FDA Prohibited Food Substances — Ingredients Banned from the U.S. Food Supply

21 CFR Part 189 is the FDA's formal list of substances that are affirmatively prohibited from use in human food — meaning they cannot be used even if a manufacturer wanted to petition for approval. These are not simply unapproved additives (of which there are thousands); they are substances that FDA has specifically reviewed and determined present a risk to public health sufficient to warrant permanent categorical exclusion from the food supply. The list includes banned artificial sweeteners, carcinogenic flavorings, a beer ingredient that caused an epidemic of fatal heart disease, the hepatotoxic compound that once flavored root beer, and a widely-used artificial sweetener that remains legal in Canada and the European Union but has been banned in the United States since 1970.

Legal Authority

• 21 U.S.C. § 348 — FDCA § 409: the food additive safety framework; food additives must be proven safe before use; the Delaney Clause (§ 409(c)(3)(A)) prohibits approval of any additive found to induce cancer in man or animal — substances proven carcinogenic are categorically banned regardless of dose
• 21 U.S.C. § 331 — FDCA § 301: prohibits introduction of adulterated food into interstate commerce; food containing a prohibited substance is adulterated per se
• 21 CFR Part 189 — FDA regulations listing substances prohibited from direct addition to food for human consumption; covers cyclamate, safrole, calamus, monobromoacetate, and chlorofluorocarbon aerosol propellants

Key Mechanics

Part 189 is a categorical prohibition list — not a risk-based regulatory scheme. Substances on the list may not be added to food in any amount, for any purpose, regardless of claimed safety. The Delaney Clause's zero-tolerance standard for carcinogens drove several entries: cyclamate (saccharin's predecessor, banned in 1969 after animal studies showing bladder tumors — still not restored to GRASE despite numerous petitions), safrole (a carcinogenic flavoring found in sassafras), and calamus oil. Other entries reflect acute toxicity or other safety concerns. The FDA's authority to add substances to the Part 189 list is broad; removal requires a petition showing that the safety basis for the prohibition was incorrect.

Current Rule (2026)

What This Rule Does

Under the Federal Food, Drug, and Cosmetic Act, any food containing a prohibited substance listed in 21 CFR Part 189 is deemed adulterated — it cannot lawfully be sold in the United States, regardless of the concentration or how the substance was introduced. The prohibition applies to any added amount of these substances (§ 189.1); there is no de minimis exception.

The Part 189 prohibitions were established over several decades as FDA reviewed substances that had been in commercial use and found them unsafe. Many were banned under the Delaney Clause (21 U.S.C. § 348(c)(3)), which categorically prohibits any food additive found to induce cancer in humans or animals — regardless of dose. Several others (including cyclamate) were banned because animal studies showed carcinogenicity even though the Delaney Clause predated FDA's review. Still others were banned after acute toxicity events — cobalt was added to beer by Canadian and Belgian breweries in the 1960s, causing an epidemic of fatal cardiomyopathy before the connection was recognized.

The Part 189 list does not include every unsafe substance — that would be impossible. Rather, it is a specific enumeration of substances that were once in commercial use, reached FDA's formal review process, and were permanently excluded. Substances that were never in food and never sought approval do not appear on the list; they simply remain unapproved under the general food additive regulatory system.

Key Provisions

• § 189.1 — General prohibition: food containing any of the listed substances is adulterated under 21 U.S.C. § 342(a)(2)(C); the prohibition applies to any added amount; naturally occurring trace amounts from unavoidable environmental contamination are addressed through separate action level guidance, not Part 189 — the Part targets intentional use

• § 189.5 — Prohibited cattle materials (BSE): the most consequential active provision — certain cattle-derived materials are prohibited from all human food because of the risk they pose as bovine spongiform encephalopathy (BSE) vectors; prohibited materials include: the brain and spinal cord of cattle 30 months of age and older; the skull, eyes, trigeminal ganglia, spinal cord, vertebral column (excluding vertebrae of the tail, the transverse processes of the thoracic and lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia of cattle 30 months and older; the tonsils and distal ileum of the small intestine of all cattle; these materials are banned from human food including dietary supplements, not just meat — preventing their incorporation into any food product; this section parallels FSIS's BSE Specified Risk Material (SRM) rule at 9 CFR § 310.22 and extends it to FDA-regulated food products

