Permanent Listing of Color Additive Lakes

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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.

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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

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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

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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

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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

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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 the absence of data

concerning the stability of Ext. D&C Yellow No. 7 during the laking

process, the agency tentatively concludes that it has insufficient data

to ensure the safety of lakes prepared with Ext. D&C Yellow No. 7.

Therefore, the agency is not proposing to permit the use of Ext. D&C

Yellow No. 7 as a component of lakes for drug or cosmetic use.

Consequently, the proposed termination of the provisional listings of

lakes (see section VI.A.2. of this document) would remove the listing

for lakes of Ext. D&C Yellow No. 7. Anyone interested in the permanent

listing of lakes of Ext. D&C Yellow No. 7 should submit, as a comment

on this proposal, data showing the stability of Ext. D&C Yellow No. 7

during the laking process. If data on the stability of Ext. D&C Yellow

No. 7 lakes are received as a comment on this proposal, the agency will

consider permanently listing the lakes of Ext. D&C Yellow No. 7 in the

final rule.

The agency has also considered the safety evaluations for the

straight colors discussed above. Based on these safety evaluations and

the data showing the stability of straight colors when the laking

process is conducted in accordance with CGMP, the agency tentatively

concludes that, when lakes are prepared under conditions of CGMP, the

certified batches of straight colors listed in proposed Secs. 74.1051

and 74.2051 are safe for use in lakes for the same drug and cosmetic

uses as part 74 allows for the straight colors. Therefore, the agency

is proposing to permit certified batches of these straight colors as

components of lakes for drug or cosmetic use.

As discussed in section IV.A.1.c. of this document, the agency is

not proposing to establish a definition of CGMP for the preparation of

lakes. Rather, FDA is proposing to permit any manufacturing method that

ensures that straight colors do not significantly degrade during

laking.

d. Use of more than one straight color in a lake. For the reasons

discussed in section IV.A.1.d. of this document, the agency is also

proposing to permit the preparation of a lake from certified batches of

more than one straight color.

2. Substrata

a. Regulatory approach. The agency is proposing to include the

following in its permanent listing regulations for lakes for drug and

cosmetic use as substrata permitted for preparing such lakes: alumina,

barium sulfate, kaolin, titanium dioxide, zinc oxide, talc, aluminum

benzoate, calcium carbonate, and rosin. In addition, gloss white will

also be permitted, although not explicitly listed in the regulations,

because FDA is proposing to allow combinations of substrata. Thus, all

of the substrata currently permitted as components of lakes for drug

and cosmetic use under Secs. 82.1051 and 82.2051, the provisional

listing regulations, will continue to be permitted under the proposed

regulations.

Ordinarily, the agency establishes identity and specification

requirements for the color additive, rather than for the components

used to make the color additive. However, because of the unique

characteristics of lakes, the agency is proposing to regulate them

under a broadly based, flexible system that permits the use, in drug

and

[[Page 8389]]

cosmetic products, of lakes that may contain a variety of components at

varying levels. As noted above in section V.A.1.b. of this document,

the agency is proposing to establish quality requirements (identity and

specifications) for the straight-color components of lakes by requiring

the use of certified batches of straight colors to prepare lakes. To

ensure the safety of lakes prepared with the substrata listed above,

and at the same time to permit manufacturers the continued flexibility

to prepare lakes using any one or mixtures of these substrata at

varying levels, the agency is proposing to establish quality

requirements (identity and specifications) for these substrata or their

components. In this way, the agency can ensure the safety of substrata

used to prepare lakes without setting rigid specifications for the

finished lake to limit impurities in substrata, which may be present at

varying levels in a lake, and without requiring analysis of the lake

itself for these impurities.

b. Alumina. In section IV.A.2. of this document, the agency

reviewed the identity and safety of alumina, and tentatively concluded

that alumina is safe as a substratum in lakes for food use.

