color additive is subject to other limitations prescribed in this part, such limitations shall be stated on the label of the color additive by a plain and conspicuous statement. Examples of such limitation statements are: "Do not use in products used in the area of the eye"; "Do not use for coloring drugs for injection."

(d) Special labeling for color additives not exempt from certification. Color additives not exempt from the certification procedures shall in addition include in the labeling the lot number assigned by the Color Certification Branch, except that in the case of any mixture for household use which contains not more than 15 percent of pure color and which is in packages containing not more than 3 ounces there appears on the label, a code number which the manufacturer has identified with the lot number by giving to the Food and Drug Administration written notice that such code number will be used in lieu of the lot number.

[28 F.R. 6439, June 22, 1963, as amended at 33 FR. 8812, June 18, 1968]

§ 8.33 Exemption of color additives for investigational use.

(a) A shipment or other delivery of a color additive or of a food, drug, or cosmetic containing such a color additive for investigational use by experts qualified to determine safety shall be exempt from the requirements of section 402 (c), 501(a), or 601(e) of the act, provided that the color additive or the food, drug, or cosmetic containing the color additive bears a label which states prominently, "Caution-Contains new color additiveFor investigational use only." No animals used in such investigations, or their products, such as milk or eggs, shall be used for food purposes, unless the sponsor or the investigator has submitted to the Commissioner data demonstrating that such use will be consistent with the public health, and the Commissioner, proceeding as he would in a matter involving section 409(1) of the act, has notified the sponsor or investigator that the proposed disposition for food is authorized.

(b) The person who introduced such shipment or who delivers the color additive or a food, drug, or cosmetic containing such an additive into interstate commerce shall maintain adequate records showing the name and post-office address of the expert to whom the color additive is shipped, date, quantity, and batch or code mark of each shipment and delivery for a period of 2 years after such

shipment and delivery. Upon the request of a properly authorized employee of the Department, at reasonable times, he shall make such records available for inspection and copying.

§ 8.34 Safety factors to be considered.

In accordance with section 706(b) (5) (A)(iii) of the act, the following safety factor will be applied in determining whether the proposed use of a color additive will be safe: Except where evidence is submitted which justifies use of a diferent safety factor, a safety factor of 100 to 1 will be used in applying animal experimentation data to man; that is, a color additive for use by man will not be granted a tolerance that will exceed 1/100th of the maximum no-effect level for the most susceptible experimental animals tested. The various species of experimental animals used in the tests shall conform to good pharmacological practice.

§ 8.35

General principles of evaluating the safety of color additives.

(a) In reaching a decision on any petition filed under section 706 of the act, the Commissioner will give full consideration to the specific biological properties of the color additive and the adequacy of the methods employed to demonstrate its safety for the proposed use. When considering color additives for food, for drugs, and for cosmetic uses that involve ingestion, the Commissioner will be guided by the principles and procedures for establishing the safety of food additives provided in current publications of the National Academy of Sciences-National Research Council. A petition will not be denied, however, by reason of the petitioner's having followed procedures other than those outlined in the publications of the National Academy of Sciences-National Research Council if, from available evidence, the Commissioner finds that the procedures used give results as reliable as, or more reliable than, those reasonably to be expected from the use of the outlined procedures. In reaching a decision, the Commissioner will give due weight to all levels and patterns of consumption of the color additive specified or reasonably to be anticipated. For the purposes of this section, the principles for evaluating safety of additives set forth in the abovementioned publications will apply to any substance that may properly be classified as a color additive as defined in section 201(t) of the act.

(b) The safety for external color additives will normally be determined by tests for acute oral toxicity, primary irritation, sensitization, subacute dermal toxicity on intact and abraded skin, and carcinogenicity by skin application. The Commissioner may waive any of such tests if data before him otherwise establish that such test is not required to determine safety for the use proposed.

(c) Upon written request describing the proposed use of a color additive and the proposed experiments to determine its safety, the Commissioner will advise a person who wishes to establish the safety of a color additive whether he believes the experiments planned will yield data adequate for an evaluation of the safety of the additive.

§ 8.36 Application of the cancer clause of section 706 of the act.

