Listing of Lakes for Use in Drugs and Cosmetics
Part 82, subpart C, identifies the lakes that are provisionally
listed for general use in drugs and cosmetics. Section 82.1051
prescribes the certification requirements for these lakes, which may be
used both in ingested and externally applied drugs and cosmetics.
Externally applied drugs and cosmetics are those that are applied to
the external parts of the body and not to the lips or any body surface
covered by mucous membrane (Sec. 70.3(v) (21 CFR 70.3(v))).
Section 82.1051 specifies that lakes for use in drugs and cosmetics
are made by extending, on one or more listed substrata, one of the
listed straight colors with one or more of the listed precipitants. The
precipitant may be added either as a component of the listed straight
color, or alone to form the salt of the listed straight color. The
following substrata, alone or in any combination, are authorized for
use in lakes for drug and cosmetic use: Alumina, blanc fixe, gloss
white, clay, titanium dioxide, zinc oxide, talc, rosin, aluminum
benzoate, and calcium carbonate. The regulation also lists the
following cation precipitants for use in lakes for drug and cosmetic
use: Sodium, potassium, aluminum, barium, calcium, strontium, and
zirconium.
The regulation provides for the use of the following straight
colors in producing lakes for drug and cosmetic use: FD&C Blue No. 1
(Sec. 82.101); FD&C Blue No. 2 (Sec. 82.102); FD&C Green No. 3
(Sec. 82.203), FD&C Red No. 4 (Sec. 82.304); FD&C Yellow No. 5
(Sec. 82.705); FD&C Yellow No. 6 (Sec. 82.706); D&C Blue No. 4
(Sec. 82.1104), D&C Green No. 5 (Sec. 82.1205), D&C Orange No. 5
(Sec. 82.1255), D&C Red No. 6 (Sec. 82.1306), D&C Red No. 7
(Sec. 82.1307), D&C Red No. 21 (Sec. 82.1321), D&C Red No. 22
(Sec. 82.1322), D&C Red No. 27 (Sec. 82.1327), D&C Red No. 28
(Sec. 82.1328), D&C Red No. 30 (Sec. 82.1330), D&C Red No. 33
(Sec. 82.1333), D&C Red No. 34 (Sec. 82.1334), D&C Red No. 36
(Sec. 82.1336), D&C Violet No. 2 (Sec. 82.1602), and D&C Yellow No. 10
(Sec. 82.1710).
The regulations for lakes of D&C Red No. 33 (Sec. 82.1333), D&C Red
No. 36 (Sec. 82.1336) and FD&C Yellow No. 6 (Sec. 82.706) further
require that lakes of these straight colors for drug and cosmetic use
be prepared from previously certified batches of the straight colors.
Uncertified batches of the remaining straight colors may be used to
prepare lakes for drug and cosmetic use. Section 82.1051 also provides
specifications for ether extracts, soluble chlorides and sulfates, and
intermediates, and prescribes rules for naming lakes that are listed
for drug and cosmetic use.
4. Provisional Listing of Lakes for Use in Externally Applied Drugs and
Cosmetics
Part 82, subpart D, identifies the lakes that are provisionally
listed for use in externally applied drugs and cosmetics. Section
82.2050 prescribes the certification requirements for these lakes.
Section 82.2051 specifies that lakes for use in externally applied
drugs and cosmetics are made by extending, on one or more listed
substrata, one or more of the listed precipitants, and the straight
color Ext. D&C Yellow No. 7 listed in Sec. 82.2707a. The precipitant
may be added either as a component of the listed straight color, or
alone to form the salt of the listed straight color.
Although Ext. D&C Yellow No. 7 is the only straight color referred
to in subpart D, its lakes are not the only lakes limited to use in
externally applied drugs and cosmetics. As noted above, certain
straight colors that were provisionally listed for general drug and
cosmetic use were restricted to use in externally applied drugs and
cosmetics as part of their permanent listing. The agency also amended
the provisional listings for the lakes of these straight colors to
impose the same restrictions. The provisional listings of the following
color additives in subparts B and C of part 82 limit the use of their
lakes to externally applied drugs and cosmetics: FD&C Red No. 4
(Sec. 82.304); D&C Blue No. 4 (Sec. 82.1104), D&C Green No. 6
(Sec. 82.1206), D&C Orange No. 4 (Sec. 82.1254), D&C Orange No. 10
(Sec. 82.1260), D&C Orange No. 11 (Sec. 82.1261), D&C Red No. 17
(Sec. 82.1317), D&C Red No. 31 (Sec. 82.1331), D&C Yellow No. 7
(Sec. 82.1707) and D&C Yellow No. 8 (Sec. 82.1708).
The substrata, precipitants, and additional specifications listed
in

[[Page 8375]]
Sec. 82.2051 for lakes used in externally applied drugs and cosmetics
are the same as those listed in Sec. 82.1051 for D&C lakes. Section
82.2051 also specifies that the listed names of Ext. D&C lakes are
derived in the same manner as for D&C lakes.
5. Permanently Listed Lakes of FD&C Red No. 40
The color additive FD&C Red No. 40 was not included in the
provisional list because FD&C Red No. 40 was not in use in 1960. In the
Federal Register of April 10, 1971 (36 FR 6892), the agency published a
final rule, in response to a color additive petition, permanently
listing FD&C Red No. 40 for use in food and drugs. The agency later
amended these regulations in response to another petition to provide
for use of the lakes of FD&C Red No. 40 in food and drugs (36 FR 23553,
December 10, 1971). Subsequently, in response to further petitions, the
agency published final rules expanding the listing of FD&C Red No. 40
to cosmetic uses. First, in the Federal Register of August 6, 1974 (39
FR 28278), the agency published a final rule permanently listing FD&C
Red No. 40 for use in dentifrices that are cosmetics. Subsequently, the
agency amended these regulations to expand the use of FD&C Red No. 40
and its lakes to cosmetics generally (39 FR 44198, December 23, 1974).
The permanent listings of FD&C Red No. 40 for food, drug, and
cosmetic use in Secs. 74.340, 74.1340, and 74.2340, respectively,
include its lakes. However, the permanent listings of these lakes cite
the provisional listings for lakes in part 82 for the preparation,
specifications, and labeling requirements applicable to FD&C Red No. 40
lakes. As a result, any agency action on the provisional listings for
lakes will affect the permanent listings for the lakes of FD&C Red No.
40. Therefore, this proposal includes consideration of the lakes of
FD&C Red No. 40.

C. The 1965 Proposal for Permanent Listing of Lakes and the 1979 Notice
of Intent

In the Federal Register of May 11, 1965 (30 FR 6490), the agency
proposed to list permanently certain lakes for use in foods, drugs, and
cosmetics under conditions similar to their current provisional
listing. However, because many straight colors were still provisionally
listed and because of the need for more information on lakes, the
agency, in 1979, terminated the rulemaking initiated by this proposal
without taking final action (44 FR 36411, June 22, 1979).
In the same issue of the Federal Register (44 FR 36411), the agency
published a notice that announced the agency's intent to repropose
regulations concerning lakes (the 1979 notice of intent (NOI)). The
agency also addressed the comments it had received in response to the
1965 proposal regarding the permanent listing of lakes. Three of the
five comments on the 1965 proposal recommended revising the regulations
to provide for the use of more than one previously certified batch of
color additive in the preparation of lakes for coloring drugs and
cosmetics. In the 1979 NOI, the agency stated its intention to consider
this recommendation in developing a new proposal for the permanent
listing of lakes. The agency also identified the following issues for
the scientific review of lakes: (1) The definition and nomenclature of
lakes; (2) the safety of lakes; and (3) the specifications for lakes
(stability and certification methodology). The agency requested
information and comments pertaining to these issues.
The agency received four comments on the 1979 NOI. These included
two brief responses from manufacturers and two extensive comments from
trade associations, the International Association of Color
Manufacturers (IACM) (formerly the Certified Color Manufacturers'
Association (CCMA)) and the Cosmetic, Toiletry, and Fragrance
Association, Inc. (CTFA). The issues raised by the agency in the 1979
NOI, along with the four comments received on that notice, and the
agency's responses to the comments, are discussed in the following
sections. This proposal does not, however, address comments related to
the straight colors that were provisionally listed in 1979 but have
been denied permanent listing in subsequent rulemakings (FD&C Red No. 3
(externally applied drug and all cosmetic uses), D&C Red Nos. 8, 9, and
19, and D&C Orange No. 17).

III. Development of Proposed Actions for Lakes

A. Terminology of Lakes

The agency is proposing the following changes to the existing
definitions relating to lakes.
1. Straight Color
Currently, Sec. 70.3(j) defines the term ``straight color'' as ``a
color additive listed in parts 73, 74, and 81 of this chapter, and
includes lakes * * *.'' Thus, the term encompasses all listed color
additives, including lakes. Current Sec. 70.3(l) defines the term
``lake'' as ``a straight color extended on a substratum by adsorption,
coprecipitation, or chemical combination that does not include any
combination of ingredients made by simple mixing process.'' These two
regulations, when read together, suggest that a lake may be used as a
color component of another lake. This implication is inconsistent with
current regulations for lakes (Secs. 82.51, 82.1051, and 82.2051) and
with the proposed regulations for lakes in this document, which do not
allow the synthesis of a lake using another lake as a color component.
There are other instances in which the existing definition of
straight color creates confusion. For example, the procedures for
requesting certification of a batch of a color additive treat straight
colors (Sec. 80.21(j)(1) (21 CFR 80.21(j)(1)) and lakes
(Sec. 80.21(j)(2)) separately. Federal Register publications relating
to color additives also commonly use the term ``straight color'' to
refer to a color additive other than a lake. For example, the 1979 NOI
referred to straight colors as distinct from lakes; the agency's
request for information concerning the usage of FD&C Red No. 3
requested data on straight colors, lakes, and mixtures (52 FR 44485;
November 19, 1987). Communications between the agency and industry also
indicate that the common usage of the term ``straight color'' does not
ordinarily include the term ``lake.'' To eliminate the confusion
resulting from the existing definition, the agency is proposing to
revise the definition for ``straight color.'' As revised, the
definition would read ``The term `straight color' means a color
additive that is listed in part 73 or 74 of this chapter, but does not
include color additive mixtures or lakes.''
2. Listed Color
As discussed in section III.A.1., the proposed definition of
``straight color'' would exclude lakes. Therefore, the agency is
proposing a new term ``listed color'' to refer to any color additive
(including a lake) listed in part 73 or 74 for any use. By definition,
the term would not include mixtures, which are not themselves listed
colors but rather combinations of listed colors. The agency is
proposing to add the following definition at Sec. 70.3(w): ``The term
'listed color' means a color additive listed in part 73 or 74 of this
chapter and includes lakes.''
3. Mixture
Currently, Sec. 70.3(k) defines the term ``mixture'' as ``a color
additive made by mixing two or more straight colors, or one or more
straight colors and one or

