In 1958, Congress amended the Federal Food, Drug, and Cosmetic Act to state that food bearing or containing any unsafe food additive shall be deemed adulterated and that a food additive is considered unsafe unless, among other things, it and its use conform to a regulation prescribing the conditions of its safe use. A regulation prescribing the conditions for safe use could be obtained through a process established in the 1958 amendment. That process describes the data for companies to include in a petition for a proposed regulation (known as a food additive petition), a time frame and standards for agency review, and an opportunity for public comment. Under this process, as further prescribed in FDA regulations, the safety of an additive does not need to be established with absolute certainty; instead, the regulations provide a science-based standard of safety, requiring a reasonable certainty that no harm will result from the intended use of an additive. If FDA finds a food additive to be safe for its intended uses, the agency will issue a regulation specifying those uses. The 1958 amendment defines “food additive” as any substance the intended use of which results, or may reasonably be expected to result, directly or indirectly, in its becoming a component of or otherwise affecting the character of any food. However, this definition excludes substances that are generally recognized as safe under the conditions of their intended use, as shown through scientific procedures or based on common usage in food prior to 1958. Therefore, unlike food additives, a GRAS substance is not considered unsafe in the absence of a regulation prescribing its safe use, allowing a company to market food containing the substance without FDA approval. Since the 1958 amendment, FDA has taken a variety of actions to determine the GRAS status of substances used in food, as figure 1 illustrates. Shortly after the passage of the 1958 amendment, FDA clarified the regulatory status of many food substances that were used in food prior to 1958 and amended its regulations to include a list of food substances, commonly referred to as the GRAS list, that, when used for the purposes indicated and in accordance with current good manufacturing practices, are GRAS. However, FDA also acknowledged the extreme difficulty in listing all substances that are GRAS for their intended use, stating in its regulations that such an effort would be “impracticable.” FDA added other categories of substances—for example, spices, seasonings, and flavorings—to the GRAS list in subsequent rule makings. During the late 1960s, new scientific information raised questions about the safety of cyclamate salts, a class of sweeteners that FDA previously considered GRAS. As a result, FDA contracted for an independent review, by contemporary standards, of the available safety information related to substances it considered GRAS. If the review confirmed that the use of a particular substance was GRAS, FDA would issue a new regulation, affirming that finding. At about the same time as this review began, FDA also established procedures—referred to as the petition affirmation process—whereby companies could petition FDA to affirm the GRAS status of substances not covered as part of the review. To the extent that companies voluntarily submitted petitions to FDA as part of the affirmation process, the agency became aware of companies’ independent GRAS determinations. Under FDA’s GRAS petition affirmation process—as described in FDA’s 1997 proposal for a new GRAS program—the agency (1) published a notice in the Federal Register; (2) requested comments on the GRAS petition; (3) comprehensively reviewed the safety of the substance; (4) drafted a detailed explanation of why the use is GRAS; and (5) published that explanation in the Federal Register. Each petition resulted in a rule making that allowed the public to comment on the proposed rule and FDA to respond to these comments before issuing the final rule. In 1997, citing the resource intensive process required to conduct the petition affirmation process, FDA proposed a new GRAS program that, among other things, would eliminate the rule-making steps under the affirmation process. FDA’s proposed rule would allow companies that had made a GRAS determination to apply to FDA for its review under a voluntary notification program. Under this new program, in which FDA invited companies to participate under an interim policy discussed in the proposed rule, FDA no longer affirms the GRAS status of a substance. Rather, once FDA completes its review of a company’s notice of a GRAS determination, it informs the company in a letter of one of the following three responses: FDA has no questions about the company’s conclusion that the substance is GRAS (referred to as a no questions letter); FDA concludes that the notice does not provide a sufficient basis for a determination that the substance is GRAS because, for example, the notice does not include appropriate data or the available data raise questions about the safety of the substance; or FDA has, at the company’s request, ceased to evaluate the GRAS notice. In proposing the rule, FDA asserted that, from the companies’ standpoint, the proposed voluntary notification program was simpler than the GRAS petition affirmation