• § 189.110 — Calamus and derivatives: calamus (dried rhizome of Acorus calamus) and oil of calamus were used as flavoring, particularly in liqueurs and some vermouths; banned because the Acorus calamus var. americanus variety contains β-asarone, a hepatocarcinogen; calamus extract and oil of calamus were found carcinogenic in animal studies; the 1968 FDA action eliminating calamus from the GRAS list was followed by the formal Part 189 prohibition

• § 189.113 — Cinnamyl anthranilate: a synthetic ester used as a cherry, grape, and strawberry flavoring; banned because animal studies showed it to be carcinogenic (hepatocellular carcinoma in rats and mice); not found naturally in food; the Delaney Clause required its prohibition once carcinogenicity was demonstrated

• § 189.120 — Cobaltous salts: cobalt acetate, cobalt chloride, and cobalt sulfate were added to fermented malt beverages (beer) in the 1960s as foam stabilizers — to prevent "gushing" (excessive foam) and improve head retention; in 1965–1966, an epidemic of fatal heart disease struck heavy beer drinkers in Quebec, Nebraska, and Leuven, Belgium — approximately 50 deaths — caused by cobalt's cardiotoxic effect at the concentrations used combined with nutritional deficiencies in heavy beer drinkers; FDA banned cobaltous salts from food after the connection was established; this is one of the few cases where a food additive caused documented mass casualties before it was banned

• § 189.130 — Coumarin: coumarin (1,2-benzopyrone) occurs naturally in tonka beans and was once widely used as a vanilla substitute and flavoring in baked goods and tobacco; banned because it is hepatotoxic — causes liver damage — at doses relevant to food use; tonka bean extract and coumarin as an added flavoring are prohibited, though coumarin that occurs naturally in cinnamon (Cinnamomum cassia, which contains 1–12g/kg coumarin) is not prohibited; the natural cinnamon exception illustrates a general principle: the Part 189 prohibition applies to intentional addition, not to naturally occurring substances in food at normal dietary intake levels

• § 189.135 — Cyclamate and its derivatives: the most politically contested entry on the list — cyclamates (calcium cyclamate, sodium cyclamate) are synthetic sweeteners approximately 30–40 times sweeter than sucrose; they were widely used in diet foods and beverages through the 1960s; FDA banned cyclamates in 1969 (effective 1970) after a study showed bladder tumors in rats fed very high doses of cyclamate-saccharin mixtures; the Delaney Clause required prohibition once the carcinogenicity finding was made; subsequent studies questioned the relevance of the rat bladder tumor mechanism to humans, and cyclamate is currently approved in Canada, the EU, Japan, and over 100 other countries; Abbott Laboratories petitioned FDA to lift the ban in 1973, 1982, and 2000 — none succeeded; FDA has not formally ruled that cyclamate is safe but has also not found sufficient evidence to initiate a rulemaking to lift the ban; cyclamate remains banned in the United States while being freely available internationally — one of the clearest examples of regulatory divergence in global food law

• § 189.140 — Diethylpyrocarbonate (DEPC): a synthetic fermentation inhibitor used to sterilize wine, beer, and fruit juices without heat; banned because DEPC reacts with ammonia (present in food) to form urethane (ethyl carbamate), a known carcinogen; the reaction occurs spontaneously in food after DEPC addition; DEPC itself degrades quickly, but the urethane formed before degradation makes the use unsafe under the Delaney Clause

• § 189.145 — Dulcin: a synthetic sweetener approximately 250 times sweeter than sucrose; banned based on animal studies showing liver and kidney damage and potential carcinogenicity; not currently used in food anywhere because of the safety findings

• § 189.165 — Nordihydroguaiaretic acid (NDGA): NDGA is an antioxidant derived from the creosote bush (Larrea tridentata), used in lard and other fats to prevent rancidity; removed from the GRAS list and subsequently prohibited after studies showed it causes kidney lesions (renal papillary necrosis) in rats; the ban illustrates that antioxidants are not categorically safe simply because they prevent oxidation — the dose and systemic effects of the antioxidant compound itself matter

• § 189.180 — Safrole: safrole is what made old-fashioned root beer taste the way it did — oil of sassafras, approximately 80% safrole, was the traditional flavoring base for root beer; banned in 1960 (before Part 189 was created; the prohibition predates the CFR codification) because safrole is a hepatocarcinogen; isosafrole and dihydrosafrole (structural derivatives) are similarly prohibited; modern root beer uses artificial flavoring or other botanical extracts instead; safrole is also a DEA-listed chemical because it is a precursor to certain illegal drugs, adding a second reason for strict control