[[Page 8376]]
more diluents.'' The agency is proposing to modify this definition to
replace the current reference to ``straight color'' with ``listed
color'' and to clarify that a mixture does not involve a chemical
reaction between its components. Proposed Sec. 70.3(k) would read ``The
term `mixture' means a color additive made by mixing two or more listed
colors, or one or more listed colors and one or more diluents, without
an accompanying chemical reaction.''
4. Lake
Currently, Sec. 70.3(l) defines the term ``lake'' as ``a straight
color extended on a substratum by adsorption, coprecipitation, or
chemical combination that does not include any combination of
ingredients made by simple mixing process.'' As discussed in sections
IV. and V. of this document, the agency is proposing to permit the
preparation of a lake using more than one straight color. Proposed
Sec. 70.3(l) would read ``The term `lake' means a color additive made
by extending one or more straight colors on one or more substrata by
adsorption, coprecipitation, or chemical combination, but does not
include mixtures.''
5. Substratum
Currently, Sec. 70.3(n) defines ``substratum'' as ``the substance
on which the pure color in a lake is extended.'' This definition
implies that it is only the pure color that is extended on the
substratum. However, the data reviewed by the agency on the stability
of straight colors after laking clearly demonstrate that intermediates
and subsidiary colors are also extended on the substratum during the
laking process. Therefore, the agency is proposing to amend the
definition of substratum to read ``The term `substratum' means the
substance on which the straight color in a lake is extended.''
6. Precipitant (Basic Radical)
Although the term ``basic radical'' is not defined in the color
additive regulations, Secs. 82.51 and 82.1051 use ``basic radical'' to
denote a substance that may be used to precipitate a lake during its
manufacture. The agency believes that ``precipitant'' is a more
descriptive and scientifically accurate term for such a substance.
``Precipitant'' is the term normally used in technical publications.
For example, the Condensed Chemical Dictionary (12th ed., 1993) defines
a lake as a pigment produced by the interaction of an ``organic dye, a
precipitant, and an absorptive inorganic substrate.'' However, the same
source contains no definition of ``basic radical.'' The publications of
trade organizations also use the term ``precipitant'' rather than
``basic radical'' in discussions of lakes (Ref. 12). Therefore, the
agency is proposing to use the term ``precipitant'' rather than the
term ``basic radical'' in new Secs. 74.50 and 74.1050. However, the
agency is not proposing any formal definition of ``precipitant'' in
Sec. 70.3.
7. Repack
Currently, Sec. 70.3 does not define the term ``repack.'' However,
repacks are one of the four forms of color additive (in addition to
straight colors, lakes, and mixtures) that are certified under the
procedures in part 80. The other three forms of color additive are
defined in Sec. 70.3. Therefore, the agency tentatively concludes that
a definition of repack should be added to Sec. 70.3. Proposed
Sec. 70.3(x) would read ``The term `repack' means all or a portion of a
batch of certified color additive that has been sealed in accordance
with Sec. 70.20 and labeled in accordance with Sec. 70.25, but has been
either opened for repackaging without further processing, or relabeled
for shipment or delivery, by a person other than the person to whom the
certificate or acceptance of a notice claiming certification for the
batch was issued.'' Under Sec. 80.32(d), such repackaging or relabeling
results in the expiration of the certificate, and the batch therefore
ceases to be a certified batch. A repack may be certified under the
procedures in part 80 at a lower fee than for the original batch
(Sec. 80.10(b)). The agency notes that if a batch or portion of a batch
is processed in any way, including heating, then it is not a repack and
must be recertified as a new batch of color additive.

B. Nomenclature of Lakes

The current nomenclature system for lakes is described in
Secs. 82.51(b), 82.1051(b) and 82.2051(b). These regulations specify
that the listed name of a lake is formed from: (1) The listed name of
the color from which the lake is prepared; (2) the name of the cation
precipitant combined in such color; and (3) the word ``lake.'' This
system of nomenclature identifies the color additive as a lake and
specifies the straight-color component of the lake and the cation
precipitant used to prepare the lake. However, the name of a lake does
not identify the substrata used to prepare the lake. Because only one
substratum (alumina) is permitted in lakes for food use, this system
presents no identity problems for these lakes. However, under the
current nomenclature system, lakes listed for drug and cosmetic use are
not fully identified, because such lakes may contain a variety of
substrata. Thus, lakes produced from a common straight color and
cation, but different substrata, are identified with the same name. For
example, two lakes of D&C Red No. 21, one prepared with the cation
aluminum and the substratum alumina, the other with the cation aluminum
and the substrata alumina and titanium dioxide, are both named ``D&C
Red No. 21 Aluminum Lake.''
In the 1979 NOI, the agency described this problem with the current
nomenclature system and stated its intention to modify the nomenclature
system to include the substrata in the name of the lake. The agency
received comments from the IACM and CTFA supporting inclusion of
substrata in the name of a lake for the purpose of more accurately
identifying the listed color additive. As explained above, although
omitting the substratum from the name of a lake for food use presents
no problems, omitting the substratum from the name of a lake restricted
to drug or cosmetic use could cause confusion as to the identity of the
lake. However, as the same batch of lake may be used for a food, a
drug, or a cosmetic (if the lake is listed for all three uses), the
agency tentatively finds that use of a single nomenclature system to
identify all lakes would present the least overall confusion to users
of these color additives. Use of a uniform nomenclature system for all
lakes is also desirable because it avoids the necessity for
manufacturers of lakes to provide different labels for packages of the
same lake. Therefore, the agency is proposing that the same
nomenclature system be used for all lakes.
Therefore, the agency is proposing to modify the nomenclature of
lakes by requiring the inclusion of the identity of substrata in the
name of a lake. The proposed nomenclature system would construct the
name of a lake from the name(s) of the straight colors present in the
lake (in descending order of predominance), followed by the names of
the cations of the precipitants, and followed by the words ``Lake on
________ and ________'' (inserting the listed names of the substrata in
descending order of predominance). For example, the name of a lake
prepared by the extension of D&C Red No. 27 and D&C Orange No. 5 on
alumina and titanium dioxide using aluminum chloride and calcium
chloride as precipitants would be ``D&C Red No. 27 and D&C Orange No. 5
Aluminum Calcium Lake on Alumina and Titanium Dioxide.''
Currently, Sec. 82.1051(b)(1) provides that the name of a D&C lake
prepared

[[Page 8377]]
from an FD&C color shall be formed from the ``listed name of the color
from which the lake is prepared, except that if such name contains the
symbol `FD&C' such symbol shall be changed to `D&C'.'' For example, the
name of the lake formed from FD&C Yellow No. 5, rosin, and zirconium
cation is D&C Yellow No. 5 zirconium lake. The agency notes that the
use of the FD&C, D&C, and Ext. D&C prefixes to designate the approved
uses of colors originated in the 1939 listings of coal tar colors,
including lakes (4 FR 1922) and was carried over into the provisional
listing of these color additives in 1960 (25 FR 9759). The permanently
listed straight colors retained the names under which they were
provisionally listed, although the prefixes no longer accurately
reflected the approved uses in some cases. For example, FD&C Red No. 4
is permitted for use only in externally applied drug and cosmetic
products.
The agency is not proposing any action in this rulemaking to change
the names of the color additives whose food, drug, or cosmetic use is
no longer correctly designated by their FD&C or D&C prefix. However,
the agency has tentatively decided not to continue the current system
described in Sec. 82.1051(b)(1), in which the prefix `FD&C' is changed
to `D&C' when naming lakes for drug or cosmetic use that have been
prepared from straight colors that contain the `FD&C' prefix in their
name. The agency tentatively concludes that continuation of this
nomenclature provision is unnecessary to identify the approved uses of
the lake and could be confusing to users of lakes. As discussed above,
the designation `D&C' does not always accurately describe the uses of
the lake. Furthermore, under Sec. 70.25, the label of the color
additive must contain a declaration of the permitted uses of the lake.
Finally, because the proposed procedure for certification of lakes (see
section VI.B. of this document) would rely on the certificate for the
straight color used to prepare the lake, the agency believes that the
name of the lake should accurately identify the certified straight
color on which the certification of the lake is based. For example,
under the proposed certification procedure for lakes, the certificate
for the straight color in the lake cited above would be for ``FD&C
Yellow No. 5,'' not ``D&C Yellow No. 5.''
In the 1979 NOI, the agency also requested comments to address an
inconsistency in the current system of nomenclature; namely, that
certain lakes of identical composition may have different names. For
example, FD&C Blue No. 1 and D&C Blue No. 4 are two separately listed
straight colors that are different salt forms of the same dye. (FD&C
Blue No. 1 is the disodium salt and D&C Blue No. 4 is the diammonium
salt of a triphenylmethane derivative.) During the laking process the
accompanying cation in the straight color is replaced by the
precipitant cation. Thus, the lakes of these two straight colors,
prepared from the same substrata and precipitants, are chemically
identical. However, they have different names. For example, under the
current nomenclature system, the aluminum lakes on alumina of these two
straight colors are named ``FD&C Blue No. 1 Aluminum Lake'' and ``D&C
Blue No. 4 Aluminum Lake.'' (Under the proposed system, they would be
named ``FD&C Blue No. 1 Aluminum Lake on Alumina'' and ``D&C Blue No. 4
Aluminum Lake on Alumina,'' respectively.)
In its comment on the 1979 NOI, CTFA agreed with the agency's
assessment of this nomenclature problem. However, the comment suggested
that this and other problematic aspects of the current system of
nomenclature are better viewed as problems with the general
nomenclature of listed colors, not problems specific to lakes.
The agency agrees with CTFA's comment that these issues concerning
the nomenclature of lakes are really issues related to the general
nomenclature of listed colors. Therefore, the agency is not proposing
any modifications in the nomenclature of lakes to address these issues,
which are outside the scope of this rulemaking.
Under this proposal, the nomenclature proposed in this section
would be used for two purposes: (1) To prescribe the listed name of the
lake, because the agency is proposing to issue umbrella regulations for
lakes rather than an individual regulation for each listed lake; (2) to
identify the color additive on the labels of lakes that are packaged
for sale to manufacturers of foods, drugs, and cosmetics to be used in
coloring those products. The agency notes that lakes are also required
to be declared as ingredients on the label of foods and cosmetics.
Section VI.C.3. of this document describes the simplified nomenclature
system that FDA is proposing for ingredient labeling of lakes on food
and cosmetic labels.

Table 1.--Current and Proposed Regulatory Status of Straight Colors Used in Lakes
----------------------------------------------------------------------------------------------------------------
Current listings Proposed listings
----------------------------------------------------------------------------------------------------------------
Proposed regulatory
Current regulatory status Straight color status Straight color
----------------------------------------------------------------------------------------------------------------
Permanently listed: Part 74 FD&C Red No. 40....... Permanently listed: FD&C Blue No. 1, FD&C Blue
(Subpart A--Foods, Subpart B-- Part 74 (Subpart A-- No. 2, FD&C Green No. 3,
Drugs and Subpart C--Cosmetics). Foods (Sec. 74.50)). FD&C Red No. 40, FD&C
Yellow No. 5, FD&C Yellow
No. 6.
Provisionally listed:
Part 82 (Subpart B--Foods, FD&C Blue No. 1, FD&C (Subpart B--Drugs FD&C Blue No.1, FD&C Blue
Drugs, and Cosmetics). Blue No. 2, FD&C (Sec. 74.1050) and No. 2 (drugs only), FD&C
Green No. 3, FD&C Subpart C--Cosmetics Green No. 3, FD&C Yellow
Yellow No. 5, FD&C (Sec. 74.2050)).. No. 5, FD&C Yellow No. 6,
Yellow No. 6, FD&C FD&C Red No. 4, FD&C Red
Red No. 4. No. 40, D&C Blue No. 4,
D&C Orange No. 4, D&C
Orange No. 5, D&C Orange
No. 10, D&C Red No. 6, D&C
Red No. 7, D&C Red No. 21,
D&C Red No. 22, D&C Red
No. 27, D&C Red No. 28,
D&C Red No. 31, D&C Red
No. 33, D&C Red No. 34,
D&C Yellow No. 10.

