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FD&C Green No. 3 (§ 9.23 of this chapter).
FD&C Yellow No. 5 (§ 8.275 of this chapter).
FD&C Yellow No. 6 (§ 9.41 of this chapter)
FD&C Red No. 2 (§ 9.61 of this chapter).
FD&C Red No. 3 (§ 8.242 of this chapter).
FD&C Red No. 4 (§ 9.63 of this chapter)
FD&C Blue No. 1 (§ 8.206 of this chapter)
FD&C Blue No. 2 (§ 9.81 of this chapter).
FD&C Violet No. 1 (§ 9.90 of this chapter).
Lakes (FD&C) (§ 9.100 of this chapter).

1 Lakes only.

tions for color additives listed in paragraphs (a), (b), and (c) of this section appear in Part 9 of this chapter. The listing of color additives in this section is not to be construed as a listing for surgical suture use unless color additive petitions have been submitted for such use or the Commissioner has been notified of studies underway to establish the safety of the color additive for such use. The color additives listed in paragraphs (a), (b), and (c) may not be used in products which are intended to be used in the area of the eye.

(a) Color additives previously and presently subject to certification and provisionally listed for food, drug, and

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(b) Color additives previously and presently subject to certification and provisionally listed for drug and cosmetic use.

D&CG reen No. 5 (§ 9.103 of this chapter).
D&CG reen No. 6 (§ 9.104 of this chapter).
D&CG reen No. 8 (§ 9.106 of this chapter).
D&C Yellow No. 7 (§ 9.130 of this chapter).
D&C Yellow No. 8 (§ 9.131 of this chapter).
D&C Yellow No. 10 (§ 9.133 of this chapter).
D&C Yellow No. 11 (§ 9.134 of this chapter).
D&C Red No. 6 (§ 9.151 of this chapter).
D&C Red No. 7 (§ 9.152 of this chapter).
D&C Red No. 8 (§ 9.153 of this chapter)
D&C Red No. 9 (§ 9.154 of this chapter).
D&C Red No. 10 (§ 9.155 of this chapter).
D&C Red No. 11 (§ 9.156 of this chapter)
D&C Red No. 12 (§ 9.157 of this chapter).
D&C Red No. 13 (§ 9.158 of this chapter).
D&C Red No. 17 (§ 9.162 of this chapter).
D&C Red No. 19 ( 9.164 of this chapter).
D&C Red No. 21 (§ 9.166 of this chapter).
D&C Red No. 22 (§ 9.167 of this chapter).
D&C Red No.27 (§ 9.172 of this chapter).
D&C Red No. 28 (§ 9.173 of this chapter).
D&C Red No. 30 (§ 9.175 of this chapter)
D&C Red No. 31 (§ 9.176 of this chapter).
D&C Red No. 33 (§ 9.178 of this chapter).
D&C Red No. 34 (§ 9.179 of this chapter).
D&C Red No. 36 (§ 9.181 of this chapter).
D&C Red No. 37 (§ 9.182 of this chapter).
D&C Orange No. 4 (§ 9.201 of this chapter)
D&C Orange No. 5 ($ 9.202 of this chapter)
D&C Orange No. 10 (§ 9.207 of this chapter).
D&C Orange No. 11 (§ 9.208 of this chapter).
D&C Orange No. 17 (§ 9.214 of this chapter).
D&C Blue No. 4 (§ 9.240 of this chapter).
D&C Blue No. 6 (§ 9.242 of this ch apter).
D&C Blue No. 9 (§ 9.245 of this ch apter).
D&C Violet No. 2 (§ 9.270 of this chapter).
Lakes (D&C) (§ 9.280 of this chapter).

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(c) Color additives previously and presently subject to certification and provisionally listed for use in externally applied drugs and cosmetics.

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(e) Color additives provisionally listed for food use on the basis of prior commercial sale but which have not been nor are now subject to certification.

Carbon black (prepared by the "impingement" or "channel" process)....

Closing date

Restrictions

Dec. 31, 1971

(f) Color additives provisionally listed for drug use on the basis of prior commercial sale but which have not been nor are now subject to certification. The color additives listed in this paragraph are listed only for the uses and purposes commercially employed prior to July 12, 1960. Thus, a color additive used only in drugs for external application is not provisionally listed for internal drug use.