• § 189.240 — Lead solders in food cans: lead solders were once commonly used to seal the side seams of metal food cans; prohibited (1995) because lead leaches from the solder into food, particularly acidic foods like canned fruits and tomatoes; lead exposure has no safe level for children — the prohibition eliminated a significant childhood lead exposure source; the U.S. lead solder ban was part of a broader elimination of lead-soldered cans that also involved industry transition to welded or cemented seam construction

• § 189.301 — Tin-coated lead foil wine capsules: lead foil capsules (the decorative covering over cork wine bottle closures) were found to leave lead residue on the bottle lip that contaminated wine when poured; prohibited (1996) because consumers regularly ingested lead from this source; most wine bottles now use polylaminate, tin, or aluminum foil capsules

How It Affects You

If you manufacture food or beverages: compliance with 21 CFR Part 189 is absolute — these substances cannot appear in your formulations. Most are not commercially available as food ingredients, so the practical risk is limited to: (1) natural botanical ingredients that contain prohibited compounds at effective levels (calamus, tonka bean, sassafras oil); (2) cattle-derived ingredients that may include BSE-prohibited materials (§ 189.5); (3) recycled packaging materials that might introduce lead from legacy solder. If you use any botanical extract in flavoring, verify that the botanical species does not contain calamus (coumarin-containing Acorus species), safrole (sassafras bark and root), or coumarin at concentrations that would constitute added coumarin. Natural flavor suppliers maintain safety files on this.

If you import food products: foreign foods containing cyclamate are banned from U.S. sale even if lawfully produced in the country of origin. This is a routine compliance issue for imported candies, soft drinks, and processed foods from markets where cyclamate is permitted. CBP and FDA detain imports that list cyclamate-containing sweeteners — the product must be destroyed or re-exported. "Diet" products from Canada, Europe, and Asia should be screened for cyclamate (typically listed as "cyclamic acid," "calcium cyclamate," "sodium cyclamate," or "E952" in EU labeling).

If you work in animal feed or supplements: § 189.5's prohibited cattle materials apply to all human food including dietary supplements — not just meat products. Collagen, gelatin, and other cattle-derived supplement ingredients must be sourced from cattle that did not contribute prohibited materials. Suppliers should provide certificates of conformance specifying the source tissues and confirming no SRM material is included.

Statutory Authority

This rule implements:

• 21 U.S.C. § 348 — Food additive safety standard: no food additive may be used unless it has been shown safe under intended conditions of use; the Delaney Clause in § 348(c)(3)(A) prohibits any food additive found to induce cancer in humans or animals at any dose; most Part 189 prohibitions rest on this carcinogenicity ground
• 21 U.S.C. § 342(a)(2)(C) — Food is adulterated if it contains any food additive that is unsafe under § 348; the Part 189 prohibited substances are per se unsafe, making food containing them per se adulterated
• 21 U.S.C. § 321(s) — Defines "food additive" broadly to include any substance the intended use of which results or may reasonably be expected to result in its becoming a component of food; this broad definition covers indirect additives (e.g., lead from can solder) as well as direct flavorings and preservatives

Recent Rulemakings

• 54 FR 24899 / 54 FR 24900 (June 9, 1989) — Added lead solder and related lead-containing packaging materials to the prohibited list following epidemiological evidence of childhood lead exposure from leaded-seam cans; concurrent rulemaking addressed industry compliance timelines
• 47 FR 11855 (March 19, 1982) — Added DEPC (diethylpyrocarbonate) based on urethane formation findings
• 42 FR 14659 (March 16, 1977) — Added several industrial chemicals (Flectol H, mercaptoimidazoline, MOCA, and others) that had been proposed or used in food packaging and were found carcinogenic; the 1977 rulemaking was the largest single expansion of Part 189 and reflected a systematic FDA review of packaging adhesives and rubber compounds
• The prohibition on cobaltous salts (§ 189.120), calamus (§ 189.110), safrole (§ 189.180), and cyclamate (§ 189.135) dates to 1968–1969 rulemaking that predates the CFR codification of Part 189

The cyclamate petition (Abbott Laboratories, petitions pending since 1973) represents the most prominent unresolved question in this Part. FDA has held the petition open without final resolution for over 50 years. A final approval would require FDA to find that the evidence of carcinogenicity in rats is not relevant to humans at dietary exposure levels — a scientific determination FDA has not made, and which the current regulatory posture effectively defers indefinitely.

Pending Action