[[Page 8378]]

(Subpart C--Drugs and FD&C Blue No. 1, FD&C Listing Terminated D&C Green No. 6, D&C Red
Cosmetics). Blue No. 2, FD&C (Does not form lakes). No. 17, D&C Red No. 30,
Green No. 3, FD&C D&C Red No. 36, D&C Violet
Yellow No. 5, FD&C No. 2.
Yellow No. 6, FD&C
Red No. 4, FD&C Blue
No. 4, FD&C Green No.
5, FD&C Green No. 6,
FD&C Orange No. 4,
FD&C Orange No. 5,
FD&C Orange No. 10,
FD&C Orange No. 11,
FD&C Orange No. 6,
FD&C Red No. 7, FD&C
Red No. 17, FD&C Red
No. 21, FD&C Red No.
22, FD&C Red No. 27,
FD&C Red No. 28, FD&C
Red No. 30, FD&C Red
No. 31, FD&C Red No.
33, FD&C Red No. 34,
FD&C Red No. 36, FD&C
Violet No. 2, FD&C
Yellow No. 7, FD&C
Yellow No. 8, FD&C
Yellow No. 10.
Listing Terminated (No D&C Green No. 5, D&C Orange
batches certified):. No. 11, D&C Yellow No. 7,
D&C Yellow No. 8.
(Subpart D-- Externally Applied Ext. D&C Yellow No. 7. Listing Terminated (No Ext. D&C Yellow No. 7.
Drugs and Cosmetics). confirmation of
stability during
laking).
----------------------------------------------------------------------------------------------------------------

C. Issues Relating to Definition of Lakes and Termination of Certain
Provisional Listings

1. Straight Colors
A summary of the current and proposed regulatory status of straight
colors for use in lakes is given in Table 1.
CTFA's comments on the 1979 NOI include information on the chemical
structure of the straight colors currently listed for use in lakes.
Based on its evaluation of these data and other information from the
published literature, the agency tentatively concludes that, to form a
lake, a straight color must contain a salt-forming group (i.e., a salt,
an acid, or a lactone group) as part of its chemical structure. The
agency finds that the following straight colors listed in part 82
contain a salt- forming group and thus are capable of forming a lake:
FD&C Red No. 4, D&C Red No. 6, D&C Red No. 7, D&C Red No. 21, D&C Red
No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No. 31, D&C Red No. 33,
D&C Red No. 34, FD&C Blue No. 1, FD&C Blue No. 2, D&C Blue No. 4, FD&C
Green No. 3, D&C Green No. 5, D&C Orange No. 4, D&C Orange No. 5, D&C
Orange No. 10, D&C Orange No. 11, FD&C Yellow No. 5, FD&C Yellow No. 6,
D&C Yellow No. 7, D&C Yellow No. 8, D&C Yellow No. 10, and Ext. D&C
Yellow No. 7.
However, based on the same information, the agency notes that the
following five straight colors listed in part 82 do not contain a salt-
forming group as part of their chemical structure and therefore cannot
form lakes: D&C Red No. 17, D&C Red No. 30, D&C Red No. 36, D&C Violet
No. 2, and D&C Green No. 6. CTFA's comment on the 1979 NOI also stated
that D&C Green No. 6 does not form a lake. Therefore, the agency
tentatively concludes that combinations of these straight colors with
substrata do not meet the definition of lake in Sec. 70.3(l).
Consequently, the agency is proposing to terminate the listing of D&C
Red No. 17, D&C Red No. 30, D&C Red No. 36, D&C Violet No. 2, and D&C
Green No. 6 as components of lakes. This proposed action would not
affect the listing of these color additives as straight colors. Under
the proposal, combinations of these straight colors with substrata that
are approved diluents or approved color additives would be color
additive mixtures rather than lakes. Such mixtures would be exempt from
certification under Sec. 80.35(b).
2. Diluents in Color Additive Mixtures for Cosmetic and Drug Use
a. Cosmetics. The agency notes that its proposed action to
terminate the listing of five straight colors as components of lakes
would not affect the use of these straight colors in cosmetic products.
Combinations of D&C Red No. 17, D&C Red No. 30, D&C Red No. 36, D&C
Violet No. 2, or D&C Green No. 6 with substrata listed in Sec. 82.1051
are color additive mixtures as defined in Sec. 70.3(k), and the
``substrata'' used in these combinations are diluents as defined in
Sec. 70.3(m). Because no regulation limits the diluents that may be
used in color additive mixtures intended for use in cosmetic products,
the proposed action to terminate the listing of D&C Red No. 17, D&C Red
No. 30, D&C Red No. 36, D&C Violet No. 2, and D&C Green No. 6 for use
in lakes would not affect their use in cosmetics as color additive
mixtures containing, as diluents, the substances now listed as
substrata in Sec. 82.1051 (alumina, blanc fixe, gloss white, clay,
titanium dioxide, zinc oxide, talc, rosin, aluminum benzoate, and
calcium carbonate).
b. Drugs. The proposed action to terminate the listing of D&C Red
No. 17, D&C Red No. 30, D&C Red No. 36, D&C

[[Page 8379]]
Violet No. 2, and D&C Green No. 6 for use in lakes would not affect
their use in drugs as color additive mixtures containing the following
substrata now listed in Sec. 82.1051: Alumina, calcium carbonate, talc,
titanium dioxide, and zinc oxide. Alumina, calcium carbonate, talc, and
titanium dioxide are listed in Secs. 73.1010, 73.1070, 73.1550, and
73.1575, respectively, as color additives exempt from certification for
use in drugs generally (ingested drugs and externally applied drugs).
Therefore, combinations of these substances with D&C Red No. 17, D&C
Red No. 30, D&C Red No. 36, D&C Violet No. 2, and D&C Green No. 6 are
permitted as color additive mixtures under existing regulations. Zinc
oxide is listed in Sec. 73.1991 as a color additive exempt from
certification for use in coloring externally applied drugs. In
addition, zinc oxide is generally recognized as safe (GRAS) for use as
a dietary supplement (Sec. 182.5991 (21 CFR 182.5991)) and as a
nutrient in food (Sec. 182.8991 (21 CFR 182.8991)). Section 73.1001
permits the use of substances listed in Sec. 73.1(a) as diluents in
color additive mixtures for ingested drug use. In turn, Sec. 73.1(a)
permits the use of substances that are GRAS under section 201(s) of the
act (21 U.S.C. 321(s)). Therefore, the agency concludes that zinc oxide
may be used with D&C Red No. 17, D&C Red No. 30, D&C Red No. 36, D&C
Violet No. 2, and D&C Green No. 6 either as an approved diluent in
color additive mixtures for coloring ingested drugs or as a straight-
color ingredient in color additive mixtures for coloring externally
applied drugs.
Rosin is currently listed in Sec. 73.1(b)(1)(i) as a diluent in
color additive mixtures for use in inks for marking food supplements in
tablet form, gum, and confectionery, and by reference, for use under
Sec. 73.1001(a)(2) in inks for branding pharmaceutical forms. In its
review of the safety of the substrata currently listed in Sec. 82.1051
(see section V.A.2.j. of this document), the agency determined that the
ingested uses of rosin are safe. However, in this same review, the
agency stated that it was aware of literature reports of dermal
irritation due to rosin (Ref. 13). Recently submitted data on human
skin sensitization and photoreaction to commercially available cosmetic
products colored with rosin lakes (Ref. 14) establish that lakes
containing rosin as a substratum are safe for externally applied drugs
and cosmetics. However, the rosin present in lakes, where it is a
component of an insoluble pigment, is not identical to free rosin
present as a diluent in color additive mixtures. Therefore, the agency
tentatively concludes that the data submitted on the safety of
externally applied rosin lakes do not resolve the safety issues
presented by the use of free rosin as a diluent in externally applied
drug products, such as the risk of allergic contact dermatitis and
occupational asthma.
Based on its safety review of rosin, the agency is proposing to
amend Sec. 73.1001 to list rosin as a diluent in color additive
mixtures for ingested drug use only. However, if the agency receives
information that adequately supports the safety of rosin as a diluent
in color additive mixtures for use in externally applied drugs, the
agency will consider listing rosin as a diluent for color additive
mixtures for both ingested and externally applied drugs. Anyone
interested in the listing of rosin for such use should submit
information on the identity, specifications, and dermal safety of the
rosin for which listing is sought.
The current regulations do not allow for the use of aluminum
benzoate, blanc fixe, clay, and gloss white as diluents in color
additive mixtures for drug use, because only the diluents provided for
in Sec. 73.1001 may be used in color additive mixtures for coloring
drugs. However, FDA has evaluated the safety of these substances, or
the materials used to make them, as part of its review of substrata in
lakes for drug and cosmetic use in section V.A.2. of this document.
This review included data on the ingested and dermal uses of barium
sulfate (blanc fixe), kaolin (clay), benzoic acid, and benzoates.
Specifically, the agency considered literature reviews of aluminum
salts, barium sulfate, kaolin and bentonite (a silicate); information
from the color additive petitions for use of certain aluminum lakes in
eye-area cosmetics; and safety reviews of aluminum compounds, benzoic
acid and benzoates, and kaolin and bentonite as food ingredients. These
safety reviews were conducted by the Select Committee on GRAS
Substances of the Federation of American Societies for Experimental
Biology and the Joint Food and Agriculture Organization (FAO)/World
Health Organization (WHO) Expert Committee on Food Additives.
Based on its review, which is discussed in section V.A.2. of this
document, the agency tentatively concludes that barium sulfate (blanc
fixe), aluminum benzoate, and kaolin (clay) are safe for use as
diluents in color additive mixtures for drug use. Therefore, as part of
its disposition of the provisional listings in part 82, the agency is
proposing to amend Sec. 73.1001 to list barium sulfate, aluminum
benzoate, and kaolin as diluents that may be safely used in color
additive mixtures exempt from certification that are intended for use
in ingested and externally applied drugs. The agency notes that gloss
white is a mixture of alumina and barium sulfate and thus would be
permitted for any use in color additive mixtures for which both alumina
and barium sulfate are permitted.
For the reasons discussed above, the agency tentatively concludes
that the proposed action to terminate the listing of D&C Red No. 17,
D&C Red No. 30, D&C Red No. 36, D&C Violet No. 2, and D&C Green No. 6
as components of lakes would not affect their use in drugs as color
additive mixtures containing alumina, calcium carbonate, kaolin (clay),
talc, zinc oxide, barium sulfate (blanc fixe), aluminum benzoate,
titanium dioxide, gloss white, or rosin (ingested drugs only). However,
the proposed termination would mean that those straight colors could no
longer be used in externally applied drugs as color additive mixtures
containing rosin, unless the agency receives data that establish the
safety of rosin as a diluent for externally applied uses.
3. Extended Toners
In the 1979 NOI, the agency requested information to identify
certain insoluble color additives, commercially described as extended
toners, that are classified as lakes under part 82. The agency
requested comments on the need to modify existing regulations or to
promulgate new regulations to address these color additives. FDA noted
its intent, in the absence of comments to the contrary, to exclude
these products from the definition of lakes.
CTFA's comment on the 1979 NOI provided information that identified
the composition of extended toners and of related insoluble color
additives known as resinated toners, extended resinated toners, and
toners. The comment requested revision of the definitions in 21 CFR
70.3 to better describe these substances. The agency has evaluated the
available information and determined that the color additives described
commercially as toners, resinated toners, extended toners, and extended
resinated toners are not lakes. These substances are either water-
insoluble straight colors or mixtures of water-insoluble straight
colors with insoluble diluents. Therefore, the agency tentatively
concludes that no new or modified regulations are needed to address
toners, resinated toners, extended toners, and extended resinated