Furthermore, alumina is listed in Sec. 73.1010 as a color additive for

use in drugs generally at levels consistent with CGMP. Based on its

review of the use of alumina as a substratum in lakes for food use and

on the listing of alumina as a color additive safe for general use in

drugs, the agency tentatively concludes that alumina is also safe for

use as a substratum in lakes for drug and cosmetic use, provided that

it either conforms to the identity and specification requirements in

Sec. 73.1010 (a)(1) and (b), or is a suspension in water of

precipitated aluminum hydroxide prepared from aluminum sulfate and

sodium carbonate or sodium hydroxide that meet the requirements of Food

Chemicals Codex 2d ed. (1972) (aluminum sulfate) or Food Chemicals

Codex 3d ed. (1981) (sodium carbonate and sodium hydroxide).

c. Barium sulfate (blanc fixe). Section 82.3(h) defines blanc fixe

as ``a suspension in water of precipitated barium sulfate.'' The

definition provides no quality requirements for blanc fixe as a

substratum. This definition covers both preformed barium sulfate that

is subsequently suspended in water and barium sulfate that is prepared

in situ, without subsequent recovery and drying.

The United States Pharmacopeia 23d ed. (1990) (USP) defines barium

sulfate as ``BaSO4 233.39; sulfuric acid, barium salt (1:1);

Barium sulfate (1:1) [7727-43-7]'' and provides specifications. The act

recognizes the USP as an official drug compendium whose specifications

are applicable to drug uses of substances listed therein (21 U.S.C.

321(g)(1)(a) and 351(b)). Although the USP specifications for barium

sulfate and other compounds discussed below that are recognized by the

USP are not directly applicable for purposes of this proposal, the

agency tentatively concludes that the USP specifications for these

compounds when used as drugs are also appropriate for these compounds

when they are used as substrata for lakes to color drugs.

The agency has approved barium sulfate for use in adhesives

(Sec. 175.105) and as a colorant for food-contact use (Secs. 178.3297

(21 CFR 178.3297) and 176.170(b)(2)). As part of the current

rulemaking, the agency also evaluated data relating to the safety of

ingested and dermal uses of barium sulfate, and found no reports in the

scientific literature of adverse effects resulting from topical use of

barium sulfate. Moreover, scientific data establish that barium sulfate

is highly insoluble. For example, the CRC Handbook of Chemistry and

Physics (59th ed., 1978) reports that precipitated blanc fixe

(BaSO4) has a solubility in water of 0.246 milligram (mg)/100 gram

(g) at 26 deg.C and 0.4113 mg/100g at 100 deg.C and 60 mg/100g in 3

percent HCl. Consequently, its absorption and toxicity are low.

However, to provide further assurance of safety, the agency is

proposing to retain the current specification for soluble barium of not

more than 0.05 percent in lakes that contain a barium salt

(Sec. 82.5(b)(3)). The agency tentatively concludes that barium sulfate

that meets the requirements of the USP is safe for use as a substratum

in lakes for drug and cosmetic use (Ref. 13).

The definition in Sec. 82.3(h) for blanc fixe and the definition in

Sec. 82.3(i) for gloss white (a suspension in water of co-precipitated

aluminum hydroxide and barium sulfate) suggest that barium sulfate may

be prepared in situ either alone or with alumina during the manufacture

of lakes. The International Pharmacopoeia 3d ed. (1979) describes the

preparation of barium sulfate suspension by mixing barium chloride

solution, sulfate-free ethanol, and potassium sulfate solution. The

WHO's Specifications for Reagents Mentioned in the International

Pharmacopoeia (1963) describes barium chloride and potassium sulfate

and provides specifications for each. However, the agency has no

information to confirm that the International Pharmacopeia method and

the identity and specifications for barium chloride in the WHO

publication represent CGMP for preparing barium sulfate in situ as

substrata for lakes for drug or cosmetic use. Therefore, the agency

requests comments on appropriate methodology for the in situ

preparation of barium sulfate as a substratum, and on identity

requirements and specifications for reagents used to prepare this

substratum. If such comments are received and the information provided

is satisfactory, the agency will list barium sulfate prepared in situ

as a substratum in lakes for use in drugs and cosmetics.