(a) Color additives that may be ingested. Whenever (1) the scientific data before the Commissioner (either the reports from the scientific literature or the results of biological testing) suggest the possibility that the color additive including its components or impurities has induced cancer when ingested by man or animal; or (2) tests which are appropriate for the evaluation of the safety of additives in food suggest that the color additive, including its components or impurities, induces cancer in man or animal, the Commissioner shall determine whether, based on the judgment of appropriately qualified scientists, cancer has been induced and whether the color additive, including its components or impurities, was the causative substance. If it is his judgment that the data do not establish these facts, the cancer clause is not applicable; and if the data considered as a whole establish that the color additive will be safe under the conditions that can be specified in the applicable regulation, it may be listed for such use. But if in the judgment of the Commissioner, based on information from qualified scientists, cancer has been induced, no regulation may issue which permits its use.

(b) Color additives that will not be ingested. Whenever the scientific data before the Commissioner suggest the possibility that the color additive, including its components or impurities, has induced cancer in man or animals by routes other than ingestion, the Commissioner shall determine whether, based on the judgment of appropriately quali

fied scientists, the test suggesting the possibility of carcinogenesis is appropriate for the evaluation of the color additive for a use which does not involve ingestion, cancer has been induced, and the color additive, including its components or impurities, was the causative substance. If it is his judgment that the data do not establish these facts, the cancer clause is not applicable to preclude external drug and cosmetic uses, and if the data as a whole establish that the color additive will be safe under conditions that can be specified in the regulations, it may be listed for such use. But if, in the judgment of the Commissioner, based on information from qualified scientists, the test is an appropriate one for the consideration of safety for the proposed external use, and cancer has been induced by the color additive, including its components or impurities, no regulation may issue which permits its use in external drugs and cosmetics. § 8.37 Request for scientific studies.

The Commissioner will consider requests by any interested person who desires the Food and Drug Administration to conduct scientific studies to support a petition for a regulation for a color additive. If favorably acted upon, such studies will be limited to pharmacological investigations, studies of the chemical and physical structure of the color additive, and methods of analysis of the pure color additive (including impurities) and its identification and determination in foods, drugs, or cosmetics, as the case may be. All requests for such studies shall be accompanied by the fee prescribed in § 8.50.

§§ 8.38-8.49 [Reserved] § 8.50 Fees for listing.

(a) Each petition for the listing of a color additive shall be accompanied by a deposit of $3,000.00 if the proposal is for listing the color additive for use generally in or on foods, in or on drugs, and in or on cosmetics.

(b) If the petition for the listing is for use in or on foods only, the deposit shall be $3,000.00.

(c) If the petition for the listing is for use in or on drugs and/or cosmetics only, the deposit shall be $2,600.00.

(d) The provisions of paragraphs (a), (b), and (c) of this section shall be applicable, whether or not the proposal contemplates any tolerances, limitations,

or other restrictions placed upon the use of the color additive.

(e) If a petition proposing the issuance of a regulation is withdrawn before it is finally accepted for filing, the deposit, less a $600.00 fee for clerical handling and administrative and technical review, shall be returned to the petitioner.

(f) If a petition proposing the issuance of a regulation is withdrawn within 30 days after filing, the deposit, less $1,800.00 if the petition is covered by paragraph (a) or (b) of this section, and less $1,600.00, if the petition is covered by paragraph (c), shall be returned to the petitioner.

(g) When a petition is withdrawn after filing and resubmitted within 6 months, it shall be accompanied by a deposit of $1,800.00 for a petition filed under paragraph (a) or (b), and $1,600.00 for a petition filed under paragraph (c) of this section. If a petition is resubmitted after 6 months, it shall be accompanied by the deposit that would be required if it were being submitted for the first time.

(h) When the resubmission pertains to a petition that had been withdrawn before acceptance for filing, a new advance deposit shall be made in full as prescribed in paragraph (a), (b), or (c) of this section.

(1) After a color additive has been listed, any request for an amendment or additional tolerance shall be accompanied by a deposit of $1,800.00 for use in the items specified in paragraphs (a) and (b) of this section, or $1,600.00 for use in items specified in paragraph (c) of this section.

(j) The fee for services in listing a diluent under § 8.30 for use in color additive mixtures shall be $250.00.

(k) Objections and request for public hearing under section 706(d) of the act or section 203 (d) (2) (C) of Public Law 86-618 (74 Stat. 404; 21 U.S.C. 376, note) shall be accompanied by a filing fee of $250.00.

