FDA’s Regulation Of Color Additives
The purpose of this article is to explain how color additives are regulated in the United States, specifically the laws and regulations that apply to color additives, how the U.S. Food and Drug Administration (FDA) evaluates their safety and how FDA ensures their compliance with these laws and regulations.
A Regulatory History and Framework
U.S. regulation of color additives can trace its roots back to the Federal Food and Drugs Act of 1906, also known as the Pure Food and Drug Act. This watershed legislation prohibited the interstate commerce of adulterated and misbranded food and drugs in the U.S. The statute also prohibited the use of poisonous or deleterious colors in confectionary products and the coloring or staining of food in a manner that concealed damage or inferiority. The burden of proving that a food or drug was adulterated or misbranded was placed on the Bureau of Chemistry in the U.S. Department of Agriculture (USDA). In 1907, USDA published a list of seven synthetic organic dyes considered to be safe for use in food. This list was based on a study of 80 dyes then in use in food. These were the first “approved” color additives, and four of the seven dyes are still permitted today.
In 1927, the regulatory functions of the Bureau of Chemistry were transferred to a new organization named the Food, Drug and Insecticide Administration, which was shortened a few years later to the Food and Drug Administration. FDA was given regulatory oversight of foods and drugs, including the coloring materials used as ingredients. Passage of the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938 added cosmetics and medical devices to the products regulated by FDA. The FD&C Act prohibited the use of most synthetic organic dyes and pigments, historically known as coal-tar colors, in foods, drugs and cosmetics unless they came from batches certified by FDA to be safe for the permitted uses. (“Coal tar” refers to a byproduct of coal processing that was first used to produce the dyes. Today, these types of color additives are synthesized from coal or petroleum sources. “Batch certification” refers to FDA’s process of analyzing representative samples of manufactured batches to verify compliance with their identities and specifications.)
In addition to mandating certification of coal-tar colors, the FD&C Act required that foods containing artificial colors must declare that fact on their labels (equivalent requirements for drugs and cosmetics were established later) and required FDA to establish regulations for listing permitted coal-tar colors and certifying new batches. The FD&C Act also provided an important exception to the listing and certification requirements for the coal-tar colors used in hair dyes as long as the hair dye products had a caution statement indicating that the product may cause skin irritation and instructions for performing a skin test.
The coal-tar colors permitted for use in foods, drugs and cosmetics (other than hair dyes) began to be listed in the recently established Code of Federal Regulations (C.F.R.) in 1938 and began to be certified in 1939. A new nomenclature was devised for the certified coal-tar colors consisting of the prefix “FD&C” to indicate food, drug and cosmetic use, “D&C” to indicate drug and/or cosmetic use, or “Ext. D&C” to indicate external drug and/or cosmetic use. The prefix is followed by the specific color, a number and, if applicable, the term “Lake.” (In this context, a lake is an insoluble pigment formed from a water-soluble dye precipitated onto a substrate such as alumina.) An example of a common certified color additive is FD&C Yellow No. 5.
The regulation of color additives was further enhanced by the 1960 Color Additive Amendments to the FD&C Act, which defined the terms “color additive” and “unsafe color additive.” The statutory term “color additive” now included vegetable, mineral and animal sources as well as coal-tar sources. The amendments required premarket approval by FDA for all color additives added to foods, drugs and cosmetics, provided exemption from certification for color additives not deemed by FDA to need that requirement, required FDA to establish a provisional list of color additives in use at that time to reevaluate their safety and required the agency to establish a petition process for permanently listing all color additives it determined to be safe and suitable for their listed uses. Additional adulteration provisions stated that a color additive is unsafe for use in food, drugs and cosmetics unless there is an authorizing regulation or exemption in effect.
The 1960 Color Additive Amendments established four factors that FDA must consider in determining the safety of a color additive: probable consumption or exposure from use; cumulative effect in the diet; appropriate safety factors for the use of animal experimentation data; and the availability of analytical methods for determining its purity and acceptable levels of impurities.