[[Page 8380]]
toners because these substances are mixtures as defined in
Sec. 70.3(k), and the ``substrata'' used in these combinations are
diluents, as defined in Sec. 70.3(m).
The proposed reclassification of toners, resinated toners, extended
toners, and extended resinated toners as color additive mixtures
containing as diluents the ingredients now listed as substrata in
Sec. 82.1051 would not affect their use in drugs, because, as discussed
in section III.C.2. of this document, these substrata (except rosin for
use in externally applied drugs) are listed as GRAS in part 182, 184,
or 186 (21 CFR part 182, 184, or 186), approved as color additives for
drug use in part 73, or the agency is proposing to list them in
Sec. 73.1001 as diluents in color additive mixtures for drug use.
Because there is no regulation that limits the diluents that can be
used in color additive mixtures for cosmetic use, the proposed
reclassification of this group of color additives from lakes to color
additive mixtures would not affect their use in cosmetics.
4. Requests for Listing of Additional Lake Components
CTFA's comments on the 1979 NOI included a request that FDA
authorize for use in lakes the following straight colors: D&C Brown No.
1, D&C Green No. 8, and Ext. D&C Violet No. 2. These three straight
colors are currently listed in part 74 for cosmetic use. In addition,
D&C Green No. 8 is currently listed in part 74 for drug use. However,
the agency notes that these straight colors are not listed either
permanently in part 74 or provisionally in part 82 for use in preparing
lakes. Therefore, the agency tentatively concludes that consideration
of these straight colors for use in lakes is outside the scope of this
proposal, which addresses only the provisionally listed lakes and their
components. Interested persons may submit a color additive petition
under Sec. 71.1 (21 CFR 71.1) to amend the regulations to permit the
use of these straight colors in lakes.
CTFA's comments on the 1979 NOI also suggested that bismuth
oxychloride and mica should be listed as acceptable substrata in lakes
for coloring drugs and cosmetics. IACM's comments requested the listing
of titanium dioxide as a substratum for lakes for coloring foods.
However, bismuth oxychloride and mica are not provisionally listed in
part 82 as substrata in lakes for drug or cosmetic use, and titanium
dioxide is not provisionally listed in part 82 as a substratum in lakes
for food use. Therefore, the agency tentatively concludes that
consideration of the requested uses of these substances as substrata in
lakes is outside the scope of this rulemaking, which addresses
provisionally listed lakes and their components. Interested persons may
submit a color additive petition under Sec. 71.1 to amend the
regulations to permit use of these substances in lakes.
5. Definition of Lakes Versus Mixtures
CTFA's comments on the 1979 NOI noted that the straight-color
component of a lake, and not the substratum, provides the coloring
effect and, therefore, requested that the agency classify lakes as
color additive mixtures and list permitted substrata as diluents for
color additive mixtures.
As discussed in section III.C.1. of this document, the agency
agrees that combinations of non-salt-forming straight colors with
substrata should be classified as mixtures rather than lakes. As to
salt-forming straight colors, however, the agency disagrees with CTFA's
interpretation. Lakes are very different from color additive mixtures
because of the chemical reaction required to produce a lake. The agency
finds that, under both the current and proposed definitions of a lake,
the substratum is an integral part of the lake. In a mixture, there is
little if any chemical interaction between the components, which
function as separate ingredients. In the preparation of a lake,
however, there is a chemical reaction between the components, and the
physical properties of the resulting lake are very different from those
of the straight-color component (see section I. of this document).
Therefore, the agency tentatively concludes that lakes are not mixtures
and that substrata used to prepare a lake are not separate ingredients,
but are components of the finished color additive.
6. Pre-Amendments Certification of Provisionally Listed Lakes
As discussed in section II.A. of this document, the transitional
provisions of the 1960 amendments limited the provisional listing of
certifiable color additives to those for which at least one batch had
been certified prior to July 12, 1960, the enactment date of the 1960
amendments. In establishing the provisional list (25 FR 9759), FDA
removed 32 colors from listing because the agency had never certified
any batches of these colors. In preparing this document, the agency
reviewed its batch certification records to confirm that each straight
color, substratum, and precipitant included in the provisional listing
regulations for lakes was a component of at least one batch of a lake
certified between 1939 and July 12, 1960.
a. Straight Colors. The agency's search of color certification
records between 1939 and the enactment of the 1960 amendments
established that the agency did not certify any batches of lakes of D&C
Orange No. 11, D&C Yellow No. 7, D&C Yellow No. 8, or D&C Green No. 5
during that time. The agency tentatively concludes that its original
provisional listing of these color additives for use in lakes for drugs
or cosmetics was therefore incorrect. Accordingly, the agency is
proposing to terminate the provisional listings of D&C Orange No. 11,
D&C Yellow No. 7, D&C Yellow No. 8, and D&C Green No. 5 as components
of lakes for use in drugs or cosmetics. Any future consideration of the
use of these color additives as components of lakes would be through
the color additive petition process (Sec. 71.1).
b. Substrata. The agency's color certification records show that
all of the substrata listed in Secs. 82.51, 82.1051, and 82.2051,
except calcium carbonate, have been in continuous use in lakes because
certification was initiated in 1939 (Ref. 15). The agency added calcium
carbonate to the list of permitted substrata in 1959 (24 FR 3818) and
certified at least one batch of a lake containing this substratum for
drug or cosmetic use before the enactment of the 1960 amendments.
c. Precipitants. Section 82.51 lists two cations (calcium and
aluminum) as components of precipitants in lakes for food use. The
agency certified batches of FD&C aluminum lakes before the enactment of
the 1960 amendments. However, in the 1979 NOI, the agency proposed to
delete calcium as a listed cation in lakes for food use because the
agency had never certified any batches of FD&C calcium lakes.
Comments on the 1979 NOI from IACM and CTFA requested the agency
not to take this action. However, because these comments provided no
information to document agency certification of any batches of FD&C
calcium lakes before the enactment of the 1960 amendments, the agency
tentatively concludes that its original provisional listing of these
lakes was incorrect. Therefore, the agency is proposing to terminate
the provisional listing of calcium as a precipitant in the preparation
of lakes for food use. Any future consideration of the use of lakes
containing calcium precipitants for coloring food would be through the
color additive petition process (Sec. 71.1).
Sections 82.1051 and 82.2051 list seven cations (sodium, potassium,
aluminum, barium, calcium, strontium, and zirconium) as components of
precipitants in lakes for drug or cosmetic use. The agency certified

[[Page 8381]]
batches of lakes containing each of these seven cations for drug or
cosmetic use before the enactment of the 1960 amendments.

IV. Safety Review and Proposed Actions for Lakes for Use in Foods

A. Review of Components of Lakes for Use in Foods

The current regulation for provisionally listed lakes for use in
foods (21 CFR 82.51) provides for use of the following components in
such lakes: (1) Certified batches of the straight colors FD&C Blue No.
1 (21 CFR 82.101), FD&C Blue No. 2 (21 CFR 82.102), FD&C Green No. 3
(21 CFR 82.203), FD&C Yellow No. 5 (21 CFR 82.705), FD&C Yellow No. 6
(21 CFR 82.706); (2) the substratum alumina; (3) precipitants
containing the cations aluminum (Al+3) and calcium (Ca+2).
Additionally, 21 CFR 74.340 permanently lists lakes of FD&C Red No. 40
that are prepared as described in 21 CFR 82.51 and that meet the
specifications and labeling requirements prescribed by Sec. 82.51.
The identity and specifications for the straight colors used in the
preparation of the provisionally listed lakes for food use are provided
in the regulations for the straight-color components of lakes in part
82, which are cited above. The regulations in part 82 cross-reference
the permanent listings of the straight colors in part 74. As to
substrata, Sec. 82.3 defines alumina, but provides no specifications
for alumina or for the materials used to prepare it in situ. Finally,
with regard to precipitants, part 82 does not identify or prescribe
specifications for the precipitants that may be used in the preparation
of these lakes, other than specifying the cation component and
providing specifications that limit the level of soluble chlorides and
sulfates in the lake.
1. Straight Colors
a. Identity. The agency has already reviewed the identity and
safety of the straight colors currently permitted as components of
lakes for food use, either as part of its scientific review of
provisionally listed straight colors or in response to petitions for
the review of new color additives. Based on these reviews, the agency
concluded that FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, FD&C
Yellow No. 5, FD&C Yellow No. 6, and FD&C Red No. 40 are safe for use
in foods and permanently listed these straight colors in 21 CFR part
74, subpart A. The agency is proposing to continue to permit the use of
these straight colors as components of lakes for use in food, subject
to the proposed requirements discussed below.
b. Use of previously certified batches. Currently, under
Sec. 82.51, manufacturers are required to prepare lakes for food use
from previously certified batches of straight colors. This requirement
was intended to ensure that the levels of intermediates, subsidiary
colors, and other impurities in straight colors that are used to
prepare lakes for food use are within the levels specified in the
applicable regulations. Impurities in the straight color, especially
the carcinogenic constituents present in some straight colors, are a
primary safety concern with the use of these color additives and their
lakes in food.
In the 1979 NOI, the agency requested submission of information
about available methods for the determination of total (free plus
bound) intermediates, as well as subsidiary colors and other
impurities, and stated that without appropriate analytical methodology
it might be necessary to require that all lakes be produced from
certified batches of straight colors. The agency stated that there was
no satisfactory analytical method to determine total intermediates in
lakes. The available methods detected free intermediates but not
necessarily the intermediates that, like the straight color, are bound
to the substratum.
The comments on the 1979 NOI did not provide suitable methodology
for the analysis of intermediates and other impurities in lakes. CTFA's
comment stated that these problems could be addressed only through a
time-consuming and difficult undertaking to develop satisfactory
analytical methods. The comment suggested that the issue of
certification methodology should be separated from that of the
permanent listing of lakes, thus allowing these lakes to be permanently
listed while the industry and the agency went on to address the issue
of certification methodology jointly.
Section 721(b)(5)(A)(iv) of the act provides that in determining
whether the proposed use of a color additive is safe, the agency must
consider, among other relevant factors, the availability of any needed
practicable methods of analysis for determining the identity and
quantity of intermediates and other impurities contained in the color
additive. If lakes are prepared from uncertified batches of straight
colors, the only way to ensure that the intermediates, subsidiary
colors, and other impurities derived from the straight color do not
exceed the specification limits for the lake is to analyze the lake
itself for those impurities. However, as indicated above, the
analytical methods to accomplish this purpose are not currently
available. Therefore, the agency tentatively concludes that the lack of
adequate analytical methods to determine the levels of intermediates
and other impurities in lakes precludes the agency from prescribing
conditions of safe use for lakes prepared from uncertified batches of
straight colors. Accordingly, to ensure the continued safety of lakes
for food use, the agency is proposing to retain the requirement that
these lakes be prepared from certified batches of straight colors. As
discussed in section V.A. of this document, FDA is also proposing to
require that lakes for use in drugs and cosmetics be prepared from
certified batches of straight colors.
c. Stability. In the 1979 NOI, the agency asked for information
about the chemical stability of straight colors during the laking
process. The agency stated that if previously certified batches of
straight colors are used in the preparation of lakes, the levels of
intermediates and subsidiary colors in these lakes should be
proportional to those in the original batch of the straight color.
However, the agency was concerned that the laking process could cause
an unstable straight color to deteriorate and, consequently, increase
the levels of intermediates and subsidiary colors.
The agency requested data to confirm the stability of previously
certified batches of straight colors during the laking process. The
agency stated that, if such data were submitted, the agency would not
require specifications for intermediates and subsidiary colors in lakes
prepared from certified batches of straight colors. The agency also
noted the lack of satisfactory methodology for identifying and
quantifying intermediates and certain other contaminants in many lakes,
but added that the lack of such methodology does not pose a problem for
lakes produced from previously certified batches of colors, provided
that there is no measurable degradation of the color during the laking
process.
The straight colors that FDA proposes to permit as components of
lakes for food use fall into the following four groups, based on
chemical structure (the Color Index Structural classification (Ref.
16), as further refined by Marmion (Ref. 17)): Monoazo (FD&C Red No.
40, FD&C Yellow No. 6); pyrazolone (FD&C Yellow No. 5);
triphenylmethane (FD&C Blue No. 1, FD&C Green No. 3); and indigoid
(FD&C Blue No. 2). The FD&C lakes of these straight colors made up
about 80 percent of the total poundage of lakes certified in fiscal
year 1995 (FY-95) (Ref. 18). FD&C lakes of three