(1) In the event of a referral of a petition under this section to an advisory committee, all costs related thereto (including personal compensation of committee members, travel materials, and other costs) shall be borne by the person or organization requesting the referral, such costs to be assessed on the basis of actual cost to the Government: Provided, That the compensation of such costs shall

include personal compensation of advisory committee members at a rate not to exceed $75.00 per member per day.

(m) In the case of requests of referrals to advisory committees, a special advance deposit shall be made in the amount of $2,500.00. Where required, further advance in increments of $2,500.00 each shall be made upon request of the Commissioner of Food and Drugs. All deposits for referrals to advisory committees in excess of actual expenses shall be refunded to the depositor.

(n) All requests for pharmacological or other scientific studies shall be accompanied by an advance deposit of $5,000.00. Further advance deposits shall be made upon request of the Commissioner of Food and Drugs when necessary to prevent arrears in such cost. Any deposits in excess of actual expenses will be refunded to the depositor. If a request is denied the advance deposit will be refunded less such costs as are incurred for review of the request.

(0) The person who files a petition for judicial review of an order under section 706(d) of the act shall pay the costs of preparing a transcript of the record on which the order is based.

(p) All deposits and fees required by the regulations in this section shall be paid by money order, bank draft or certifled check drawn to the order of the Food and Drug Administration, collectible at par at Washington, D.C. All deposits and fees shall be forwarded to the Food and Drug Administration, Department of Health, Education, and Welfare, Washington 25, D.C., whereupon after making appropriate record thereof they will be transmitted to the Treasurer of the United States for deposit in the special account "Salaries and Expenses, Certification, Inspection, and Other Services, Food and Drug Administration."

(q) The Commissioner of Food and Drugs may waive or refund such fees in whole or in part when in his judgment such action will promote the public interest.

(r) Any person who believes that payment of these fees will work a hardship on him may petition the Commissioner of Food and Drugs to waive or refund the fees.

of each request for certification submitted in accordance with § 8.22(j) (1) and (2), shall be 15 cents per pound of the batch covered by such requests, but no such fee shall be less than $100.00.

(b) Fees for repacks of certified color additives and color additive mixtures. The fees for the services provided under the regulations in this part in the case of each request for certification submitted in accordance with § 8.22(j) (3) and (4) shall be:

Weight of batch 100 pounds or less. Over 100 pounds but not over 1,000 pounds. Over 1,000 pounds.

$6.00

Fees

$6.00 plus 4 cents for

each pound over 100 pounds. $42.00 plus 1 cent per pound for each pound in excess of 1,000 pounds.

(c) Advance deposits. Any person regularly requesting certification services may deposit funds in advance of requests as prepayment of fees required by this section.

(d) Method of payment. All deposits and fees required by this section shall be paid by money order, bank draft, or certified check, drawn to the order of the Food and Drug Administration, collectable at par at Washington, D.C. All such deposits and fees shall be forwarded to the Food and Drug Administration, Department of Health, Education, and Welfare, Washington 25, D.C., whereupon after making appropriate records thereof, they will be transmitted to the Treasurer of the United States for deposit to the special account "Salaries and Expenses, Certification, Inspection, and Other Services, Food and Drug Administration."

(e) Refunds from advance deposits. Whenever in the judgment of the Commissioner the ratio between fees collected (which are based upon experience and the best estimate of costs and the best estimate of earnings) and the costs of providing the service during an elapsed period of time, in the light of all circumstances and contingencies, warrants a refund from the fund collected during such period, he shall make ratable refunds to those persons to whom the services were rendered and charged, except that no refund shall be made where the com

§ 8.101

General restrictions on use of color additives.

(a) Color additives for use in the area of the eye. No listing or certification of a color additive shall be considered to authorize the use of any such color additive in any article intended for use in the area of the eye unless such listing or certification of such color additive specifically provides for such use. Any color additive used in or on any article intended for use in the area of the eye, the listing or certification of which color additive does not provide for such use, shall be considered to be a color additive not listed under Subparts E, F, G, and H of this part, even though such color additive is certified and/or listed for other

uses.

