Safety and Regulatory Status of Food, Drug, and Cosmetic Color

Chapter 31

Safety and Regulatory Status of Food, Drug, and Cosmetic Color Additives 1

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Joseph F. Borzelleca and John B. Hallagan 1

Department of Pharmacology, Medical College of Virginia, Richmond, VA 23298 Daniel R. Thompson, P.C., 1620 I Street, NW, Suite 925, Washington, DC 20006 2

Color additives have long been used as a means of enhancing the esthetic value of foods, beverages and cosmetics, and for identifying drugs and other products. Archaeological evidence dates the use of color additives in cosmetics to 5000 B.C. The use of color additives in drugs is documented in ancient Egyptian writings and historic evidence of the use of color additives in foods is dated back to at least 1500 B.C.; natural substances such as turmeric, paprika and saffron, and inorganic mineral pigments were used. In the middle of the nineteenth century, synthetic organic dyes were developed creating a more economical and extensive array of colorants. Unfortunately, the use of color additives to adulterate products also has a long history. This misuse of color additives led to the imposition of controls by regulatory bodies and user associations. In 1906, with the passage of the Federal Pure Food and Drug Act, certain color additives including F D & C Red No. 3 and F D & C Blue No. 2 were approved for food use. F D & C Yellow No. 5 was approved in 1916; F D & C Green No. 3 in 1927; and F D & C Yellow No. 6 and F D & C Blue No. 1 in 1929. In 1908, the United States Department of Agriculture initiated a voluntary certification program for synthetic food color additives. Under the certification system, batch samples of color additives are submitted to the agency for analysis and confirmation that they comply with established specifications. The Federal Food, Drug and Cosmetic Act of 1938 (FFDCA) instituted mandatory certification and extended governmental control to colorings for drugs and cosmetics as well as foods. New scientific investigations of the safety of the color additives was promoted by the enactment of the 1960 Color Additive Amendments to the F F D C A and color additives have been the subject of extensive investigations since. The seven currently approved F D & C color additives are identified in Table 1 and Figure 1. The total pounds certified by the U.S. Food and Drug Administration in recent years are presented in Figure 2. It is anticipated that the use of F D & C color additives will continue to increase with the introduction of new food, drug and cosmetic products. A separate regulatory class of color additives are exempt from certification; this 0097-6156/92/0484-0377$06.00/0 © 1992 American Chemical Society In Food Safety Assessment; Finley, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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FOOD SAFETY ASSESSMENT

Table 1. Regulatory Status of the FD&C Color Additives in the United States


Color Additive

Dye

Lake

FD&C Red No. 40

PermanenUy listed for all uses at GMP. 21 CFR §§74.340 74.1340,74.2340 39 Fed Reg 44198 (23 December 1974)

Permanently listed for all uses at GMP. 21 CFR §§74.340, 74.1340,74.2340 39 Fed Reg 44198 (23 December 1974)

FD&C Blue No. 1

Permanently listed for all uses at GMP. 21 CFR §§74.101, 74.1101,74.2101 47 Fed Reg 42563 (28 September 1982)

Provisionally listed or all uses at GMP. 21 CFR §82.101

FD&C Blue No. 2

Permanently listed for all uses at GMP. 21 CFR §§74.102, 74.1102 48 Fed Reg 5252 (4 February 1983)

Provisionally listed for all uses at GMP. 21 CFR §82.102

FD&C Green No. 3

Permanently listed for all uses at GMP. 21 CFR §§74.203, 74.1203,74.2203 47 Fed Reg 52140 (19 November 1982)


FD&C Yellow No. 5

Permanently listed for all uses at GMP. 21 CFR §§74.705, 74.1705,74.2705 50 Fed Reg 35774 (4 September 1985)


FD&C Yellow No. 6

Permanently listed for all uses at GMP. 21 CFR §§74.2706, 74.1706,74.2706 51 Fed Reg 41765 (19 November 1986)


FD&C Red No. 3

Permanently listed for foods and ingested drugs at GMP. 21 CFR §§74.303, 74.1303 34 Fed Reg 7446 (8 May 1969) Delisted for cosmetic uses 55 Fed Reg 3516 (1 February 1990)

Delisted for all uses. 55 Fed Reg 3516 (1 February 1990)

In Food Safety Assessment; Finley, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

31. BORZELLECA & HALLAGAN

Food, Drug, and Cosmetic Color Additives

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FD&C Blue No. 1 B r i l l i a n t Blue FCF C l a s s : Triphenylmethane CAS No.: 2650-18-2

FD&C Blue No. 2 I n d i g o Carmine, I n d i g o t i n e Class: Indigoid CAS No.: 860-22-0 Ο FD&C Green No. 3 F a s t Green FCF C l a s s : Triphenylmethi CAS No.: 2353-45-9

FD&C Red No. 3 Erythrosine C l a s s : Xanthene CAS No.: 16423-68-0

FD&C Red No. 40 A l l u r a Red C l a s s : Monoazo CAS No.: 25956-17-6

FD&C Yellow No. 5 Tartrazine C l a s s : Monoazo CAS No.: 1934-21-0

FD&C Y e l l o w No. 6 Sunset Y e l l o w FCF C l a s s : Monoazo CAS No.: 2783-94-0 S0 Na 3

FIGURE 1.

FD&C Color

Additives



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1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990

Year FIGURE 2 .