The agency is also proposing to substitute the name ``barium

sulfate'' for ``blanc fixe.'' CTFA's comment on the 1979 NOI suggested

this change in terminology. The agency notes that, in the past, the

name ``blanc fixe'' was typically used to identify the substratum

composed of barium sulfate in requests for certification of lakes.

However, more recently, the name typically used for this substratum in

requests for certification is ``barium sulfate.'' Therefore, the agency

agrees with CTFA's comment and is proposing to substitute the name

``barium sulfate'' for the name ``blanc fixe.''

d. Gloss white. Section 82.3(i) defines gloss white as ``a

suspension in water of co-precipitated aluminum hydroxide and barium

sulfate''. As discussed above, the agency is proposing to permit both

alumina and barium sulfate as substrata in lakes for drug or cosmetic

use.

Therefore, the agency is proposing not to list gloss white as a

substratum in lakes for drug and cosmetic use, because the proposed

regulations provide for combinations of substrata.

e. Kaolin (clay). In the 1979 NOI, the agency stated that the term

``clay'' does not adequately identify the chemical structure of this

material. The NOI requested comments identifying the material and

suggesting specifications to ensure its safe use as a substratum in

lakes. CTFA's comment, submitted in response to the 1979 NOI,

identified kaolin as the substratum material used in lakes.

The USP (23d ed., 1995) defines kaolin as ``a native hydrated

aluminum silicate, powdered and freed from gritty particles by

elutriation,'' and provides specifications. The agency has affirmed

clay (kaolin) as GRAS in Sec. 186.1256 as an indirect food ingredient.

Section 186.1256 identifies clay (kaolin) as hydrated aluminum silicate

(Al2O3.2SiO2.nH2O) and provides a CAS Registry

number of 1332-58-7.

The agency has reviewed data relating to the safety of ingested and

dermal uses of kaolin and bentonite (a related

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mineral containing magnesium aluminum silicate). These data included

data developed for the GRAS review of these compounds and data in a

color additive master file, which included dermal toxicity data. The

agency also considered a 90-day feeding study on magnesium aluminum

silicate.

Based on its review, the agency finds that kaolin is inert when

applied externally and is not absorbed by the gastrointestinal tract. A

search of the scientific literature revealed no reports of adverse

effects resulting from topical use of kaolin. Therefore, the agency

tentatively concludes that kaolin that meets USP specifications is safe

for use as a substratum in lakes for drug and cosmetic use (Ref. 13).

f. Titanium dioxide. The color additive regulation for titanium

dioxide (Sec. 73.575) identifies titanium dioxide as ``synthetically

prepared TiO2'' and provides specifications. Titanium dioxide is

listed as a color additive exempt from certification for use in food

(Sec. 73.575), in drugs generally (Sec. 73.1575), in cosmetics

generally (Sec. 73.2575), and in certain medical devices

(Sec. 73.3126). The USP (23d ed., 1995) recognizes titanium dioxide,

defines it as ``TiO2 79.88; Titanium oxide (TiO2); Titanium

oxide (TiO2) [13463-67-7],'' and provides specifications.

The agency has evaluated the available data relating to the safety

of ingested and dermal uses of titanium dioxide, including data

supporting its use as a color additive, and more recent genetic and

chronic toxicity studies in rats and mice. Based on these data, the

agency tentatively concludes that titanium dioxide that meets the

requirements of Sec. 73.575 (a)(1) and (b) is safe for use as a

substratum in lakes for drug and cosmetic use (Ref. 13).

g. Zinc oxide. The color additive regulation for zinc oxide

(Sec. 73.1991) identifies zinc oxide as ``a white or yellow-white

amorphous powder manufactured by the French process (described as the

indirect process whereby zinc metal isolated from the zinc-containing

ore is vaporized and then oxidized).'' Section 73.1991(b) provides

specifications for zinc oxide. The USP (23d ed., 1995) recognizes zinc

oxide, defines it as ``ZnO 81.39; Zinc oxide; Zinc Oxide [1314-13-2],''

and provides specifications.