[[Page 8382]]
straight colors (FD&C Yellow No. 5, FD&C Yellow No. 6, and FD&C Red No.
40) made up about 90 percent of the FD&C lakes certified in FY-95.
Lakes of FD&C Blue No. 1 and FD&C Blue No. 2 made up the remaining 10
percent. No batches of FD&C Green No. 3 lakes were certified in FY-95.
Because lakes of monoazo and pyrazolone dyes make up such a high
proportion of lakes certified, the agency is particularly concerned
about possible degradation of FD&C lakes of these dyes.
CTFA submitted data (Ref. 19) to confirm the stability during
laking on alumina of three straight colors (FD&C Blue No. 1, FD&C Red
No. 40, and FD&C Yellow No. 5) that represent three of the four
structural groups. The data presented a comparison of the high
performance liquid chromatography (HPLC) evaluations of each of five
samples of FD&C Red No. 40, FD&C Yellow No. 5, and FD&C Blue No. 1 with
the corresponding lake made from each sample. FDA has evaluated the
data submitted by CTFA. A quantitative comparison of the levels of
intermediates and subsidiary colors present in the straight color and
the corresponding lake confirmed that the levels of intermediates and
subsidiary colors in the lakes (after adjustment for the percent
straight color in the lake) did not differ significantly from those in
the corresponding straight colors (Ref. 20).
The agency also conducted a brief study on the stability of FD&C
Blue No. 2 during the laking process (Ref. 21). This study presented a
comparison of the HPLC evaluations of a sample of a certified batch of
FD&C Blue No. 2 and a sample of a certified batch of the aluminum lake
prepared from this batch. A quantitative comparison of the levels of
intermediates and subsidiary colors present in the straight color and
the corresponding lake confirmed that the levels of intermediates and
subsidiary colors in the lake (after adjustment for the percent
straight color in the lake) did not differ significantly from those in
the corresponding straight color.
The data evaluated by the agency provide evidence that lakes of the
straight colors FD&C Yellow No. 5, FD&C Red No. 40, FD&C Blue No. 1,
and FD&C Blue No. 2 can be produced without significant degradation of
the straight color. When produced under conditions of current good
manufacturing practice (CGMP), these lakes meet the specifications for
intermediates and subsidiary colors in the straight color, after
adjustment for total color content of the lake. Although data have not
been submitted for all of the straight colors FDA proposes to permit as
components of lakes for food use, the remaining such straight colors
(FD&C Green No. 3 and FD&C Yellow No. 6) have chemical structures that
are similar to other straight colors (FD&C Blue No. 1 and FD&C Red No.
40, respectively) discussed above. The stability of FD&C Yellow No. 6
aluminum lake, which makes up over 25 percent of the total poundage of
FD&C lakes certified in FY-95, is also supported by published studies.
In these studies, the FD&C Yellow No. 6 aluminum lake showed greater
thermal stability than did FD&C Red No. 40 aluminum lake (Ref. 22), and
the straight color FD&C Yellow No. 6 was as stable as the straight
color FD&C Red No. 40 under the pH conditions studied, showing no
appreciable change over a week's exposure (Ref. 17). The agency
tentatively finds that because of the similarity of chemical structure,
the data available for the lakes of FD&C Blue No. 1 and FD&C Red No. 40
are adequate to confirm the stability of FD&C Green No. 3 and FD&C
Yellow No. 6, respectively, during the manufacture of lakes in
accordance with CGMP. In addition, the published data on FD&C Yellow
No. 6 and its aluminum lake provide corroborative evidence for the
stability of this straight color during the laking process when
conducted under conditions consistent with CGMP.
Based on its previous evaluations of the safety of the straight
colors that FDA proposes to permit as components of lakes for food use
and on the scientific evidence that lakes of these straight colors can
be produced under conditions consistent with CGMP without significant
degradation of the straight color, the agency now tentatively concludes
that certified batches of FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green
No. 3, FD&C Yellow No. 5, FD&C Yellow No. 6, and FD&C Red No. 40 are
safe for use as components of lakes for food use that are prepared
under conditions of CGMP. Therefore, the agency is proposing to permit
certified batches of these straight colors as components of lakes for
food use in Sec. 74.50.
The agency is not, however, proposing to establish any definition
of CGMP for the preparation of lakes for food use. FDA recognizes that
CGMP for laking will vary with the straight color used, may include a
variety of combinations of conditions, and may change over time with
the introduction of new combinations of conditions. The agency's
regulatory goal is to protect the public health by assuring that laking
is conducted in a manner such that no significant degradation of the
straight color occurs, not to prescribe the details of industry
practice. Safety issues relating to the use of CGMP in preparing lakes
are discussed further in sections IV.B.5 and IV.C. of this document.
d. Use of more than one straight color in a lake. The agency also
tentatively concludes that the current prohibition on the use of more
than one straight color in a lake is unnecessary. This prohibition was
instituted as part of the original listing of lakes as certified colors
in 1939 (4 FR 1922, 4 FR 3931, and 5 FR 1138). At that time, the
regulations did not require that lakes be prepared from previously
certified batches of straight color, and the only food use for which
lakes were listed was for dyeing eggs in the shell. The requirement
that lakes for food use be prepared from previously certified batches
of straight color was initiated in 1959, when the regulations were
amended to permit, for the first time, the use of certain lakes in
foods generally (24 FR 3818 and 24 FR 5302). The agency now tentatively
concludes that, because of the proposed requirement that certified
batches of straight colors be used in preparing all lakes, the evidence
for the stability of straight colors during the laking process, and the
proposed certification requirement for lakes (discussed in section
IV.C. of this document), the prohibition against the use of more than
one straight color to make a lake is unnecessary. Therefore, the agency
is proposing to permit the preparation of a lake from certified batches
of more than one straight color.
2. Substratum--Alumina
Alumina is the only substratum provisionally listed for lakes for
food use. Section 82.3(g) defines alumina as ``a suspension in water of
precipitated aluminum hydroxide'' but prescribes no quality
requirements for alumina substratum. This definition covers both
preformed (precipitated and dried) alumina that is subsequently
suspended in water and alumina that is prepared in situ, without
subsequent recovery and drying.
As noted in section I. of this document, alumina may be prepared in
situ from aluminum sulfate and sodium hydroxide or sodium carbonate
during the manufacture of lakes. Aluminum sulfate is GRAS for food use
(Sec. 182.1125) and is subject to the specifications in the Food
Chemicals Codex 2d. ed. (1972) (Sec. 170.30(h)(1) (21 CFR
170.30(h)(1))). Sodium carbonate and sodium hydroxide are affirmed as
GRAS for food use (Secs. 184.1742 and 184.1763, respectively) and are
required

[[Page 8383]]
to meet the specifications in the Food Chemicals Codex, 3d. ed. (1981).
In addition, Sec. 73.1010 lists alumina (dried aluminum hydroxide)
as a color additive for use in drugs and provides identity and
specifications for alumina as a color additive. The agency tentatively
concludes that, although the listed use of alumina (dried aluminum
hydroxide) is for coloring drug products, alumina that meets the
identity and quality requirements in Sec. 73.1010 (a)(1) and (b) is
safe as a substratum for lakes for food use (Ref. 13).
The agency has evaluated the available data relating to the safety
of aluminum salts. These data included literature reviews, information
from a color additive petition for use of several aluminum lakes on
alumina in eye-area cosmetics, and safety reviews of aluminum compounds
(including aluminum salts) as food ingredients by the Select Committee
on GRAS Substances of the Federation of American Societies for
Experimental Biology and the Joint FAO/WHO Expert Committee of Food
Additives. Based on this evaluation, the agency tentatively concludes
that alumina conforming to the identity and quality requirements set
forth in Sec. 73.1010 (a)(1) and (b) (Refs. 13, 23, and 24) is safe for
use as a substratum in lakes for food use. The agency also tentatively
concludes that alumina prepared from aluminum sulfate and sodium
carbonate or sodium hydroxide that meet the requirements for these
compounds in the Food Chemicals Codex 2d ed. (1971) (aluminum sulfate)
or 3d ed. (1981) (sodium carbonate and sodium hydroxide) is safe as a
component of lakes for food use.
3. Precipitants
a. Aluminum cation (Al+3). In its safety review of alumina
(see section IV.A.2. of this document), the agency evaluated the safety
of the use of the aluminum salts (salts containing the aluminum cation
(Al+3)). Based on this safety review, the agency tentatively
concluded that the use of alumina as a substratum in lakes is safe.
Based on the same data, the agency also tentatively concludes that the
use of the aluminum cation as a component of precipitants used in the
preparation of lakes for food use is safe (Ref. 13, 23, and 24).
Aluminum cation is added as a precipitant with an accompanying anion.
If an aluminum salt is added as a precipitant, the anion is added as
part of the salt. Alternatively, if aluminum oxide or hydroxide is used
as a precipitant, the anion is added as an acid to ensure the
solubility of the aluminum cation to function as a precipitant. The
anions that the agency proposes to permit for use in lakes are
discussed in section IV.A.3.c. of this document.
The agency is not proposing to establish quality requirements for
precipitants used in the preparation of lakes for food use. The agency
recognizes that a variety of precipitant ingredients can be used to
produce the aluminum cation that functions as a precipitant in lakes
for food use. Furthermore, the agency does not anticipate that the use
of precipitant ingredients that form the aluminum cation, under
conditions consistent with CGMP, would introduce contaminants that
require limitation by specifications for the precipitant ingredients.
Precipitants are used at low levels (a small percentage of the total
batch weight) and, by virtue of their function in the laking process,
are always water-soluble cations. Because lakes are washed when
prepared in accordance with CGMP, the agency anticipates that only low
levels of water-soluble contaminants will remain in the finished lake.
The only possible concern would be the presence of heavy metals
deriving from contaminants in the precipitants. To address this
potential problem, as discussed below, the proposed specifications for
lakes will limit the levels of heavy metal contaminants permitted in
the end product. Therefore, the agency tentatively concludes that
quality requirements for the ingredients used to form precipitants in
lakes for food use are unnecessary.
b. Calcium cation (Ca+2). As discussed in section III.C.6.c.
of this document, the agency is proposing to terminate the listing of
calcium as a cation in lakes for food use because calcium lakes were
not used in food in 1960 and thus should not have been provisionally
listed. Any future consideration of the use of calcium lakes for
coloring foods would be through the color additive petition process
(Sec. 71.1).
c. Accompanying anions. The use of the aluminum cation in
preparation of lakes results in the formation of chloride or sulfate
anions. Chloride and sulfate are components of many food ingredients
that the agency has listed or affirmed as GRAS for general food use
(for example: Aluminum sulfate, Sec. 182.1125; calcium sulfate,
Sec. 184.1230; table salt (sodium chloride), Sec. 182.1(a); potassium
chloride, Sec. 184.1622). In the safety reviews conducted as part of
the GRAS rulemakings for these ingredients, the agency found that
ingestion of chloride and sulfate (in the presence of the accompanying
cation) was safe at levels that vastly exceed possible levels of
exposure to these anions as components of lakes. Therefore, the agency
tentatively concludes that the presence of these anions in lakes for
food use is safe when CGMP is observed (Ref. 13).