process and, therefore, could provide an incentive for manufacturers to inform FDA of their GRAS determinations. A flowchart presenting steps in the voluntary notification program is found in appendix III. In the proposal, FDA invited companies to submit notifications to the GRAS notification program described in the proposed rule until it published a final rule. FDA did not formally terminate the petition affirmation process, but has stated it no longer commits resources to the process. Because the rule has not been made final, FDA has operated the interim GRAS notification program under this proposed rule since 1997. One way for citizens to question GRAS determinations is through citizen petitions. FDA regulations establish procedures for petitioning FDA to issue, amend, or revoke a regulation or order; or take or refrain from taking any other form of administrative action. If a petition appears to meet the requirements for submission, FDA is required to furnish a response within 180 days of its receipt, if not sooner. In reviewing a petition, FDA may use the following procedures: (1) conferences, meetings, discussions, and correspondence; (2) a hearing; (3) a Federal Register notice requesting information and views; (4) a proposal to issue, amend, or revoke a regulation; or (5) other specifically established procedures. The record of any of these steps becomes part of the administrative record for the petition. FDA must generally respond to a petition within 180 days and (1) approve it and, therefore, concurrently take appropriate action implementing the approval (for example, publishing a Federal Register notice); (2) deny it; or (3) provide a tentative response, indicating why the agency has been unable to decide on it (for example, because of the existence of other agency priorities, or a need for additional information). FDA’s tentative response may indicate its likely ultimate decision and may specify when this final decision is to be provided. FDA must notify the petitioner in writing of its decision. FDA may grant or deny citizen petitions, in whole or in part, and may take other action as the petition warrants. Researchers are studying nanotechnology—the creation and manipulation of materials at a very small scale—to explore its many potential uses in food manufacturing, including uses potentially beneficial to food safety. Nanotechnology can involve processes, materials, and applications that span physical, chemical, biological, engineering, and electronic sciences. Although definitions of nanotechnology vary, the National Nanotechnology Initiative, a federal program established in 2001 to coordinate nanotechnology research and development, has defined it as the understanding and control of matter between 1 and 100 nanometers, known as the nanoscale. A nanometer is one billionth of a meter, a size that can best be understood by comparison to other very small objects— for example, the diameter of a human hair is approximately 80,000-100,000 nanometers, that of a red blood cell is approximately 8,000 nanometers, and that of a typical virus between 80 and 120 nanometers. Nanomaterials are materials at the nanoscale; or they can be larger, if they retain the characteristics of nanomaterials, such as novel properties compared with the same materials at their natural scale. Nanomaterials can be found in nature, such as in soot; or be an inadvertent product of traditional manufacturing practices, such as nanomaterials present as emulsions in homogenized milk or mayonnaise. Engineered nanomaterials, however, are materials that are deliberately manufactured to take advantage of the novel properties that occur at the nanoscale. When reduced to the nanoscale, substances can take on novel properties that allow them to be used in applications for many different purposes across different industries. For example, by reducing materials to the nanoscale, the materials’ surface area is increased, which can affect the nanomaterials’ ability to react with other substances. In addition, nanomaterials may have a greater ability to move across biological membranes. Because of these properties, nanotechnology may offer technological advancements in food packaging and storage that enhance the shelf life of fresh foods. Applications of nanotechnology may also offer more efficient nutrient delivery. Such applications in food and food packaging are relatively new, and FDA has approved only a few such uses in food contact substances so far. FDA reviews those GRAS determinations that companies choose to submit to the voluntary notification program. However, FDA generally does not have information about other GRAS determinations because companies are not required to inform the agency of their GRAS determinations. Furthermore, FDA has not taken certain steps that could help ensure the safety of GRAS determinations, particularly those for which the agency has not been notified. Notably, a trade association routinely informs FDA of its GRAS determinations, even though it does not submit notices to FDA’s voluntary notification program. From 1998—the first year a company submitted a notice of a GRAS determination—through 2008, companies chose to submit 274 GRAS determinations to FDA under the 1997 proposed voluntary notification program, or about 25 annually.