Zinc oxide is listed as a color additive exempt from certification

for use in externally applied drugs (Sec. 73.1991) and in cosmetics

generally (Sec. 73.2991). Zinc oxide is also GRAS for use as a dietary

supplement (Sec. 182.5991) and as a nutrient (Sec. 182.8991).

The agency has evaluated data relating to the safety of ingested

and dermal uses of zinc oxide, including a safety review of zinc

compounds as food ingredients by the Select Committee on GRAS

Substances of the Federation of American Societies for Experimental

Biology and the data supporting the safety of zinc oxide as a color

additive. Based on these data, the agency tentatively concludes that

zinc oxide that meets the requirements of Sec. 73.1991 (a)(1) and (b)

is safe for use as a substratum in lakes for drug and cosmetic use

(Ref. 13).

h. Talc. The color additive regulation for talc (Sec. 73.1550)

identifies talc as ``a finely powdered, native, hydrous magnesium

silicate sometimes containing a small proportion of aluminum silicate''

and provides specifications. Talc is a color additive exempt from

certification for use in coloring drugs generally (Sec. 73.1550) and is

GRAS for certain indirect food uses (Secs. 182.70 and 182.90). The USP

(23d ed., 1995) defines talc as ``a native, hydrous magnesium silicate,

sometimes containing a small proportion of aluminum silicate,'' and

provides specifications.

The agency has evaluated the available data relating to the safety

of ingested and dermal uses of talc, including a safety review of

silicates (including talc) as food ingredients by the Select Committee

on GRAS Substances of the Federation of American Societies for

Experimental Biology and the data supporting the safety of talc as a

color additive. Based on these data, the agency tentatively concludes

that talc that meets the requirements of Sec. 73.1550 (a)(1) and (b) is

safe for use as a substratum in lakes for drug and cosmetic use (Ref.

13).

i. Aluminum benzoate. During the preparation of a lake with

aluminum benzoate as a substratum, aluminum benzoate is produced in

situ using benzoic acid and the aluminum cation. The Merck Index (11th

ed., 1989) identifies aluminum benzoate as C21H15AlO6 or

Al(C6H5COO)3 with a molecular weight of 390.30. The USP

(23d ed., 1995) recognizes aluminum chloride, aluminum sulfate, and

benzoic acid (the components used to prepare aluminum benzoate). The

USP (23d ed., 1995) defines benzoic acid as ``C7H6O2

122.12; Benzoic acid; Benzoic acid [65-85-0]'' and provides

specifications. The U.S.P. (23d ed., 1995) defines aluminum chloride as

``AlCl3 6H2O; Aluminum chloride, hexahydrate; Aluminum

chloride hexahydrate [7784-13-6]; Anhydrous 133.34 [7446-70-0]'' and

provides specifications. The USP (23d ed., 1995) defines aluminum

sulfate as ``Al2(SO4)3 xH2O (anhydrous) 342.16;

Sulfuric acid, aluminum salt (3:2), hydrate; Aluminum sulfate (2:3)

hydrate [17927-65-0]; Anhydrous 342.16 [10043-01- 3]'' and provides

specifications.

The agency has affirmed benzoic acid (Sec. 184.1021) and sodium

benzoate (Sec. 184.1733) as GRAS for use in food as flavoring agents

and adjuvants and as antimicrobial agents. In addition, the standard of

identity for margarine (21 CFR 166.110) permits the use of the sodium,

potassium, and calcium salts of benzoic acid as preservatives. The

agency has also reviewed safety data on the ingested and dermal uses of

benzoic acid and benzoates, including a safety review of benzoic acid

and benzoates as food ingredients by the Select Committee on GRAS

Substances of the Federation of American Societies for Experimental

Biology and information identified in a search of the scientific

literature published from 1981 to 1987 on benzoic acid and benzoates.

The agency's review found no reports of adverse toxicological effects

of ingested or topically administered benzoic acid.

The agency's evaluation of the safety of aluminum salts, including

aluminum chloride and aluminum sulfate, is discussed in section IV.A.2.

of this document under the safety of alumina as a substratum in lakes

for food use.