T o t a l Pounds o f FD&C Dyes C e r t i f i e d by Year




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class includes many of the "natural" color additives including beta-carotene, annatto and carmine. The color additives exempt from certification have not been extensively tested but a long history of use in food suggests safety. The history and status of the F D & C color additives were previously reviewed by Borzelleca et al., (7), Marmion (2) and Newsome (3). This brief review summarizes the large body of scientific information on the F D & C color additives by concentrating on the results of lifetime toxicity/carcinogenicity studies, reproduction and teratology studies, metabolism studies and genotoxicity assays. The regulatory status of the color additives is also summarized. The Safety of the F D & C Color Additives In general, the safety of the F D & C color additives has been evaluated in multiple species, acutely and chronically. Additional studies include genetic toxicity, reproduction and development, and absorption, distribution, biotransformation, excretion and kinetics in animals and humans. Special studies, such as mechanistic studies, have been conducted on several color additives in animals and humans. The weight of the available evidence indicates that the F D & C color additives are safe for their intended uses. F D & C Red No. 40. F D & C Red No. 40 (Allura Red) is a monoazo color additive which has many applications including confectionery and candy products, alcoholic and nonalcoholic beverages, dairy products, meat and poultry products, bakery products and drugs and cosmetics. The amount certified in 1990 was 2,595,720 pounds. It was negative in genotoxicity tests (4-75). The acute oral toxicity is low; for example, the acute oral L D in rats is > 10,000 mg/kg (76). Lifetime dietary administration studies of F D & C Red No. 40 in rats (17) and mice (18) demonstrated no evidence of carcinogenicity in either species. There were no consistent compound-related adverse effects in either species except a reduction in body weight in female rats that received the highest dose (a dietary concentration of 5.19%). The no observable adverse effect levels reported were: rats ~ males, 2829 mg/kg/ day and females, 901 mg/kg/day; mice - males, 7200 mg/kg//day and females, 8300 mg/kg/day. There were no adverse effects on reproductive performance in a multigeneration study in rats (79). There were no adverse developmental effects in rats or rabbits (2023). F D & C Red No. 40 appears to be poorly absorbed from the gastrointestinal tract where it undergoes azo reduction (24,25). The acceptable daily intake established by the Joint Expert Committee on Food Additives of the World Health Organization (JECFA) in 1989 is 0-7.0 mg/kg/day. The maximum anticipated daily intake is calculated to be 0.19 mg/kg/day. 5 0


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F D & C Yellow No. 5. F D & C Yellow No. 5 (Tartrazine) is a monoazo color additive used in candies, beverages, desserts, preserves, canned and frozen vegetables, drugs and cosmetics. The amount certified in 1990 was 1,642,914 pounds. A weight of evidence analysis demonstrates that F D & C Yellow No. 5 is not genotoxic (6-10,13,14,26-41). The acute oral toxicity is low; for example, the acute oral L D in mice is 12,750 mg/kg (42). Chronic toxicity/carcinogenicity studies (dietary administration) of F D & C Yellow No. 5 in rats and mice were reported by Borzelleca and Hallagan (43,44); there was no evidence of carcinogenicity in either species nor evidence of consistent compound-related adverse effects. The no observable adverse effect levels were: rats - males, 2641 mg/kg/day and females, 3348 mg/kg/day; mice - males, 8103 mg/kg/day and females, 9753 mg/kg/ day. No carcinogenic or significant toxic effects were noted in rats that received F D & C Yellow No. 5 in drinking water at up to 2.0% for two years (45). There were no adverse reproductive effects reported in a multigeneration study in rats (46) and there were no adverse developmental effects in rats or rabbits (47). There were no significant effects on the development of the central nervous system in the offspring of female rats fed F D & C Yellow No. 5 (48). F D & C Yellow No. 5 undergoes bacterial azo reduction in the gastrointestinal tract of rats, rabbits, and humans (49-54). The major biotransformation product is sulfanilic acid (55,56). Sulfanilic acid may have minor behavioral effects on young rats which the authors conclude cannot be extrapolated to humans (57). The acceptable daily intake established by JECFA in 1964is 0-7.5 mg/kg/day. The maximum anticipated daily intake is calculated to be 0.11 mg/kg/day.


5 0

F D & C Yellow No. 6. F D & C Yellow No. 6 (Sunset Yellow FCF)is a monoazo color additive used to color confectionery products, beverages, dessert powders, bakery products, dairy products and drugs and cosmetics. The amount certified in 1990 was 1,606,997 pounds. It is not genotoxic by a weight of evidence analysis (5-10,13,14,30-33,39-41,5868). The acute oral toxicity is low; for example, the acute oral L D in rats is > 10000 mg/ kg (69). There was no evidence of carcinogenicity in dietary administration lifetime studies in rats or mice (70, 71). An increased incidence of pelvic mineralization and chronic nephropathy was reported in female rats at the two highest levels fed (1.5% and 5.0%) in the C C M A study (70). The no observable adverse effect levels in the C C M A study were: rats - males, 1635 mg/kg/day and females, 503 mg/kg/day; mice - males, 2608 mg/kg/day and females, 11443 mg/kg/day. The no observable adverse effect level in the NTP studies (71) was a dietary concentration of 2.5% for rats and mice; compound consumption data are unavailable. There were no adverse reproductive effects reported in a multigeneration study in rats and there were no adverse developmental effects in rats or rabbits (46,47). 5 0




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Like F D & C Yellow No. 5, F D & C Yellow No. 6 is poorly absorbed (

Safety and Regulatory Status of Food, Drug, and Cosmetic Color

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