B. Specifications for Lakes for Use in Foods

1. Intermediates and Other Impurities Derived From Straight Colors
A typical straight color contains, in addition to the primary color
component, intermediates and subsidiary colors. Intermediates are
unreacted starting materials used to synthesize the primary color.
Subsidiary colors are colored by-products of the synthesis of the
primary color. As discussed in section IV.A.1.b. of this document, the
agency is proposing to require that lakes be prepared from certified
batches of straight color. The regulations for straight colors contain
specifications that limit the levels of intermediates and subsidiary
colors that may be present in the straight color. In this proposal, the
agency has also tentatively concluded that the straight colors in lakes
for food use do not degrade significantly during preparation of the
lakes under conditions consistent with CGMP. Therefore, the agency
tentatively concludes that the specifications for intermediates and
subsidiary colors in straight colors are sufficient to ensure the
safety of lakes prepared from certified batches of straight colors and
that separate specifications for intermediates and subsidiary colors in
lakes are unnecessary.
2. Heavy Metals
The current specifications for lakes for food use (Sec. 82.5)
establish limits of 10 ppm lead, 1.4 ppm arsenic, and ``not more than
trace'' levels of total heavy metals (other than lead and arsenic). In
the 1979 NOI, the agency proposed adding a specification for mercury in
lakes. The agency tentatively finds that the manufacturing processes
for lakes use metal salts that are sources of potential contamination
by heavy metals; moreover, in its certification of lakes, the agency
has rejected batches because of the presence of heavy metals, including
lead. Therefore, the agency tentatively concludes that specifications
to limit the levels of lead, arsenic, and mercury in lakes are
necessary to ensure their safe use in food. As a result of its safety
reviews of the straight colors used in food, the agency established
limits of not more than 10 parts per million

[[Page 8384]]
(ppm) lead, 3 ppm arsenic, and 1 ppm mercury in the specifications for
most color additives permanently listed for food use in parts 73 and
74. The agency tentatively concludes that such specifications are also
sufficient to ensure the safety of lakes.
FDA is unaware of any heavy metals, other than lead, arsenic, and
mercury, that have a significant level of toxicity and that would be
expected to occur in lakes. Therefore, the agency tentatively concludes
that a general heavy metal specification is unnecessary to ensure the
safety of lakes for food use.
One comment received in response to the 1979 NOI suggested that a
limitation on iron be included in the specifications for lakes for food
use. Iron salts may be present in lakes as contaminants inadvertently
introduced during the manufacturing process. For example, a batch of
lake prepared using rusted equipment or water with a high iron content
may contain iron salts.
The agency has evaluated the safety of iron salts as a contaminant
in lakes to determine whether their presence would present a sufficient
safety hazard to warrant inclusion of a specification for iron. The
agency notes that iron is an essential mineral, and that iron and many
of its salts are affirmed as GRAS in part 184 for use as nutrients in
food (for example, elemental iron, Sec. 184.1375; ferric ammonium
citrate, Sec. 184.1296; ferric chloride, Sec. 184.1297; ferric sulfate,
Sec. 184.1307; ferrous carbonate, Sec. 184.1307b; ferrous sulfate,
Sec. 184.1315). However, the agency also notes that high levels of iron
consumption can be toxic, especially for certain subpopulations. (See,
e.g., 59 FR 51030, October 6, 1994).
Lakes are generally used at low levels (typically less than 0.05
percent) in foods, except for some low-consumption food items such as
candy and candy coatings, colored sugar and frostings, dietary
supplements, seasonings, flavorings, and chewing gum (Ref. 25).
Therefore, consumption of iron due to its presence in lakes as a
contaminant would be low. Under these circumstances, the agency finds
no evidence of a safety hazard from exposure to iron as a contaminant
in lakes for food use. Therefore, the agency tentatively concludes that
a specification to limit the level of iron is unnecessary to ensure the
safety of lakes for food use. Moreover, the agency notes that the
conditions and practices that lead to the presence of iron salts as a
contaminant in a batch of lake are addressed by the proposed
requirement that lakes be prepared in accordance with CGMP (see section
IV.B.5. of this document).
3. Soluble Chlorides and Sulfates
Current Sec. 82.51 contains a specification that limits the content
of the soluble chloride and sulfate anions in lakes for food use. The
agency finds that the washing of the lake during the manufacturing
process removes most of these water-soluble anions. Furthermore, as
discussed above in section IV.A.3.c. of this document, the agency found
in safety reviews conducted as part of several GRAS rulemakings that
soluble chloride and sulfate anions are safe in foods at levels
considerably greater than those found in lakes (Ref. 13). Therefore,
the agency tentatively concludes that a specification to limit the
levels of soluble chlorides and sulfates is unnecessary to ensure the
safety of lakes prepared in conformity with CGMP for food use.
4. Inorganic Material Insoluble in HCl
Current Sec. 82.51 contains specifications that limit the content
of inorganic material insoluble in HCl in lakes. This specification was
intended to ensure that the lake was prepared in accordance with CGMP
and that no foreign material was inadvertently added during the laking
process. However, agency certification records for lakes for food use
in the past 20 years show that only one batch of lake has been denied
certification based on this specification. Even without the
specification for inorganic material insoluble in HCl, this batch of
lake would not have met the requirements in this proposal because the
alumina used as a substratum would not have met the applicable quality
requirements. Furthermore, the agency is proposing to include in the
specifications for lakes a provision to require that lakes be prepared
in accordance with CGMP. Therefore, the agency tentatively concludes
that a specification for material insoluble in HCl is unnecessary for
lakes that meet the other proposed requirements for lakes, and such a
specification is not included in this proposal.
5. Other Impurities and Contaminants
The agency has tentatively concluded above that specifications to
limit the level of total heavy metals (except lead, arsenic, and
mercury), soluble chlorides and sulfates, and material insoluble in HCl
are unnecessary to ensure the safety of lakes for food use as long as a
general provision is included in the specifications for lakes to ensure
that they are prepared in conformity with CGMP. The identity
requirements and specifications in color additive regulations include
impurities that are expected to occur at significant levels in a color
additive that has been prepared in accordance with CGMP. In its
certification of color additives, FDA has occasionally denied
certification for batches of color additives due to the presence of
significant levels of impurities for which the listing regulation
contains no specifications. In a few instances, these impurities could
be linked to improper storage of the color additive or to cross-
contamination from insufficiently cleaned processing equipment. In most
cases, the source of the impurity was unknown. Based on the agency's
experience in certifying thousands of batches of color additives
annually, corroborated by the agency's analyses of reference standards
(reference batches of color additives) used in toxicological studies of
various straight colors as part of the safety reviews of these color
additives, FDA believes that the impurities in the rejected batches
would not have been present had the color additives been manufactured
under conditions consistent with CGMP.
As noted above in section IV.A.1.c. of this document, it is
important that lakes be prepared in accordance with CGMP to ensure that
the straight color does not degrade during preparation of the lake.
Manufacturing conditions must be controlled so that levels of uncolored
components in the straight color, including the carcinogenic
constituents in certain monoazo and pyrazolone straight colors, do not
increase during preparation or handling of the lake. CGMP includes use
of proper temperatures, especially during drying, to avoid affecting
the composition of the lake, and sufficient washing of the lake to
remove water-soluble impurities. For example, the agency recently
rejected a batch of a monoazo straight color because the batch exceeded
the specifications for certain carcinogenic constituents. Subsequent
discussions with the manufacturer revealed that the batch had been
previously certified, but had failed to meet the manufacturer's
microbiological specifications and had been reprocessed (redried).
After redrying, the batch no longer met the specification for trace-
level carcinogenic constituents. The agency notes, however, that
because of their chemical properties, such carcinogenic constituents
are unlikely to be incorporated into lakes to the same extent as into
straight colors, and sufficient washing of the lake could significantly
decrease the levels of these constituents.
To ensure the safety of lakes for use in foods, FDA is proposing to
continue

[[Page 8385]]
the requirement in existing Sec. 82.5 that lakes shall be free from
impurities other than those named in the specifications, to the extent
that such impurities may be avoided by CGMP. However, the agency is not
proposing to define specific conditions that would constitute CGMP in
the preparation of lakes. The agency recognizes that appropriate
manufacturing conditions may differ for the preparation of different
lakes and, in fact, may change over time. Furthermore, even the
preparation of a single lake that meets the requirements of part 74 may
be accomplished using different conditions of manufacture. The agency
wants to retain the current flexibility in preparation of lakes for
food use, but maintain the assurance that there will be no significant
degradation of the straight color during preparation of the lake and
that the resulting lake will be otherwise in compliance with the
requirements of part 74. To accomplish this objective, the agency is
not proposing to define any specific conditions of CGMP; however, in
its review of notices claiming certification for batches of lake, the
agency is proposing to use the accountability of the straight color in
the lake, calculated as described below, as an indicator of the use of
CGMP in the preparation of the lake.
Under the current certification procedure for FD&C lakes, the
agency can monitor both the use of certified batches of straight color
in lakes for food use and indicators for the use of CGMP in the
preparation or repack of a batch of lake. In a request for
certification for a batch of lake, the firm must declare the certified
lot number and the poundage from that lot for the straight color that
is added to prepare the lake. The agency can determine a poundage
accountability of the batches of straight colors that are used to
prepare FD&C lakes. This accountability ensures that no more straight
color is used in FD&C lakes than has been certified. For example, a
firm that owns a 100-pound batch of straight color cannot credibly
claim to use 1,000 pounds from that batch to make lakes.
From the information in the request for certification and from
analysis of the sample submitted with the request, the agency
determines the total color accountability for each batch of lake (the
amount of total color that was added to the batch of lake compared to
the total color of the resulting batch). This accountability for total
color is an indicator for the use of CGMP in the preparation or repack
of a batch of lake. In its determination of accountability of the
straight color in lakes for food use, the agency calculates a
theoretical range for the expected total color content of a lake based
on the minimum total color permitted in the listing regulation for the
straight color, the maximum total color possible for the straight color
(100 percent), the weight of straight color used to prepare the lake,
and the weight of the lake. For example, for a 100-pound batch of FD&C
Yellow No. 5 aluminum lake on alumina that was prepared from 25 pounds
of FD&C Yellow No. 5, the theoretical range for the expected total
color content of the lake would be from 21.8 percent to 25 percent.
This theoretical range allows for variations in total color resulting
from factors that normally occur during the manufacture of a lake, such
as incomplete laking of the color and bleeding of the color during
washing.
The agency is requesting comments on the usefulness of total color
accountability as an indicator of the use of CGMP in the preparation
and repacking of batches of lake.