Based on these data, the agency tentatively concludes that aluminum

benzoate prepared from benzoic acid and aluminum chloride or aluminum

sulfate that meet the USP specifications for these compounds is safe

for use as a substratum in lakes for drug and cosmetic use (Ref. 13).

j. Calcium carbonate. The color additive regulation for calcium

carbonate (Sec. 73.1070) identifies calcium carbonate as ``a fine,

white, synthetically prepared powder consisting essentially of

precipitated calcium carbonate (CaCO3).'' Calcium carbonate is

listed as a color additive exempt from certification for use in drugs

generally (Sec. 73.1070). Calcium carbonate has also been affirmed as

GRAS for general food use (Sec. 184.1191) and is GRAS for dietary

supplement use (Sec. 182.5191).

The agency has evaluated the available data relating to the safety

of ingested and dermal uses of calcium salts, including calcium

carbonate. These data, including a safety review of calcium salts as

food ingredients by the Select Committee on GRAS Substances of the

Federation of American Societies for Experimental Biology and data

supporting the safety of calcium carbonate as a color additive,

establish that calcium is ubiquitous in nature and

[[Page 8391]]

that its salts are commonly found in food. Based on its review, the

agency tentatively concludes that calcium carbonate that meets the

requirements of Sec. 73.1070 (a)(1) and (b) is safe for use as a

substratum in lakes for drug and cosmetic use (Ref. 13).

k. Rosin. ``Rosin'' is a generic term encompassing a variety of

substances that may vary considerably in their composition. For

example, the Merck Index (11th ed., 1989) defines rosin as ``Residue

left after distilling off the volatile oil from the oleoresin obtained

from'' various species of Pinus. Gum rosin is obtained from the

oleoresin of living pine trees and wood rosin is extracted from the

wood of the stumps of pine trees. Another type of rosin is tall oil

rosin, a by-product of the wood pulp industry. The CRC Handbook of

Chemical Synonyms and Trade Names (8th ed., 1978) also lists rosin

under its synonym 'colophony' and defines it as ``The residue which

remains after the volatile oils have been removed by the distillation

of crude turpentine.'' The CRC Handbook lists several varieties of

rosins obtained from different species of pine.

Rosin is approved as a food additive for use as a natural flavoring

substance for alcoholic beverages (Sec. 172.510). Various rosins and

rosin derivatives are approved for other food additive uses: In

coatings of fresh citrus fruits (Sec. 172.210) and as plasticizing

materials or softeners in chewing gum base (Sec. 172.615). Rosin and

rosin derivatives are approved as diluents in color additive mixtures

for use in inks for marking food supplements in tablet form, gum,

confectionery, fruit, and vegetables (Sec. 73.1(b)) and, by reference,

in inks for branding pharmaceutical forms (Sec. 73.1001(a)(2)).

Numerous rosins and rosin derivatives are approved as indirect food

additives (substances that are not added to food directly but that may

become part of food through migration from materials in contact with

the food) (Sec. 178.3870).

The agency has evaluated the available data relating to the safety

of rosin and related compounds, including data supporting the food

additive and color additive diluent uses of rosin and rosin

derivatives, and data obtained by the agency from searches of the

scientific literature in 1988 and 1994 for information concerning

rosin. The agency's literature searches did not find any reports of

adverse toxicological effects from ingested rosin. However, many

publications reported cases of allergic contact dermatitis and

occupational asthma resulting from exposure to certain rosin materials

(Ref. 13).

In the 1979 NOI, the agency requested information on the chemical

composition of rosin and suggestions for specifications to ensure its

safe use in lakes for drug and cosmetic use. CTFA's comment on the 1979

NOI provided general information on rosin, but did not identify the

specific types of rosin that are used as substrata in lakes. However,

the monograph for rosin in the CTFA International Cosmetic Ingredient

Dictionary, 5th ed., 1993 defines rosin as ``the residue left after

distilling off the volatile oil from the oleoresin obtained from Pinus

palustris and other species of Pinaceae (Ref. 29). Because this

definition clearly identifies gum rosin, and not wood rosin or tall oil

rosin, the agency tentatively concludes that the rosin used in cosmetic

products is gum rosin.