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[32 F.R. 10930, July 26, 1967; 32 F.R. 10981, July 27, 1967; 32 F.R. 11733, Aug. 15, 1967; 32 F.R. 12715, Sept. 2, 1967; 32 F.R. 12943, Sept. 12, 1967; 33 F.R. 982, Jan. 26, 1968; 33 F.R. 5987, Apr. 19, 1968; 33 F.R. 10844, July 31, 1968; 33 F.R. 12228, Aug. 30, 1968; 34 F.R. 435, Jan. 11, 1969; 34 F.R. 2112, Feb. 13, 1969; 34 F.R. 9795, June 25, 1969; 34 F.R. 11542, July 12, 1969; 36 F.R. 3806, Feb. 27, 1971]

§ 8.502 Termination of provisional listings of color additives.

(a) Ext. D&C Yellow Nos. 9 and 10. These colors cannot be produced with any assurance that they do not contain B-naphthylamine as an impurity. While it has been asserted that the two colors can be produced without the impurity named, no method of analysis has been suggested to establish the fact. B-Naphthylamine is a known carcinogen; therefore, there is no scientific evidence that will support a safe tolerance for these colors in products to be used in contact with the skin. The Commissioner of Food and Drugs, having concluded that such action is necessary to protect the public health, hereby terminates the provisional listing of Ext. D&C Yellow No. 9 and Ext. D&C Yellow No. 10 (§§ 9.309 and 9.310 of this chapter).

(b) (1) D&C Red Nos. 8, 9, 10, 19, 33, 37; D&C Yellow No. 7; D&C Orange Nos. 3, 4, 5, and 17. Subacute studies have established that these colors are toxic substances, unsafe for unrestricted use in drugs and cosmetics.

(2) D&C Red Nos. 11, 12, and 13. These colors are chemically related to D&C Red No. 10, being the calcium, barium, and strontium salts of the same dye, and are chemically indistinguishable from D&C Red No. 10 in the analysis of a product in which such colors have been used. They therefore must be sub

ject to the same restrictions imposed on D&C Red No. 10.

(3) D&C Yellow No. 8. This color is chemically and pharmacologically related to D&C Yellow No. 7, and therefore must be subject to any restriction imposed on that color.

The Commissioner of Food and Drugs, having concluded that such action is necessary for the protection of the public health, hereby terminates the provisional listing for the colors named in this section for unrestricted use in drugs and cosmetics. These colors are now listed in Part 9 of this chapter as follows:

D&C Red No. 8 (§ 9.153 of this chapter).
D&C Red No. 9 (§ 9.154 of this chapter).
D&C Red. No. 10 (§ 9.155 of this chapter).
D&C Red No. 11 ( 9.156 of this chapter).
D&C Red. No. 12 (§ 9.157 of this chapter).
D&C Red. No. 13 (§ 9.158 of this chapter).
D&C Red. No. 19 (§ 9.164 of this chapter).
D&C Red No. 33 (§ 9.178 of this chapter).
D&C Red No. 37 (§ 9.182 of this chapter).
D&C Yellow No. 7 (§ 9.130 of this chapter).
D&C Yellow No. 8 (§ 9.131 of this chapter).
D&C Orange No. 3 (§ 9.200 of this chapter).
D&C Orange No. 4 (§ 9.201 of this chapter).
D&C Orange No. 5 (§ 9.202 of this chapter).
D&C Orange No. 17 (§ 9.214 of this chapter).

(c) FD&C Red No. 1. Results of recent feeding tests of this color additive have demonstrated it to be toxic upon ingestion:

(1) Groups of 50 rats are being fed diets containing FD&C Red No. 1 at levels of 5 percent, 2 percent, 1 percent, 0.5 percent, and 0 percent. At this stage of the tests, which have now been in progress for from 15 months to 18 months, 116 animals from the 250 being fed FD&C Red No. 1 at various levels and 27 of the 100 controls have died. Of these, 11 being fed at the 5 percent level, 16 being fed at the 2 percent level, 11 being fed at the 1 percent level, and 2 being fed at the 0.5 percent level, have shown liver damage. None of the controls that have died have shown liver damage.

(2) Groups of 100 mice are being fed diets containing 2 percent, 1 percent, 0.5 percent, and 0.1 percent FD&C Red No. 1, with 400 mice as controls. All mice on dosage levels of 2 percent and 1 percent died before the seventieth week. Gross liver damage has been observed in all groups fed at the 0.5 percent diet and above.

