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Appendix B: Case Studies of the Implementation of the Direct Food and Color Additives Amendments to the Federal Food, Drug, and Cosmetics Act of 1938
Pages 111-140

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From page 111...
... Discrimination and speed have increased almost as much, with a consequent, and comparable, reduction in cost per analysis. As a consequence, there is now far more information on the enormous complexity and variability of the trace constituents in the food supply (IFBC, 1990; NAS, 19961.
From page 112...
... However, the debate about how to measure, analogize, or transfer results in test animals to humans continues. In 1973, a quick, inexpensive screening test was developed by Ames and co-workers (Ames, 1973)
From page 113...
... For most toxic endpoints, such as neurotoxicity or non-carcinogenic organ damage, this approach continues to be used and well serves human health. FDA commonly uses the concept, although seldom employs it explicitly, preferring instead to rely on "the weight of all of the evidence." In the last few decades, however, and particularly for substances that show carcinogenic effects in test animals, that approach has been replaced by "quantitative risk assessment" (QRA)
From page 114...
... However, if the level of exposure is many orders of magnitude below the levels at which effects have been observed in test animals or humans, the significance of possible synergistic effects is still likely to be negligible. This is not true as exposure to a component of a mixture approaches the ADI, or some other appropriately conservative interpretation of the available biological data.
From page 115...
... Consumer pressure and publications were prominent in the passage of the 1906 and 1938 Food and Drug Acts and in activity leading to the Food Additives Amendment of 1958. Since then, they have been frequent, often vocal, but unevenly effective contributors to food safety issues.
From page 116...
... The standards, "may render it injurious," in the statute, and "reasonable certainty of no harm," from the legislative history of the 1958 Food Additives Amendment, are more stringent standards that are appropriate for those changes that are intentional and which are therefore under human choice and control.
From page 117...
... CYCLAMATE Overview In 1969, the FDA banned cyclamate from use in food after studies suggested that it might be an animal carcinogen. The reintroduction of this food additive petition, by Abbott Laboratories, Inc.
From page 118...
... 1973 On November 13, Abbott submitted a petition to gain approval for cyclamates as a new food additive. The petition provided all relevant data for cyclamate and the cycIamate/saccharin mixture for the twenty years that it had been used in the United States, plus new unpublished data on cyclamate and cyclohexylamine (CHA)
From page 119...
... However, Abbott has failed to establish that cyciam ate is not a carcinogen. 1980 On September 16, the FDA published the Commissioner's Final Decision denying the food additive petition for cyclamate.
From page 120...
... 11. Careful selection of outside expert panels and educating their members on the regulatory safety evaluation process is mandatory for assuring relevant ant!
From page 121...
... 1979 The FDA review of toxicology data resulted in a request for additional data from the animal feeding studies by the Central Institute for Food and Nutrition Research, TNO Laboratories, The Netherlands, and Bio Research Laboratories. 1981 Joint FAO/lAEAJWHO Expert Committee on the Wholesomeness of Irradiated Food (JECIF)
From page 122...
... . Consumers, interest in irradiation increased after the 1981 publication of FDA's advanced notice of proposed rulemaking for irradiated foods.
From page 123...
... 5. Irradiated foods are examples of"food additives" (by statutory definition only)
From page 124...
... 5. Unanticipated scientific questions and issues usually arise during a research program on new food additives, before or after market introduction, requiring close and frequent interaction between the petitioner and FDA as well as with outside experts, and later, with the public at large.
From page 125...
... 1964 The FAD/WHO Joint Committee on Food Additives (JEFCA) evaluated amaranth (Red No.
From page 126...
... 1980 The FDA Commissioner issued a final denial of the petition for permanent listing of the color. 1984 JEFCA reevaluated amaranth and assigned it a permanent ADI of 0-0.5 mg/kg/
From page 127...
... 1985 Color Additives Scientific Review Panel (organized by NCTR) reviewed data on Red No.
From page 128...
... The court made clear that its decision applied only to the clause in the Color Additives Amendment, not the Food Additives Amendment, where, although the wording was closely similar, "the context is clearly different." Since then, the FDA dropped any explicit use of cle minimis but has continued to develop and apply its "constituents policy" to (lirect and indirect food additives. This policy has been sustained in court (Scott v.
From page 129...
... A court decision denied it the use of the de minimis concept under the Color Additives Amendment. The FDA has continued to employ the cle minimis principle, although not explicitly, in the formulation and use of its "constituents policy." 5.
From page 130...
... 1976 NCA began a research and testing program on DCM. In the course of that effort and related activities by individual firms, General Foods spent $300,000 for metabolism studies for use in PBPK evaluation and for designing chronic drinking water studies in rats and mice.
From page 131...
... 19871. On the basis of that decision however, and the results of the NCI inhalation studies on DCM, FDA terminated cosmetic uses of DCM, but stated that it would take some time to assess the impact of that decision on the food uses, for which listing continues (FR 54, 124, 27328 ff.~.
From page 132...
... 1976 FEMA expert pane! reviewed all available data on d-limonene and affirmed the previous GRAS status.
From page 133...
... , which compares the average intake of added flavoring materials to the quantities consumed as components of traditional foods, indicates that benzy} acetate is consumed about as much as a flavor ingredient as it is as a constituent of traditional foods. Its reported consumption volume of 22,500 kg in 1970 drew the interest of the NTP in testing and evaluating the toxicity of benzy!
From page 134...
... expert panels noted several troubling issues. A high degree of infection noted in mice of both sexes; poor handling of the untreated control groups; a lack of significant tumor incidence between the benzy!
From page 135...
... Chronology 1965 FEMA expert pane} determined iso-amy} acetate to be GRAS. 1975 FEMA expert pane} affirmed the previous GRAS status for iso-amy!
From page 136...
... FEMA expert pane} affirmed the previous GRAS status of furfural for use as a flavor ingredient. Pre-1990 NIP conducted toxicity and carcinogenicity investigations of furfural (>99% pure)
From page 137...
... The FEMA expert panel's GRAS conclusion, and subsequent affirmation and reaffirmation were based upon a contextual understanding of the wide range of studies conducted with furfural. Institutions that conduct primary research with regulatory implications must hold themselves to a high protocol standard, just as regulatory agencies that utilize these studies must be able to place referred studies into context with the questions of human risk.
From page 138...
... The company sought FDA guidance on the regulatory steps that would be necessary before the novel technology could be commercialized. Since the law categorizes sources of radiation used to treat food as a "food additive" unless they are GRAS, submission of a food additive petition, and its subsequent approval by FDA, were necessary.
From page 139...
... The inherent safety of the final chymosin product was confirmed from feeding studies in rats and dogs, and from a genotoxicity test battery. 1988 Pfizer submitted both a Food Additive Petition (FAP)
From page 140...
... 140 APPENDIX B most policy questions were dealt with rather expediently (i.e., within a few months) because the scientific review conducted was definitive and conclusive to affirm GRAS status.


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