C. Certification Requirement

The agency has evaluated the necessity, in the interest of public
health, for the certification of lakes prepared from certified batches
of straight color. The agency tentatively concludes that continued
batch certification of lakes is necessary to protect the public health.
The agency bases this tentative conclusion on two safety issues: The
need to ensure the safety of the components (straight colors,
precipitants, and substrata) used to prepare a lake; and the need to
ensure that lakes are prepared and repacked under conditions of CGMP to
prevent degradation of the straight color.
The agency's traditional means for postmarket assurance of product
safety is the collection and analysis of a sample. However, as
discussed in section IV.A.1.b. of this document, suitable analytical
methodology is not available to identify and quantify all potentially
harmful impurities that may be present in lakes. Therefore, the agency
tentatively concludes that the premarket controls afforded by the
certification requirement are necessary to allow FDA to verify that the
conditions for safe use of lakes are being met. Therefore, the agency
is proposing to list lakes in part 74 as color additives subject to
certification.
Certification will allow the agency to confirm, before a lake is
marketed, that only safe and suitable components have been used to
prepare it; that any batches of straight color used in the lake were
previously certified; and that the straight-color component of the lake
has not degraded during manufacture or repacking. The agency
tentatively concludes, however, that not all aspects of the current
batch certification procedure are necessary to accomplish these
objectives, and is proposing a simplified procedure for certifying
batches of lakes. This proposed procedure is discussed in section VI.B.
of this document.
The agency is specifically requesting, as comments on this
proposal, comments on the usefulness of its proposed certification
procedure for the intended purpose of protecting the public health.

D. Provisions of Proposed Sec. 74.50 Lakes for Use in Foods

The agency is proposing new Sec. 74.50 to list lakes permanently
for use in foods as color additives subject to certification. Section
74.50(a)(1), (a)(2), and (a)(3) would designate the components
permitted for use in lakes for coloring food. These paragraphs would
authorize the use of certified batches of one or more of the straight
colors FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, FD&C Yellow
No. 5, FD&C Yellow No. 6, and FD&C Red No. 40; the substratum alumina
that either conforms to the requirements for alumina under
Sec. 73.1010(a)(1) and (b), or is a suspension in water of precipitated
aluminum hydroxide prepared from aluminum sulfate that meets the
requirements of the Food Chemicals Codex 2d ed. (1972) and sodium
carbonate or sodium hydroxide that meets the requirements of the Food
Chemicals Codex 3d ed. (1981); and precipitants that form the aluminum
cation (Al+3) and the anion chloride (Cl-1) or sulfate
(SO4-2).
Proposed Sec. 74.50(a)(4) would provide that only diluents that are
permitted in mixtures of straight colors for food use may be used in
color additive mixtures containing lakes for such use.
Proposed Sec. 74.50(b) would prescribe the following specifications
for lakes for food use: Lead (not more than 10 ppm), arsenic (not more
than 3 ppm), mercury (not more than 1 ppm). It would also state that
lakes shall be free from impurities other than those named in the
specifications, to the extent that such impurities may be avoided by
CGMP.
Proposed Sec. 74.50(c)(1) would permit the use of lakes in foods
generally, except in foods subject to a standard of identity that does
not authorize such use. The proviso relating to standardized foods
would clarify that authorization for use of lakes in this regulation
does not take precedence over any restrictions on color additive use in
a food standard regulation.

[[Page 8386]]
Currently, all the straight colors authorized for use in lakes for food
use are approved for the same food uses. Because this may not always be
the case, however, proposed Sec. 74.50(c)(2) would restrict the use of
a lake manufactured from more than one straight color to those uses
common to all of the straight colors in the lake.
Proposed Sec. 74.50(d) would identify each lake made as prescribed
in Sec. 74.50(a) as a listed color and would prescribe the formation of
its listed name from the names of the certified straight colors present
in the lake (in descending order of predominance), followed by the name
of the cation of the precipitant (aluminum) and followed by the words
``lake on alumina.'' The anion component of the precipitant would not
be included in the name of the lake because this anion is removed
during processing under conditions of CGMP and is not a component of
the final lake.
Proposed Sec. 74.50(e)(1) would require that the label of the lake
and of any mixtures prepared from it for coloring purposes conform to
the requirements of Sec. 70.25. Proposed Sec. 74.50(e)(2) would require
that the label of food products that contain a lake declare the
presence of the lake in accordance with Sec. 101.22(k) (21 CFR
101.22(k)). Proposed Sec. 74.50(e)(3) would require that butter,
cheese, and ice cream that contain a lake of FD&C Yellow No. 5 or FD&C
Yellow No. 6 be labeled in accordance with Sec. 101.22(k)(1). These
proposed labeling provisions are discussed more fully in sections
VI.C.2. and VI.C.3. of this document.
Proposed Sec. 74.50(f) would require that all batches of lakes be
certified in accordance with proposed regulations in part 80.

V. Safety Review and Proposed Actions for Lakes for Use in Drugs and
Cosmetics

A. Review of Components of Lakes for Use in Drugs and Cosmetics

The current provisional listing regulations for lakes for use in
drugs and cosmetics generally (Sec. 82.1051) and for use in external
drugs and cosmetics only (Sec. 82.2051) provide for use of the
following components: (1) The straight colors FD&C Blue No. 1
(Sec. 82.101), FD&C Blue No. 2 (Sec. 82.102), FD&C Green No. 3
(Sec. 82.203), FD&C Yellow No. 5 (Sec. 82.705), FD&C Yellow No. 6
(Sec. 82.706), D&C Blue No. 4 (Sec. 82.1104), D&C Green No. 5
(Sec. 82.1205), D&C Green No. 6 (Sec. 82.1206), D&C Orange No. 4
(Sec. 82.1254), D&C Orange No. 5 (Sec. 82.1255), D&C Orange No. 10
(Sec. 82.1260), D&C Orange No. 11 (Sec. 82.1261), FD&C Red No. 4
(Sec. 82.304), D&C Red No. 6 (Sec. 82.1306), D&C Red No. 7
(Sec. 82.1307), D&C Red No. 17 (Sec. 82.1317), D&C Red No. 21
(Sec. 82.1321), D&C Red No. 22 (Sec. 82.1322), D&C Red No. 27
(Sec. 82.1327), D&C Red No. 28 (Sec. 82.1328), D&C Red No. 30
(Sec. 82.1330), D&C Red No. 31 (Sec. 82.1331), D&C Red No. 33
(Sec. 82.1333), D&C Red No. 34 (Sec. 82.1334), D&C Red No. 36
(Sec. 82.1336), D&C Violet No. 2 (Sec. 82.1602), D&C Yellow No. 7
(Sec. 82.1707), D&C Yellow No. 8 (Sec. 82.1708), D&C Yellow No. 10
(Sec. 82.1710), and Ext. D&C Yellow No. 7 (Sec. 82.2707a); (2) the
substrata alumina, blanc fixe, gloss white, clay, titanium dioxide,
zinc oxide, talc, rosin, aluminum benzoate, and calcium carbonate; (3)
precipitants containing the cations sodium (Na+1), potassium
(K+1), aluminum (Al+3), barium (Ba+2), calcium
(Ca+2), strontium (Sr+2), and zirconium (Zr+4).
Additionally, the lakes of FD&C Red No. 40 prepared with the substrata
and precipitants listed above are permanently listed in Secs. 74.1340
and 74.2340.
The identity and specifications for the straight colors used to
prepare lakes are provided in the regulations cited above and generally
cross-reference the requirements of the permanent listing for the
straight color in part 74. As to substrata, Sec. 82.3 defines three of
the substrata used in lakes (alumina, blanc fixe, gloss white), but
provides no specifications for the materials to be used. Part 82 does
not identify or prescribe specifications for other substrata (clay,
titanium dioxide, zinc oxide, talc, rosin, aluminum benzoate, and
calcium carbonate) for lakes for drug or cosmetic use, or for the
precipitants to be used in the preparation of these lakes.
1. Straight Colors
a. Identity and uses. As discussed in sections III.C.1. and
III.C.6.a. of this document, the agency has tentatively concluded that
several of the straight colors currently listed for use in lakes for
coloring drugs and cosmetics either do not form lakes (D&C Red No. 17,
D&C Red No. 30, D&C Red No. 36, D&C Violet No. 2, and D&C Green No. 6)
or were not present in any batch of lake certified for drug or cosmetic
use before the enactment of the 1960 amendments (D&C Orange No. 11, D&C
Yellow No. 7, D&C Yellow No. 8, and D&C Green No. 5). The proposed
termination of the provisional listing of these straight colors for use
in lakes would mean that lakes of these straight colors would no longer
be permitted for coloring drugs and cosmetics. (See Table 1 in section
III.C. of this document for a summary of the current and proposed
regulatory status of straight colors addressed in this rulemaking.)
The agency has already reviewed the identity and safety of the
remaining straight colors currently permitted as components of lakes
for coloring drugs and cosmetics, either as part of its scientific
review of provisionally listed straight colors or in response to
petitions for the review of new color additives (Sec. 71.1). On the
basis of these reviews, the agency concluded that these straight colors
are safe for use in drugs and cosmetics and issued regulations in part
74 permanently listing them for such uses. The agency is proposing to
continue to permit the use of these straight colors as components of
lakes for use in drugs and cosmetics, subject to the exceptions and
proposed requirements discussed below.
In the Federal Register of September 30, 1975 (40 FR 44812), the
agency restricted the provisional listing of FD&C Blue No. 2 to uses in
foods and ingested drugs, the uses for which a petition had been filed
for the permanent listing of the color additive. In the Federal
Register of February 4, 1983 (48 FR 5252), the agency published a final
rule permanently listing FD&C Blue No. 2 for use in food (Sec. 74.102)
and ingested drugs (Sec. 74.1102). However, the provisional listing for
the lake of FD&C Blue No. 2 (Sec. 82.102) was not amended accordingly.
Therefore, despite the lack of a listing in part 74 authorizing the use
of FD&C Blue No. 2 in cosmetics, the provisional listing regulations
still permit the use of lakes of FD&C Blue No. 2 in cosmetics. Proposed
Sec. 74.2050 would correct this inconsistency by excluding FD&C Blue
No. 2 from the straight colors permitted as components of lakes for
cosmetic use.
The lakes of D&C Red No. 34 are provisionally listed in part 82 for
use in drugs and cosmetics without any restrictions. However, the
straight color is listed in part 74 for external drug and external
cosmetic uses only (Secs. 74.1334 and 74.2334), based on the agency's
safety evaluation of the straight color. The proposed permanent
listings for lakes for drug and cosmetic use (Secs. 74.1050 and
74.2050) would correct this inconsistency by limiting the use of a lake
to the use(s) permitted for the straight-color component(s) of the
lake. Thus, under the proposed regulations, any lake containing D&C Red
No. 34 would be allowed for use only in externally applied drugs and
externally applied cosmetics.
b. Use of previously certified batches. Currently, under
Secs. 82.1051 and 82.2051, manufacturers may use uncertified batches of
straight colors to