(3) Groups of 4 dogs are being fed diets containing 2 percent, 1 percent,

0.25 percent, and 0 percent FD&C Red No. 1. Three of the dogs on the 2 percent dosage level died before 32 weeks; the other is living. Three of the dogs on the 1 percent dosage level died or were sacrificed within 13 months. All deceased or sacrificed dogs have shown liver damage grossly and/or microscopically. Deceased dogs on the 1 percent and 2 percent dosage level showed poor physical condition.

The Commissioner of Food and Drugs, having concluded that ingestion of this color additive over a long period of time would be unsafe, and in order to protect the public health, hereby terminates the provisional listing of FD&C Red No. 1 (§ 9.60 of this chapter) for use in foods, drugs, and cosmetics.

(d) FD&C Red No. 4. Feeding tests of this color additive have been conducted with three species:

(1) Rats of the Osborne-Mendel and Sprague-Dawley strains were fed FD&C Red No. 4 for 2 years at levels of 5 percent, 2 percent, 1 percent, and 0.5 percent of the diet. No effect was found.

(2) Mice of the C3Hf and C57BL strains were fed FD&C Red No. 4 for 2 years at levels of 2 percent and 1 percent of the diet. No effect was found.

(3) Dogs were fed FD&C Red No. 4 at levels of 2 percent and 1 percent of the diet. Adverse effects were found at both levels in the urinary bladder and in the adrenals. Three dogs of five fed on the 2-percent level died after 6 months, 9 months, and 51⁄2 years on the test. Two of the dogs on the 2-percent level and all five of the dogs on the 1-percent level survived to the completion of the 7 year study.

The Commissioner of Food and Drugs has concluded that the data available to him do not permit the establishment of a safe level of use of this color additive for a long period of time in food and in ingested drugs and cosmetics. In order to protect the public health, the Commissioner hereby terminates the provisional listing of FD&C Red No. 4 (§ 9.63 of this chapter) for use in food and in drugs and cosmetics that may be ingested. The Commissioner does not find that the facts now before him require a prohibition of the use of FD&C Red No. 4 in drugs and cosmetics which are not ingested and the provisional listing with respect to these uses remains in effect. [25 F.R. 9760, Oct. 12, 1960, as amended at 25 F.R. 10600, Nov. 5, 1960, 25 FR. 11214,

169

Nov. 26, 1960, 26 F.R. 7579, Aug. 16, 1961, 29 F.R. 16893, Dec. 11, 1964]

§ 8.503 Temporary tolerances.

Two-year chronic rat feeding studies, including histopathology, of D&C Red. No. 9 and D&C Red. No. 10 have been completed. A final determination of the status of these colors for ingestion must await chronic feeding studies with a nonrodent species. However, pharmacologists of the Food and Drug Administration have concluded, on the basis of chronic feeding studies with the rat, that a no-effect level of feeding of 100 parts per million will be accepted pending chronic feeding studies with a nonrodent species. Since the subacute toxicity of the two colors is of the same order of subacute toxicity as the other nine colors listed in § 8.502(b) (1), it can be assumed for the purpose of temporary tolerances that the same no-effect level of feeding for the nine colors is also 100 parts per million. Data have been submitted which indicate that the maximum amount of the color additives listed in paragraph (a) of this section likely to be ingested daily from lipstick will correspond to about 0.1 part per million in the daily diet. On this basis, it is not inconsistent with the protection of the public health to allow, during this transitional period, continued use of these products in lipstick and in other products that may be ingested in the amounts specified in this section.

(a) Pursuant, therefore, to the authority in section 203 (d) (1) (C) of the Color Additive Amendments of 1960, temporary tolerances are established for the following color additives:

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D&C Orange No. 5 (§ 9.202 of this chapter)

D&C Orange No. 17 (§ 9.214 of this chapter)

D&C Red No. 8 (§ 9.153 of this chapter) D&C Red No. 9 (§ 9.154 of this chapter) D&C Red No. 10 (§ 9.155 of this chapter) D&C Red No. 11 (§ 9.156 of this chapter) D&C Red No. 12 (§ 9.157 of this chapter) D&C Red No. 13 (§ 9.158 of this chapter) D&C Red No. 19 (§ 9.164 of this chapter) D&C Red No. 33 (§ 9.178 of this chapter) D&C Red No. 36 (§ 9.181 of this chapter)

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These color additives are therefore retained on the provisional list for use in lipstick with the indicated temporary-tolerances which are expressed as percent pure dye by weight of each lipstick. These color additives may be used in combina

tions provided the individual tolerance is not exceeded and the total percent of all colors used does not exceed 6 percent pure dye by weight of the lipstick. These color additives and D&C Yellow No. 7, D&C Yellow No. 8, and D&C Red No. 37 are retained without tolerance restrictions for externally applied drugs and cosmetics.