The term “color additive” is defined in Section 201(t) of the FD&C Act as a “dye, pigment or other substance made by a process of synthesis or similar artifice, or extracted, isolated or otherwise derived, with or without intermediate, or final change of identity, from a vegetable, animal, mineral or other source, and when added or applied to food, drug or cosmetic, or to the human body, or any part thereof, is capable, alone or through the reaction with other substance, of imparting color thereto.” Color, for the purposes of this definition, includes black, white and shades of gray. FDA’s regulations state that a color additive includes an ingredient used in animal feed that is intended to impart color to the meat, milk or eggs of the animal. For example, the use of astaxanthin in feed for farm-raised salmon to impart a pink/orange color to their flesh is regulated as a color additive. Some exemptions to the definition of a color additive are provided by the regulations. A substance used to color a container for packaging food, drugs or cosmetics is not a color additive unless the customary use of the container is reasonably expected to result in transmittal of the color to the contents of the container. If such transfer to food does not occur, these substances are regulated as colorants for use in paper or polymers. In addition, food ingredients that are foods themselves such as cherries or green peppers that impart their own natural color are not considered color additives. However, juice extracted from a fruit or vegetable to color foods meets the definition of a color additive, such as beet juice used to make pink lemonade.
Some may wonder why color additives are used at all. Color additives are used to affect or offset color loss, or to correct natural variations in color. They are used to enhance colors that naturally occur but are less intense than those levels usually associated with a given product. Color additives may correspond to flavors, such as in candy, and are often used to decorate foods such as cakes and frostings. An important use of color additives is to provide unique identities to products such as drugs so they are easily distinguishable. Unlike other additives that have a functional effect, color additives are usually used at low concentrations and the amount used is generally self-limiting in that the maximum use level is limited to the color intensity that is desired. For that reason, many color additive regulations require that the amount used should be consistent with Current Good Manufacturing Practices (CGMPs) rather than a specified upper limit.
According to Section 721 of the FD&C Act, a color additive is unsafe unless there is an authorizing regulation or exemption. The use of an unsafe color additive in food makes the food adulterated under Section 402(c) of the FD&C Act. Likewise, cosmetics, drugs and devices with unsafe color additives are deemed adulterated under other parts of the act. It is important to note that one distinction between the statutory definitions of “food additive” and “color additive” is that, unlike the definition for “food additive,” the definition of “color additive” does not have an exclusion for substances that are generally recognized as safe (GRAS) under the intended conditions of use. That is, there is no GRAS exemption for color additives.
Color Additive Regulations
The 1960 Color Additive Amendments created a premarket petition process for approving new color additives or amending an existing color additive regulation. Any interested person may petition FDA for the use of a proposed color additive. Supporting data must be provided as part of the petition. Importantly, it is the petitioner’s responsibility to demonstrate safety of any proposed use of a color additive. If, upon evaluation of the data in the petition, FDA finds that the proposed color additive is safe and suitable for the intended use, the agency will issue a new color additive regulation or alter an existing one. These decisions are announced in the Federal Register.
The color additive regulations are divided into two categories—the approved color additives exempt from batch certification, which are listed in 21 C.F.R. Part 73, and those subject to batch certification, which are listed in 21 C.F.R. Part 74. Most color additive lakes are listed in Part 82 and are required to be certified. The color additives exempt from certification tend to be substances derived from plant, mineral or animal sources, whereas the color additives subject to certification are typically synthetic organic dyes and pigments. The criteria that FDA considers when deciding whether to list a color additive as exempt or subject to certification are discussed later in this article.
The color additive listing regulations generally follow a format consisting of the identity of the color additive, a description of the permitted uses and restrictions, purity specifications and labeling requirements. It is important for a manufacturer to make sure that each color additive in a product is permitted for the intended use and complies with all the requirements in the applicable regulation. For example, FD&C Blue No. 2 is not permitted for use in cosmetics, and FD&C Red No. 4 may be used only in externally applied drugs and cosmetics.
Color Additive Premarket Approval Process
FDA’s regulations in 21 C.F.R. Part 71 describe the requirements and process for petitioning FDA to authorize the use of a color additive. A color additive petition generally consists of three types of information—chemical, toxicological and environmental. The chemistry information includes data and information on the identity, composition, manufacturing process, physical and chemical properties, use and use level, stability data, proposed specifications, analytical methods, proposed labeling of the marketed color additive and information necessary to estimate probable exposure from the proposed use of the color additive. The toxicology information is needed to demonstrate that the color additive will be safe at the expected level of exposure, including full reports of investigations of the safety of the color additive and all available raw data from those studies. The environmental component, as required by the National Environmental Policy Act, must consist of an environmental assessment or a request for FDA to determine that the petition is one of the classes of actions that are categorically excluded. FDA has developed a number of guidance documents to assist companies in preparing color additive petitions, which are available from the agency’s website. However, it is important to keep in mind that while the guidance reflects the agency’s current thinking on the subject, it is not binding on industry or FDA, and a petitioner is free to use an alternative approach that satisfies the requirements of the applicable statutes and regulations.