(b) Color additives for use in injections. No listing or certification of a color additive shall be considered to authorize the use of any such color additive in any article intended for use in injections unless such listing or certification of such color additive specifically provides for such use. Any color additive used in or on any article intended for use in injections, the listing or certification of which color additive does not provide for such use, shall be considered to be a color additive not listed under Subparts E and F of this part, even though such color additive is certified and/or listed for other uses.

(c) Color additives for use in surgical sutures. No listing or certification of a color additive shall be considered to authorize the use of any such color additive in any article intended for use as a surgical suture unless such listing or certification of such color additive specifically provides for such use. Any color additive used in or on any article intended for use as a surgical suture, the listing or certification of which color additive does not provide for such use, shall be considered to be a color additive

(a) Identity. (1) The color additive Citrus Red No. 2 is principally 1-(2,5dimethoxyphenylazo) -2-naphthol.

(2) The following diluents may be used in aqueous suspension, in the percentages specified, to facilitate application to oranges in accordance with paragraph (c) (1) of this section:

(i) Suitable diluents used in accordance with § 8.300 (a).

(ii) Volatile solvents that leave no residue after application to the orange. (iii) Salts of fatty acids meeting the requirements of § 121.1071 of this chapter.

more thar 0.05 percent.

(b) Specifications. Citrus Red No. 2 shall conform to the following specifications and shall be free from impurities, other than those named, to the extent that such other impurities may be avoided by good manufacturing practice: Volatile matter (at 100° C.), not more than 0.5 percent.

Water-soluble matter, not more than 0.8 percent.

Matter insoluble in carbon tetrachloride, not more than 0.5 percent.

Uncombined intermediates, not more than 0.05 percent.

Subsidiary dyes, not more than 2.0 percent. Lead (as Pb), not more than 10 parts per million.

Arsenic (as As), not more than 1 part per million.

Pure color, not less than 98 percent.

(c) Uses and restrictions. (1) Citrus Red No. 2 shall be used only for coloring the skins of oranges that are not intended or used for processing (or if so used are designated in the trade as "Packinghouse elimination") and that meet minimum maturity standards established by or under the laws of the States in which the oranges are grown.

(2) Oranges colored with Citrus Red No. 2 shall bear not more than 2.0 parts per million of such color additive, calcu

lated on the basis of the weight of the whole fruit.

(d) Labeling. The label of the color additive and any mixtures prepared therefrom and intended solely or in part for coloring purposes shall conform to the requirements of § 8.32. To meet the requirements of § 8.32 (b) and (c) the label shall bear:

(1) The statement (or its equivalent) "To be used only for coloring skins of oranges."

(2) Directions for use to limit the amount of the color additive to not mor than 2.0 parts per million, calculated on the basis of the weight of the whole fruit.

(e) Certification. All batches of Citrus Red No. 2 shall be certified in accordance with regulations in Subpart A of this Part 8.

[33 F.R. 8813, June 18, 1968]

§ 8.202 Orange B.

(a) Identity. (1) The color additive Orange B is principally the disodium salt of 1 (4-sulfophenyl)-3-ethylcarboxy-4(4-sulfonaphthylazo) - 5-hydroxypyr

azole.

(2) The diluents in color additive mixtures for food use containing Orange B are limited to those listed in Subpart D of this part as safe and suitable in color additive mixtures for coloring foods.

(b) Specifications. Orange B shall conform to the following specifications: Volatile matter (at 135° C.), not more than 6.0 percent.

Chlorides and sulfates (calculated as the

sodium salts), not more than 7.0 percent. Water insoluble matter, not more than 0.2 percent.

1-(4-Sulfophenyl) - 3 - ethylcarboxy-5-hydroxypyrazolone and 1-(4-sulfophenyl)-3carboxy-5-hydroxypyrazolone, not more than 0.7 percent.

Naphthionic acid, not more than 0.2 percent. Phenylhydrazine-p-sulfonic acid, not more than 0.2 percent.

The trisodium salt of 1-(4-sulfophenyl)-3carboxy-4- (4 - sulfonaphthylazo)-5-hydroxypyrazole, not more than 6.0 percent. Other subsidiary dyes, not more than 1.0 percent.

Lead (as Pb), not more than 10 parts per million.

Arsenic (as As), not more than 1 part per million.

Pure color, not less than 87.0 percent.

(c) Uses and restrictions. Orange B may be safely used for coloring the casings or surfaces of frankfurters and