Based on its review of available data (Refs. 29 and 30), the agency

has tentatively identified the rosin used as a substratum in lakes for

drug and cosmetic use as gum rosin, and is proposing to define and set

specifications for rosin based on this tentative conclusion. It is

unclear, however, whether all lake manufacturers who use rosin as a

substratum are using gum rosin. Therefore, any manufacturer who uses

rosin other than gum rosin that meets the requirements in the proposed

regulation as a substratum in lakes for drug or cosmetic use should

submit information about the identity and specifications of such rosin

as a comment on this proposal. The comment should include the

manufacturer's product specifications and any analytical data that

establish the identity and purity of the rosin. The agency will

consider modifying the identity and specifications for rosin if it

receives information to substantiate the safe use of rosin other than

gum rosin.

In response to the concerns raised by the agency about the topical

safety of rosin lakes, the CTFA submitted reports of numerous human

sensitization and photosensitization studies on cosmetic products

colored with rosinated lakes of D&C Red No. 6, D&C Red No. 7, and D&C

Red No. 34. The studies involved a total of 2,381 subjects for

sensitization and 312 subjects for photosensitization; products tested

included lipsticks, lip liner, blush, rouge, and nail polish. No skin

sensitization/photoallergic reactions were reported in any of the test

subjects. The agency tentatively concludes that these studies show that

there is little risk of developing a skin sensitization reaction from

skin contact with various cosmetic products that contain rosinated

color additive lakes at levels found in such products, and, therefore,

that use of rosin as a substratum in color additive lakes for external

drug and cosmetic use is safe (Ref. 14).

3. Precipitants

a. Aluminum (Al+3), barium (Ba+2), and calcium

(Ca+2) cations. The safety of salts of the cations aluminum,

barium, and calcium is discussed in the safety evaluations of alumina

(sections IV.A.2. and V.A.2.b. of this document), barium sulfate (blanc

fixe) (section V.A.2.c. of this document), and calcium carbonate

(section V.A.2.j. of this document). Based on those evaluations, the

agency tentatively concludes that these cations are safe as components

of precipitants used in the preparation of lakes for drug and cosmetic

use (Ref. 13). However, as stated in the discussion of the safety of

barium sulfate as a substratum (section V.A.2.c.), the agency is

proposing to retain the current specification for soluble barium (0.05

percent) in lakes for drug or cosmetic use.

b. Zirconium cation (Zr+4). Zirconium is a rare earth metal

that closely resembles aluminum in pharmacological and chemical

properties. The agency has evaluated data relating to the safety of

ingested and dermal uses of zirconium salts. These data, including a

review of published literature on the toxicity, physiological effects,

and medicinal uses of zirconium and its salts, revealed nothing to

indicate any likelihood of harm from topical administration or

ingestion of low levels of zirconium salts (Ref. 13). Therefore, the

agency tentatively concludes that zirconium is safe as a component of

precipitants used in lakes for drug and cosmetic use.

c. Sodium (Na+) and potassium (K+) cations. The salts of

the sodium and potassium cations, sodium chloride and potassium

chloride, are ubiquitous in nature. Sodium chloride (table salt) is

GRAS (Sec. 182.1(a)) and potassium chloride has been affirmed as GRAS

for food use (Sec. 184.1622). Most of the permanently listed water-

soluble straight colors subject to certification, including all the

straight colors used as components of lakes under Sec. 82.51, are

sodium salts. By virtue of their GRAS status, sodium chloride and

potassium chloride are permitted under Sec. 73.1(a)(1) for use as

diluents in color additive mixtures for coloring food, and under

Sec. 73.1001(a)(1) and (b) are also permitted for use as diluents in

color additive mixtures for coloring ingested drugs and externally

applied drugs. Therefore, the agency tentatively concludes that these

salts are safe for

[[Page 8392]]

use as components of precipitants in lakes for drug or cosmetic use.