A color additive petition should be submitted to FDA’s Office of Food Additive Safety (OFAS) for processing and review. Upon receipt of the petition, FDA will form a review team consisting of chemists, toxicologists and other scientists who will conduct an initial review. FDA will notify the petitioner within 15 days whether, based on the team’s assessment, the petition can be filed. If the petition is accepted for filing, the agency will publish a notice of filing in the Federal Register containing a brief description of the scope of the petition and information regarding the petitioner. If the petition is not accepted for filing, FDA will inform the petitioner of the reasons for not filing it and the petitioner will have an opportunity to address the deficiencies. After the petition is filed, FDA will begin its detailed review.
The review of a color additive petition is managed by the OFAS. OFAS scientists frequently work with scientists in FDA’s Office of Cosmetics and Colors in the review of color additive petitions. A chemistry reviewer assigned to the petition is responsible for establishing the identity of the color additive, including the components of the color additive and possible impurities. The chemistry reviewer also is responsible for determining specifications of identity and purity to ensure the color additive’s safe use. The chemistry reviewer considers whether the submitted analytical methods are adequate to identify and quantify the color additive, its components and impurities to ensure compliance with the proposed specifications, and to identify and quantify the color additive under its intended condition of use to ensure the safety of the color additive. In addition, the chemistry reviewer determines whether the use level corresponds to an amount consistent with CGMPs. The same or another chemistry reviewer is responsible for estimating the likely consumer exposure to the color additive at the petitioned-use level. A toxicology reviewer is responsible for the review of the available toxicity information to determine the information that is relevant to the safety decision for the color additive and whether the information provided by the petitioner and other available information demonstrate that the proposed use of the color additive is safe. Finally, an environmental reviewer is responsible for assessing whether the proposed action may significantly affect the quality of the human environment.
Exposure Level as a Factor
One critical aspect of FDA’s review is the estimation of consumer exposure to the color additive at the petitioned-use level. Various approaches for estimating consumer exposure may be used. However, no matter which method is used, it must produce a suitably conservative estimate that provides an adequate margin of safety. For food use, the typical approach for exposure assessments employs information from food consumption surveys, combined with maximum concentrations of the color additive in foods, to arrive at a range of exposures across the consumer population. Exposure is usually estimated for the mean and 90th percentile of consumers age two or older, as well as for relevant subpopulation groups (e.g., children). However, other approaches may be appropriate to estimate exposure. For example, disappearance (i.e., into the food supply) or production poundage data may be sufficient in circumstances where a color additive is used in a wide variety of foods such that it will be present in the diet of a large proportion of the population. The exposure estimate for an ingested color additive is referred to as the estimated daily intake (EDI). FDA encourages petitioners to discuss the appropriate approach to estimating exposure to color additives from these uses when preparing a petition.
Another critical aspect of FDA’s review is the determination of whether consumer exposure to the color additive at the petitioned-use level is safe. FDA has published toxicology guidance known as the “Redbook” (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food) for determining the relevant safety data needed to address the anticipated consumer exposure to a color additive petitioned for use in foods. The testing paradigm in the Redbook uses a tiered approach based on the structure of the compound and expected exposure. Essentially, the higher the exposure, the more safety data are needed to support that level of exposure. The Redbook can serve as an initial reference to petitioners for safety studies of color additives intended for use in foods. However, FDA strongly recommends that petitioners consult with the agency before conducting any safety studies.
For color additives intended for use in foods, the toxicology data set would generally be analyzed to determine an acceptable intake level, based on the most appropriate endpoint in the most sensitive species. This endpoint is typically based on either a no-observable-adverse-effect level or a benchmark dose level. Safety factors are then typically applied to ensure an adequate margin of safety, considering inter- and intraspecies variations and any limitations on the data set. The result is either the establishment of an acceptable daily intake (ADI) or an acceptable level of exposure. If the EDI is at or below the ADI, the color additive is determined to be safe.
During the review of the petition, FDA decides whether batch certification will be necessary to ensure the safety of the color additive. According to 21 C.F.R. Part 71.20, in determining whether certification of the color additive is necessary, FDA considers the composition of the color additive, its manufacturing process, possible impurities, its toxic potential, control (e.g., recordkeeping) and analytical procedures necessary to ensure compliance with the listing specifications and the variability of its composition. As discussed above, color additives exempt from certification are generally derived from animal, botanical or mineral sources, whereas the color additives subject to certification are generally synthesized from coal or petroleum sources.
