Lifetime toxicity/carcinogenicity study of FD & C Red No. 3 (erythrosine) in mice.

Charles River CD-1 mice were fed FD & C Red No. 3 in the diet at levels of 0.3, 1.0 and 3.0% in a long-term toxicity/carcinogenicity study. Each group consisted of 60 males and 60 females. Two concurrent control groups each of 60 males and 60 females received the basal diet. Maximum exposure was 24 months. The no-adverse-effect levels established in this study were 3.0% (an average intake of 4759 mg/kg/day) for male mice and 1.0% (1834 mg/kg/day) for female mice.

Multigeneration study of FD & C Red No. 3 (erythrosine) in Sprague-Dawley rats.

Sprague-Dawley rats received dietary admixtures containing 0.0, 0.25, 1.0 or 4.0% FD & C Red No. 3 (25 rats/sex/group) in a three-generation reproduction study. Each generation was bred twice and breeders for subsequent generations were selected after weaning of the second mating from each generation. There were no compound-related adverse effects on reproductive indices and no gross anomalies were observed. The body weights of parents and pups were significantly reduced (P less than 0.05) in all generations at the 4.0% dietary concentration. Maternal body-weight gain during gestation was frequently reduced in the 1.0 and 4.0% groups. The conservative no-observed-adverse-effect level established in this study was 0.25% (approximately 149 and 255 mg/kg body weight/day for males and females, respectively).

Chronic toxicity/carcinogenicity studies of FD & C Yellow No. 5 (tartrazine) in rats.

FD & C Yellow No. 5 was fed to Charles River CD rats as a dietary admixture in two long-term toxicity/carcinogenicity studies. The studies were conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at levels of 0.0, 0.0, 0.1, 1.0 or 2.0% ('original study') and 0.0 or 5.0% ('high-dose study'). The concurrent control groups received the basal diet. After random selection of the F1 animals, the long-term phase was initiated using the same dietary levels with 70 rats of each sex/group, including the three control groups. The maximum exposure to the colouring was 113 and 114 wk for males and females, respectively, in the 'original' study and 122 and 125 wk for males and females, respectively, in the 'high-dose' study. No compound-related effects were noted. The no-adverse-effect level found in this study was 5.0% in the diet providing an average intake of 2641 and 3348 mg/kg/day for male and female rats, respectively.

A chronic toxicity/carcinogenicity study of FD & C Yellow No. 5 (tartrazine) in mice.

Charles River CD-1 mice were fed FD & C Yellow No. 5 in the diet at levels of 0.0, 0.0, 0.5, 1.5 or 5.0% in a long-term toxicity/carcinogenicity study. Each group consisted of 60 males and 60 females. Maximum exposure was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse effect level established in this study was 5.0% (8103 mg/kg/day and 9735 mg/kg/day for male and female mice, respectively.)

Lifetime toxicity/carcinogenicity studies of FD & C Blue No. 1 (brilliant blue FCF) in rats and mice.

FD & C Blue No. 1 was fed to Charles River CD rats and CD-1 mice as a dietary admixture in lifetime toxicity/carcinogenicity studies. The rat study was conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at dietary concentrations of 0.0%, 0.0%, 0.1%, 1.0% or 2.0%. After randomly selecting the F1 animals, the lifetime phase was initiated at the same levels with 70 rats/sex/group, including two control groups. The maximum exposure times were 116 and 111 wk for males and females, respectively. The no-observed-adverse-effect levels are dietary concentrations of 2.0% for males (1072 mg/kg body weight/day), and 1.0% for females (631 mg/kg/day) based on a 15.0% decrease in terminal body weight and decreased survival in the high-dose females compared with the combined control groups. Charles River CD-1 mice (60/sex/group) were fed FD & C Blue No. 1 as a dietary admixture at levels of 0.0%, 0.0%, 0.5%, 1.5% or 5.0% in a lifetime toxicity/carcinogenicity study. The maximum exposure time was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse-effect level established in this study is a dietary concentration of 5.0% (7354 mg/kg/day and 8966 mg/kg/day for male and female mice, respectively.

The safety and regulatory status of food, drug and cosmetics colour additives exempt from certification.

Colour additives exempt from certification (also known as 'natural colour additives') are commonly used in the United States to colour foods, drugs and cosmetics. The US Food and Drug Administration established regulations governing the use of these colour additives, and the labelling of the products that contain them. The safety of these colour additives has been demonstrated by safety testing programs that have yielded a significant amount of toxicology data, and also by a long and well documented history of safe use in the United States and elsewhere. In this report we review the data supporting the safety of the colour additives that are exempt from certification and approved for use in the USA, and conclude that the safety of these colour additives is well supported by the available data. Relevant aspects of the regulation of these colour additives are also described.

Lifetime toxicity/carcinogenicity study of FD & C Red No. 3 (erythrosine) in rats.