(b) (1) The colors named in this paragraph may safely be used, during the transitional period, in drug products and in such other preparations subject to ingestion as mouthwashes and dentifrices, where total usage reasonably to be expected to be ingested does not contribute more than 1 part per million of any such color additive or combination of color additives to the human diet. Therefore, to meet this limitation the following colors are retained on the provisional list of color additives for use in drug products for internal use, mouthwashes, dentifrices, and proprietary products, under a temporary tolerance, provided that in no instance shall such color additives contribute more than 0.75 milligram of the color additive, expressed as pure dye, to the amount of the product reasonably expected to be ingested in 1 day.

D&C Orange No. 5 (§ 9.202 of this chapter).
D&C Red No. 8 (§ 9.153 of this chapter).
D&C Red No. 12 (§ 9.157 of this chapter).
D&C Red No. 19 (§ 9.164 of this chapter).
D&C Red No. 33 (§ 9.178 of this chapter).
D&C Red No. 37 (§ 9.182 of this chapter).

(2) D&C Red No. 36 (§ 9.181 of this chapter) is retained on the provisional list of color additives for use in drug products for internal use, mouthwashes, dentifrices, and proprietary products, under a temporary tolerance, provided that in no instance shall it contribute more than 1.7 milligrams of the color additive, expressed as pure dye, to the amount of the product reasonably expected to be ingested in 1 day.

(c) Since the action outlined in § 8.502 (d) on December 11, 1964, additional studies with two species of animals have been completed. An over-all evaluation of the studies indicates that there would be no hazard to the public health if the use of FD&C Red No. 4 were restricted as follows:

(1) It may be used in food only for the coloring of maraschino cherries at a level not to exceed 150 parts per million by weight of the maraschino cherries. Such weight shall not include packing

media, or in the case of candied maraschino cherries, added sugar.

(2) It may be used without quantitative restriction in externally applied drugs and cosmetics. It may be used in ingested drugs, provided that the labeling does not recommend nor suggest continuous administration to patients, and the amount of FD&C Red No. 4 used is such that not more than 5 milligrams of the color additive is consumed per day if the recommended drug dosage is followed. For the purpose of this order, a recommendation or suggestion for use longer than 6 weeks shall be considered to be a recommendation for continuous administration.

(3) Labels of the color additive and mixtures containing it shall bear, in addition to other statements required by the act and regulations:

(1) A statement of the quantity of FD&C Red No. 4 in weight per unit volume or percent by weight; and

(ii) The following statement or its equivalent: "This color additive may be used in or on food only for coloring maraschino cherries at a level not to exceed 150 p.p.m. by weight of the maraschino cherries. Such weight shall not include packing media, or in the case of candied maraschino cherries, added sugar. It may be used in externally applied drugs and cosmetics without quantitative restriction. Use in ingested drugs is subject to quantity and period of use restrictions. Consult Color Additive Regulations of the U.S. Food and Drug Administration before using." [26 F.R. 7579, Aug. 16, 1961, as amended at 30 F.R. 10289, Aug. 19, 1965, 30 F.R. 13056, Oct. 14, 1965; 35 F.R. 19749, Dec. 30, 1970] § 8.510 Cancellation of certificates.

(a) Certificates issued heretofore for colors being removed from the provisional list (§ 8.502(a)) are cancelled and of no effect after December 1, 1960, and use of such color additives in drugs or cosmetics after that date will result in adulteration.

(b) (1) Certificates issued heretofore for the color additive designated FD&C Red No. 1 (§ 9.60 of this chapter) are cancelled as of the date of the publication of this Order, and use of this color additive in the manufacture of foods, drugs, or cosmetics after that date will result in adulteration.

(2) The Commissioner finds that no action needs to be taken to remove foods, drugs, and cosmetics containing this

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