The FD&C Act stipulates that FDA has 90 days to complete action on a filed color additive petition by issuing either a regulation or denial of the petition, and may extend the review by an additional 90 days for a total of 180 days. However, the review of a color additive petition can be an iterative process. That is, FDA places the responsibility on the petitioner to address relevant safety and other questions. This can result in requests for additional data or analyses during the review of the petition, or the imposition of additional limitations on the color additive to reduce exposure. If a substantive amendment to the petition is submitted, FDA will establish a new filing date for the petition based on the date the new information was received. The 180-day review clock then begins anew.
Upon completion of the review of a color additive petition, FDA must decide whether the information in the petition and other information available to FDA establish that the color additive is safe for the petitioned use. FDA’s safety decision regarding a color additive must meet the same legal and scientific standard as for food additives, which is reasonable certainty of no harm under the intended conditions of use. That safety decision must be based on a fair evaluation of the data. In plain terms, this means that all relevant data must be considered, whether they support or contradict the safety of the proposed use of the substance. When relevant contradictory evidence exists, all data must be considered in a weight-of-evidence approach, taking into account the relative probative value of differing data to reach a conclusion.
The “reasonable safety of no harm” standard comes from the legislative history of the 1960 Color Additive Amendments. It is important to understand that the standard does not require proof of absolute safety or that no harm will result under any conceivable circumstances. The standard means that FDA must always make safety decisions under some level of uncertainty. Also, as is the case with food additives, FDA’s decision on a color additive petition cannot weigh in any possible benefits of the color additive and is based only on the safety of the intended use. It is also important to note that safety decisions are made based on all relevant scientific information available at the time. As such, the agency can and will reconsider decisions if new information raises significant questions related to the safety of that color additive.
If FDA decides that a petition establishes that the proposed use of a color additive is safe, the agency will proceed with granting the petition by issuing a final rule in the Federal Register, amending the color additive regulations to list the color additive for that use. If FDA determines that the petition fails to establish that the petitioned use of the color additive is safe, the agency has the authority and obligation to deny the petition. FDA will notify the petitioner when a petition is going to be denied. The petitioner then can withdraw the petition without prejudice to any future filing of a petition for that color additive. If a petition is denied, FDA will publish an order denying the petition in the Federal Register.
Any person adversely affected by a final rule listing a color additive or an order denying a color additive petition has the option of filing an objection within 30 days of the action. A final rule for a color additive petition becomes effective the day after the 30-day period for submitting objections ends, providing no objections to the final rule are received. The FD&C Act provides that, as soon as practicable after a 30-day period for filing objections has passed, FDA must publish a notice either specifying the parts of the rule stayed by the filing of objections, or if no objections have been filed, stating that in a notice confirming the effective date of the color additive listing. If objections are received, FDA will evaluate the merits of the objections and issue an order on them, which is subject to judicial review. Any person who files an objection may also request a hearing or may waive the right to a hearing. If a person waives the right to a hearing and is adversely affected by FDA’s final order on the objection, the person may seek judicial review in the U.S. Court of Appeals in the circuit in which the person resides or has a place of business. Any person who files a timely objection and requests a hearing will be granted a hearing by FDA if the person raises relevant and material issues in the objection.
For FDA to protect public health, the FD&C Act provides numerous enforcement tools to address adulterated and misbranded products. To ensure compliance with the color additive regulations, FDA routinely samples and analyzes both domestically produced and imported regulated products in interstate commerce. Telltale signs of color additive violations include product label declarations of color additives that are not permitted in the U.S., such as ponceau 4R or carmoisine, or no declaration of a color additive when the product obviously contains added color. Another common violation is declaration of a certifiable color additive by its common dye name, E number or Color Index (C.I.) number instead of the name of its certified form, for example, tartrazine, E102 or C.I. 19140 instead of FD&C Yellow No. 5, which is not only misbranding but also may be adulteration if the color additive does not come from a certified batch. In addition, the color additives FD&C Yellow No. 5, cochineal extract and carmine are specifically required to be declared on food labels because they may be allergens or sensitizers. When such violations are found, FDA will take necessary enforcement action. For products with violations, FDA may issue warning letters or seek seizure, injunction or criminal prosecution. FDA also may request a recall or issue a letter to inform the responsible company of the violation and request action to correct the violation. For violations involving imported products, the products are denied entry and the companies and products may be placed on an FDA import alert. To prevent a color additive violation, if a company is proposing the use of a color additive in an FDA-regulated product and is unsure about its regulatory status, the company should consult with FDA.