d. Strontium cation (Sr+2). Strontium is an alkaline earth

element and is a metabolic analog of calcium. The agency has evaluated

published data on the safety of strontium cation. Because strontium can

substitute for calcium, it can influence certain physiological

parameters; however, the concentrations required to adversely affect

these parameters are significantly higher than the levels encountered

when strontium is used as a precipitant in a lake. Based on its review

of the published data, the agency tentatively concludes that the use of

strontium cation is safe as a component of precipitants used in lakes

for drug and cosmetic use (Ref. 13).

e. Accompanying anions. In section IV.A.3.c. of this document, the

agency considered the safety of soluble chlorides and sulfates as

components of precipitants in lakes for food use. As discussed more

fully in that section, chloride and sulfate anions are found in many

GRAS ingredients. In the safety reviews conducted as part of the GRAS

rulemakings for these ingredients, the agency found that ingestion of

chlorides and sulfates (in the presence of the accompanying cation) was

safe at levels that vastly exceed the possible level of exposure to

these anions as components of lakes. Therefore, the agency tentatively

concludes that the presence of these anions in lakes prepared for food

use is safe (Ref. 13). Furthermore, by virtue of their GRAS status, the

salts of chloride and sulfate are permitted under Sec. 73.1(a)(1) for

use as diluents in color additive mixtures for coloring food, and under

Sec. 73.1001 (a)(1) and (b) are also permitted for use as diluents in

color additive mixtures for coloring ingested drugs and externally

applied drugs. Therefore, the agency tentatively concludes that these

anions are safe for use as components of precipitants in lakes for drug

or cosmetic use.

f. Tentative conclusions. The agency tentatively concludes that the

water-soluble chloride and sulfate salts of aluminum, barium, calcium,

zirconium, sodium, potassium, and strontium are safe for use as

components of precipitants in the preparation of lakes for drug or

cosmetic use. The agency notes that, although these substances are

discussed as distinct chemical compounds, the proposal would permit

their use in other forms to prepare lakes, provided that no substance

or ion that is not provided for in the regulation is introduced. For

example, the proposal would allow the use of a precipitant formed in

situ from the combination of a listed cation (as the hydroxide) and

either hydrochloric or sulfuric acid.

4. Diluents in Color Additive Mixtures Containing Lakes

The agency is not proposing any limitations on the diluents

permitted in color additive mixtures for cosmetic use that are made

with lakes. The part 74 listings for the straight colors that are

components of lakes for cosmetic use do not limit the use of diluents

in mixtures for coloring cosmetics. Moreover, no regulation in part 73

specifies safe diluents for cosmetic use. However, the agency notes

that cosmetic products containing color additive mixtures are subject

to the adulteration provisions of section 601 of the act.

B. Specifications for Lakes for Use in Drugs and Cosmetics

1. Intermediates and Other Impurities Derived from Straight Colors

The provisional listing regulations for lakes for drug or cosmetic

use (Secs. 82.1051 and 82.2051) contain specifications for ether

extracts (not more than 0.5 percent) and intermediates (not more than

0.2 percent) in such lakes. The agency established these specifications

to limit the levels of intermediates and other impurities in lakes

prepared from uncertified batches of straight colors. However, as

discussed in section IV.A.1.b. of this document, proven methodology to

analyze all lakes for intermediates and other impurities is not

available. Therefore, the agency is proposing to require the use of

certified batches of straight colors to ensure safe levels of

intermediates and other impurities in lakes. In light of this proposed

requirement, the agency tentatively concludes that specifications for

ether extracts, intermediates, and subsidiary colors in lakes for drug

or cosmetic use are unnecessary to ensure the safety of such lakes.

2. Precipitants

Because lakes are washed when prepared in accordance with CGMP, the

agency anticipates that only low levels of water-soluble contaminants

from these precipitants will remain in the finished lake. Furthermore,

the proposed specifications for the lake would limit the levels of

contaminants of toxicological concern (primarily heavy metals)

permitted in the end product. However, the agency tentatively concluded

in its discussion of barium sulfate as a substratum (section V.A.2.c.

of this document) and barium as a precipitant (section V.A.3.a. of this

document) that a specification to limit soluble barium in lakes for

drug or cosmetic use should be retained to provide an extra margin of

safety. Based on these considerations, the agency tentatively concludes

that specifications for residues from precipitants used in lakes for

drug or cosmetic use, except for soluble barium, are unnecessary.