[[Page 8387]]
prepare most lakes for drug and cosmetic use. The resulting lake is
then subject to batch certification. The exceptions are the lakes of
D&C Red No. 33 (Sec. 82.1333), D&C Red No. 36 (Sec. 82.1336), and FD&C
Yellow No. 6 (Sec. 82.706), which must be prepared from previously
certified batches of the straight color. (As discussed in section
III.C.1. of this document, the agency is proposing to terminate the
listing of D&C Red No. 36 as a straight-color component of a lake for
drug or cosmetic use because it does not contain a salt-forming group.)
For the reasons discussed in section IV.A.1.b. of this document,
the agency tentatively concludes that the lack of adequate analytical
methods to determine levels of intermediates and other impurities in
lakes prepared from uncertified batches of straight colors precludes
the agency from prescribing conditions of safe use for lakes prepared
from uncertified batches of straight colors. Accordingly, the agency is
proposing to require that lakes for use in drugs and cosmetics,
including externally applied drugs and cosmetics, be prepared from
certified batches of straight colors.
As discussed above, under current regulations the lakes of many D&C
straight colors are prepared from uncertified batches of the straight
colors. However, lakes of D&C Red Nos. 6, 7, 31, and 34 are commonly
produced in situ (a process described in section I. of this document).
In FY-95 (Ref. 18), lakes of these straight colors represented about 55
percent of the total quantity of D&C lakes certified. The agency
recognizes that its proposal to require the use of certified batches of
straight color to prepare lakes for coloring drugs and cosmetics would,
in effect, prohibit use of the in situ process for preparing lakes.
However, as noted above, the reason for this proposed requirement is
that the safety of lakes prepared from uncertified batches of straight
color (including lakes prepared in situ) has not been demonstrated.
Specifically, the agency is not aware of the existence of any methods
that may be used to demonstrate that lakes produced by the in situ
process meet the specifications for impurities, including carcinogenic
constituents (e.g., para-toluidine in D&C Red Nos. 6 and 7), in the
listing regulation for the straight color. Because FDA has the
responsibility to ensure that color additives in foods, drugs, and
cosmetics are safe for their intended uses, the fact that no methods
that allow the safety of lakes produced in situ to be demonstrated
appear to be available leads the agency to propose that use of the in
situ method be discontinued. FDA recognizes, however, that the
potential costs associated with this proposed action may be
considerable, and therefore solicits proven methodology for analysis of
the lake for the impurities specified in the listing regulation for the
straight color. If such information is received in response to this
proposal, the need to prohibit the use of lakes prepared by the in situ
process will be obviated.
c. Stability. The straight colors that FDA proposes to permit as
components of lakes for drug or cosmetic use fall into the following
eight groups, based on chemical structure (Refs. 16 and 17):
Triphenylmethane (FD&C Blue No. 1, FD&C Green No. 3, D&C Blue No. 4);
pyrazolone (FD&C Yellow No. 5); monoazo (FD&C Red No. 4, FD&C Red No.
40, FD&C Yellow No. 6, D&C Orange No. 4, D&C Red No. 6, D&C Red No. 7,
D&C Red No. 31, D&C Red No. 33, and D&C Red No. 34); indigoid (FD&C
Blue No. 2); fluoran (D&C Orange No. 5, D&C Orange No. 10, D&C Red No.
21, and D&C Red No. 27); xanthene (D&C Red No. 22 and FD&C Red No. 28);
quinoline (D&C Yellow No. 10), and nitro (Ext. D&C Yellow No. 7). In
FY-95, D&C lakes accounted for approximately 20 percent of the total
poundage of lakes certified (Ref. 18). Of the D&C lakes certified in
FY-95, approximately 55 percent were lakes of the monoazo dyes
(primarily lakes of D&C Red Nos. 6 and 7), about 20 percent were lakes
of the fluoran and xanthene dyes (primarily lakes of D&C Red Nos. 21
and 27), and about 15 percent were lakes of quinoline dye (D&C Yellow
No. 10). No batches of lakes of the nitro dye (Ext. D&C Yellow No. 7)
were certified in FY-95.
Section IV.A.1.c. of this document sets forth the agency's
evaluation of data confirming the stability of certain straight colors
in the triphenylmethane, pyrazolone, monoazo and indigoid classes
during the laking process. This information includes data received from
CTFA in response to the 1979 NOI (Ref. 19), data generated by FDA (Ref.
21), and published studies (Refs. 17 and 22). In addition to these
data, the agency received a preliminary stability study for two
additional lakes prepared from monoazo dyes (FD&C Red No. 4 and D&C
Orange No. 4) (Ref. 26). The study, which was conducted by a color
additive manufacturer, compared the levels of total color, uncombined
intermediates, and subsidiary color in a certified batch of each
straight color to the levels of these materials in an aluminum lake
prepared from the batch. The study found no evidence that the straight
color degraded during manufacture of the lake.
Based on its evaluation of all these data, the agency tentatively
concludes that when prepared in accordance with CGMP,straight colors in
the monoazo, triphenylmethane, pyrazolone, and indigoid classes do not
degrade significantly during preparation of lakes for use in drugs or
cosmetics.
The agency received no studies evaluating the stability of the
straight colors in the fluoran, xanthene, quinoline, or nitro groups
during the laking process. However, the agency has reviewed
certification records for batches of lakes made from straight colors in
the fluoran, xanthene (Ref. 27), and quinoline (Ref. 28) classes. The
agency has not certified a batch of lake of Ext. D&C Yellow No. 7 since
1975; therefore, no recent certification data are available for lakes
of Ext. D&C Yellow No. 7.
The lakes of straight colors in the fluoran, xanthene, and
quinoline groups are not required to be prepared from certified batches
of straight color. Nevertheless, for lakes of the quinoline dye, D&C
Yellow No. 10, the agency determined that one manufacturer used
certified lots of D&C Yellow No. 10 to prepare the lake. The agency
evaluated certification reports for the 36 such batches of D&C Yellow
No. 10 lake that were certified in FY-95. The agency compared the
levels, adjusted for total color content of the lake, of one
intermediate (24 batches) and one subsidiary color (36 batches) in the
batches certified to the levels permitted for these impurities in the
straight color. The agency also determined total color accountability
for all 36 batches. As discussed in section IV.B.5. of this document,
the total color accountability was determined by comparing the actual
total color content of each batch of lake with the range of estimated
total color content for the same batch. The actual total color content
of the batch of lake was determined during certification of the batch.
The range of expected total color content of the lake was determined
from the amount (weight) of straight color in the batch, multiplied by
the range of expected total color content of the batch of straight
color (as a percentage), and divided by the weight of the batch of
lake. The lower limit of the range of expected total color content of
the straight color was the minimum total color permitted by the
applicable specification in the listing regulation for the straight
color. The upper limit of the range was assumed to be 100 percent.
All but one of the batches contained levels of the intermediate and
subsidiary color that, adjusted for total color content of the lake,
were within the limit set by the specification for the

[[Page 8388]]
straight color. These data show that it is technologically feasible to
prepare lakes of D&C Yellow No. 10 from certified batches of straight
color without significant increases in impurities derived from the
straight color. Over 40 percent of the batches had a total color
content within the theoretical range of expected color content. The
data showed that, after an adjustment for the total color content of
the lake, the levels of sulfonated quinaldines, which are presumptive
products of decomposition, remained within the specification limit for
the straight color. Therefore, the agency tentatively finds that the
data are adequate to conclude that there is no significant degradation
of D&C Yellow No. 10 during laking under conditions of CGMP.
The agency also evaluated FY-95 certification reports for lakes of
the fluoran and xanthene straight colors. These lakes were all prepared
from uncertified batches of straight color. To make its evaluation as
accurate as possible, the agency compared levels (adjusted for total
color content of the lake) of impurities found in the lakes to the
maximum levels permitted for the same impurities in certified batches
of straight color. The agency combined the data from the fluoran and
xanthene classes of lakes because, during the laking process, the
lactone group in the xanthene dyes is converted to the corresponding
salt. Therefore, lakes of straight colors from the xanthene class are
structurally identical to the lakes of comparable straight colors from
the fluoran class.
The agency evaluated the certification reports from the 104 batches
of lakes of the fluoran and xanthene straight colors that had been
certified in FY-95, including 16 reports for lakes of the xanthene
straight colors D&C Red No. 22 (3 batches) and D&C Red No. 28 (13
batches) and 88 reports for lakes of the fluoran straight colors D&C
Orange No. 5 (4 batches), D&C Red No. 21 (23 batches), and D&C Red No.
27 (61 batches). The agency compared the levels (adjusted for total
color content of the lake) of three intermediates (55 batches) and one
subsidiary color (104 batches) in these batches to the levels of these
impurities permitted by the specifications in the listing regulation
for the straight color. The agency also determined the total color
accountability for 104 batches. (The theoretical range of expected
total color content for these batches of lakes was determined in the
same manner as described above for batches of D&C Yellow No. 10 lakes.)
All but four of the batches contained levels of the intermediates and
subsidiary color that, after adjusting for the total color content of
the batch, met the specifications for the straight color. These data
show that it is technologically feasible to prepare lakes of the
fluoran and xanthene straight colors without significant degradation of
the straight color. Over 60 percent of the batches had a total color
content that was within the theoretical range of expected color
content. The analyses showed that, after adjustment for the total color
content of the lake, levels of the subsidiary colors
tribromofluoresceins (D&C Red Nos. 21 and 22) and the lower halogenated
fluoresceins (D&C Red Nos. 27 and 28), which are prime indicators of
possible dehalogenation (a decomposition reaction) of the parent
compound, remained within the applicable specifications for the
straight color. Therefore, the agency tentatively finds that the data
are adequate to conclude that no significant degradation of these
straight colors occurs during preparation of lakes under conditions
consistent with CGMP.
The agency tentatively concludes that the available information
provides sufficient evidence for the stability of the straight-color
component of lakes prepared from colors in the monoazo, pyrazolone,
triphenylmethane, indigoid, fluoran, xanthene, and quinoline classes.
Although the agency has not evaluated data for all of the straight
colors that FDA is proposing to approve as components of lakes for drug
and cosmetic use, the agency tentatively concludes that the available
information is adequate to conclude that there is no significant
degradation of straight colors in these classes during the preparation
of lakes in accordance with CGMP.
The agency has no data on the stability of the nitro straight
color, Ext. D&C Yellow No. 7, during the laking process. No lakes of
this straight color were certified in FY-95; the last batch of this
lake was certified by the agency in 1975. Based on

[Text truncated at 120,000 characters. The full text is on the page linked above.]

---

Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A96-4584. Public record. Not legal advice.