FD & C Red No. 3 was fed to Charles River CD rats as a dietary admixture in two long-term toxicity/carcinogenicity studies. The studies consisted of an in utero and an F1 phase. In the former, the compound was administered to five groups of the F0 generation rats (60 of each sex/group) at levels of 0.0, 0.0, 0.1, 0.5 or 1.0% ('original study') and 0.0 or 4.0% ('high-dose study'). The concurrent control groups received the basal diet. After random selection of the F1 animals, the long-term phase was initiated using the same dietary levels and 70 rats of each sex/group, including the three control groups. Rats were exposed for a maximum of 30 months. No compound-related effects were noted in the in utero phase. Mean body weights of the female F1 rats on 4.0% FD & C Red No. 3 (3029 mg/kg/body weight/day) were significantly lower than those of controls (P less than 0.01) throughout the study. Food consumption increased in all treated groups in a dose-related manner. There were no significant effects on the haematology, serum chemistry and urinalysis and no compound-related effects on survival. In male rats receiving 4.0% FD & C Red No. 3 (2464 mg/kg/day) thyroid weights were increased, with a mean weight of 92 mg compared to 44 mg for controls, and statistically significant increases in the incidence of thyroid follicular cell hypertrophy, hyperplasia and adenomas were recorded. A numerically increased incidence of thyroid follicular adenomas in female rats given 0.5, 1.0 or 4.0% FD & C Red No. 3 was not statistically significant. The no-observed-adverse-effect levels established in these studies were 0.5% (251 mg/kg/day) for male rats and 1.0% (641 mg/kg/day) for females.

Assessment of cassia gum.

Cassia gum is approved for use in Europe by the Commission Directive (EEC No. E 499) and is listed in the Annex of the Council Directive (70/524/EEC) as a stabilizer (thickening and gelling agent) in the manufacture of canned pet foods (for cats and dogs). It is also approved for use in Japan and is listed as a food additive in The Ministry of Health and Welfare Announcement No. 160 (10 August 1995). A panel of experts in the areas of toxicology, pharmacology and food science was assembled to review the safety of cassia gum for use as a thickening agent in human and pet foods in the United States. The available data on cassia gum and structurally related gums demonstrate a lack of toxic effects in animals. This review is the basis for the consideration of cassia gum as generally recognized as safe (GRAS) under conditions of its intended use as a thickening agent in human and pet foods.

The FEMA GRAS assessment of alicyclic substances used as flavour ingredients.

For over 35 years, an independent panel of expert scientists has served as the primary body for evaluating the safety of flavour ingredients. This group, the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA), has achieved international recognition from the flavour industry, government regulatory bodies including the Food and Drug Administration, and the toxicology community for its unique contributions. To date, the Expert Panel has evaluated the safety of more than 1700 flavour ingredients and determined the vast majority to be "generally recognized as safe" (GRAS). Elements that are fundamental to the safety evaluation of flavour ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavour ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. The elements of the GRAS assessment program as they have been applied by the Expert Panel to the group of 119 alicyclic substances used as flavour ingredients, and the relevant scientific data which provide the basis for the GRAS status of these substances, are described herein.

FEMA GRAS--a GRAS assessment program for flavor ingredients. Flavor and Extract Manufacturers Association.

The generally recognized as safe (GRAS) assessment program of the Flavor and Extract Manufacturers Association (FEMA) of the United States was initiated in 1959 to provide for the assessment of flavor ingredients as GRAS under the Food Additives Amendment to the U.S. Federal Food, Drug, and Cosmetic Act. FEMA sponsored the formation of an independent panel of experts to perform GRAS assessments and to provide their conclusions to the U.S. Food and Drug Administration, the food and flavor industries, and the public. The program was designed to account for the legal, regulatory, and scientific issues associated with GRAS assessments and has continued to incorporate changes in the law and in science. This review describes the legal and scientific foundation of the FEMA program.

The role of natural color additives in food allergy.

A critical evaluation of the available information demonstrates that reactions to natural color additives are rare. Studies of turmeric and carotenoid pigments administered in mixtures with other food colorings failed to definitely identify reactions to either color additive. For carotenoids, the one case report of an adverse reaction was not conclusive. An anaphylactic reaction to saffron does suggest an IgE-mediated reaction, but the high use of saffron as compared with this single report of an adverse reaction suggests that sensitivity to saffron is extremely rare. Numerous reports of reactions to grapes or grape products have been reported in the literature, but no reports of sensitivities to grape skin extract or grape color extract were found. In rare cases, annatto dye may provoke a severe, adverse reaction in individuals with an uncommon hypersensitivity, and may aggravate the symptoms of patients suffering from recurrent urticaria. In its long history of use, there has been only one reported case of anaphylaxis resulting from the ingestion of annatto. Studies designed to investigate the role of annatto in recurrent urticaria sufferers were limited due to the absence of double-blind challenge and placebo controls. A number of cases of adverse reactions to carmine following ingestion have been reported in the literature. These adverse reactions suggest an IgE-mediated hypersensitivity. In many of the reported cases, the cause of sensitization to carmine was topical exposure from the use of carmine-containing cosmetics or occupational exposure to carmine and not from ingestion of carmine-containing foods and beverages. Following sensitization, affected individuals would be sensitive to carmine and the amounts present in foods and beverages could elicit allergic reactions. It is not known whether all individuals with carmine sensitivity induced through topical use are sensitive to the ingestion of carmine in foods. However, reactions to carmine solely because of ingestion are likely to be exceedingly rare due to the low use levels of carmine in foods and beverages. Despite their widespread use in food products, few reports of allergic reactions following ingestion have been reported for the majority of natural color additives. It is concluded that the ingestion of natural color additives presents a very low risk of provoking adverse reactions.