3. Heavy Metals

As discussed in section IV.B.2. of this document, the manufacturing

processes for lakes involve reagents that are sources of potential

contamination by metals. Currently, lakes are subject to the following

general specifications in Sec. 82.5 for provisionally listed colors for

drug or cosmetic use: 20 ppm lead, 2 ppm arsenic, 0.003 percent total

heavy metals (except for lead and arsenic), and, for those colors that

contain a barium salt, a limit of 0.05 percent on soluble barium. As

discussed in section IV.B.2. of this document, FDA is proposing limits

for lead, arsenic, and mercury in lakes for food use. The agency

tentatively concludes that specifications to limit the levels of lead,

arsenic, mercury, and soluble barium are also necessary to ensure safe

use of lakes in drugs and cosmetics. The agency is unaware of any other

heavy metals 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 drug or cosmetic use.

The agency is proposing to maintain the specifications of not more

than 20 ppm lead and 0.05 percent soluble barium for lakes for drug or

cosmetic use and to raise the arsenic specification from not more than

2 ppm to not more than 3 ppm. The agency is also proposing to include a

mercury specification of not more than 1 ppm. The proposed levels for

arsenic and mercury are the levels that the agency tentatively

concludes are necessary to ensure the safety of color additives used in

drugs and cosmetics, based on safety evaluations in rulemakings for the

permanent listing of numerous straight colors.

4. Soluble Chlorides and Sulfates

Current Secs. 82.1051 and 82.2051 contain a specification that

limits the content of the soluble chloride and sulfate anions in lakes

for drug and cosmetic use. As noted in section IV.B.3. of this

document, most of the water-soluble chloride and sulfate anions are

washed out during preparation of the lake under CGMP conditions. In its

safety review, the agency found that these anions are safe in foods,

drugs, and cosmetics at levels considerably greater than those found in

lakes (Ref. 13). Therefore, the agency

[[Page 8393]]

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 drug or cosmetic use.

5. Other Residues

The 1979 NOI requested information on certain other chemicals

occasionally used in the laking process, such as citrate, acetate, and

surfactants. CTFA's comment did not provide a list of such substances,

but stated that the substances used were GRAS. A comment from a color

manufacturer identified specific substances that the company uses in

the manufacture of lakes and characterized them as food additives or

GRAS substances. The company stated that the surfactants were used at

very low concentrations and that the nature of the use prevented any

significant amount from being present in the final lake.

The agency recognizes that it is impracticable to set

specifications for every chemical used in the manufacture of a color

additive. The agency generally sets specifications to limit the

substances that are normally expected to be present in the final

additive, especially those substances that could present a safety

hazard at foreseeable levels of exposure. The agency agrees with the

comment that the surfactants and other chemicals mentioned are used at

low concentrations. The agency further agrees that, because of the

washing of lakes during manufacture, these chemicals are unlikely to be

present at significant levels in a lake that has been prepared under

conditions of CGMP and that is otherwise in compliance with applicable

regulations. Therefore, the agency is not proposing specifications for

residues of these substances in lakes for drug and cosmetic use.

6. Other Impurities and Contaminants

The agency has tentatively concluded above that specifications to

limit the levels of total heavy metals (except lead, arsenic, mercury,

and soluble barium), soluble chlorides and sulfates, and residues of

other chemicals are unnecessary to ensure the safety of lakes for drug

and cosmetic use, as long as a general provision is included in the

specifications for lakes to ensure that they are prepared in conformity

with CGMP. Therefore, the agency is proposing to continue the

requirement in existing Sec. 82.5 that lakes be free from all

impurities other than those named in the specifications, to the extent

that such impurities can be avoided by CGMP.

C. Certification Requirement

As discussed in section IV.C. of this document, the agency has

evaluated the necessity for the certification of lakes and has

tentatively concluded that certification is necessary to protect the

public health. The simplified procedure the agency is proposing for

certification of lakes is described in section VI.B. of this document.

D. Provi

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