FDA Veterinary Drug Regulations — Animal Drugs, Feeds, and Food Safety

The FDA Center for Veterinary Medicine (CVM) regulates drugs, feeds, and food additives for animals under the Federal Food, Drug, and Cosmetic Act (FD&C Act). The regulatory framework governs two intersecting public health concerns: animal welfare (ensuring drugs are safe and effective for treated animals) and human food safety (ensuring that edible products from treated animals — meat, milk, eggs — are free from harmful drug residues). The foundational regulations for these general rules appear at 21 CFR Part 500 and in several adjacent parts of Title 21, Chapter V (Animal and Veterinary).

Legal Authority

• 21 U.S.C. § 360b — FDCA § 512: requires premarket approval (New Animal Drug Application, NADA) for new animal drugs; establishes safety and effectiveness standards; authorizes extra-label use conditions; addresses veterinary prescription requirements
• 21 U.S.C. § 360ccc — FDCA § 573: authorizes conditional approval for minor-use, minor-species (MUMS) animal drugs where full approval is impractical; allows limited marketing while efficacy data is collected
• 21 CFR Parts 510–558 — FDA Center for Veterinary Medicine (CVM) regulations covering new animal drug applications, veterinary feed directive drugs, manufacturing standards, labeling requirements, and medicated feed regulations

Key Mechanics

Animal drug regulation operates through a two-track system: prescription veterinary drugs (requiring veterinarian authorization) and over-the-counter animal drugs (sold without a prescription). New Animal Drug Applications (NADAs) must demonstrate safety for the target animal species, safety of drug residues in human food (for food-producing animals), and effectiveness. Medically important antimicrobials (antibiotics used in both humans and animals) are subject to special restrictions — since 2017, they may only be used in food-producing animals for therapeutic purposes under veterinary oversight (Veterinary Feed Directive, VFD). CVM's Office of Surveillance and Compliance monitors antibiotic resistance risks from agricultural use; the National Antimicrobial Resistance Monitoring System (NARMS) tracks resistance trends in foodborne pathogens.

Current Rule (2026)

What This Rule Does

Part 500 establishes general administrative rules and specific safety determinations governing the manufacture, labeling, and use of drugs and feeds for animals. It covers three primary domains:

Administrative rulings on specific drugs and substances: FDA uses the administrative rulings in Subpart B (§§ 500.23–500.65) to clarify the regulatory status and labeling requirements for specific animal drug categories — including anthelmintics (deworming agents), timed-release dosage forms, and veterinary biologics — without initiating formal rulemaking for each product.

Prohibited and restricted substances: Subpart B also identifies substances that are not generally recognized as safe (GRAS) for animal drugs or animal feed: gentian violet (a fungal dye formerly used in poultry), hexachlorophene (an antiseptic), propylene glycol in cat food, polychlorinated biphenyls (PCBs) in animal feed, and methylene blue products for cats and dogs. These determinations establish the legal framework under which products containing these substances are considered adulterated new animal drugs requiring pre-market approval.

Carcinogenic compounds in food-producing animals (Subpart E): the most technically complex portion of Part 500, establishing the framework FDA uses to approve drugs that are carcinogenic — or whose metabolites are carcinogenic — when used in food-producing animals, implementing the Delaney Clause exception for veterinary drugs codified at 21 U.S.C. § 360b(d)(1)(H).

Key Provisions

• § 500.23 — Thermally processed low-acid animal foods: the manufacturing, processing, and packing of low-acid foods in hermetically sealed containers for animal consumption must comply with Parts 507 and 113 (the regulations for commercial sterilization of canned goods); this applies the human food safety standard for canned goods to the parallel animal food product category
• § 500.24 — Emergency permit control: the emergency permit provisions of Part 108 apply to manufacturers of thermally processed low-acid animal foods, giving FDA authority to require permits and shut down operations that pose an imminent hazard — even before a formal recall or seizure
• § 500.25 — Anthelmintic (deworming) drugs: anthelmintic drugs that do not bear a prescription legend must be labeled to provide adequate directions for use sufficient to ensure safe and effective treatment; the labeling must identify the target parasite species, the dosage, administration route, and any meat/milk withdrawal period; anthelmintics are among the most commercially important over-the-counter veterinary drugs — used in livestock, horses, dogs, and cats
• § 500.27 — Methylene blue in cats and dogs: FDA determined that methylene blue products for oral use in cats or dogs (formerly marketed as urinary antiseptics) are unsafe — methylene blue causes Heinz body anemia in cats at therapeutic doses and is not generally recognized as safe and effective for the claimed uses; products intended for oral use in cats or dogs are new animal drugs subject to § 360b approval (effectively prohibiting them absent an approved NDA)
• § 500.29 — Gentian violet in animal feed: FDA determined gentian violet (a triphenylmethane dye with antifungal properties, historically used in poultry feed) is not GRAS as a feed additive and is a food additive subject to § 409 approval; absent an approved food additive petition, gentian violet in animal feed is unlawful; FDA made this determination based on carcinogenicity data showing tumor formation in rodents at high doses
• § 500.30 — Gentian violet as a veterinary drug: gentian violet is also not GRAS as a veterinary drug for food animals; any veterinary drug use in food animals requires an approved new animal drug application
• § 500.45 — PCBs in animal feed: polychlorinated biphenyls (PCBs) are prohibited as intentional components of animal feed production, handling, or storage; PCBs may not be used as lubricants, solvents, or heat transfer fluids in contact with animal feed; PCB contamination of animal feed is an adulteration violation regardless of concentration; the prohibition reflects PCBs' persistence in biological tissues and their human health risks through the food chain
• § 500.46 — Hexachlorophene in animal drugs: hexachlorophene (a chlorinated bisphenol antiseptic) may be used only in topical products for non-food-producing animals (companion animals); it is prohibited for any food animal use and for oral or systemic use in any species; the restriction reflects hexachlorophene's neurotoxicity (particularly to immature nervous systems) and absorption through skin at therapeutic concentrations
• § 500.50 — Propylene glycol in cat food: propylene glycol in or on cat food is not GRAS and is a food additive subject to § 409 approval; FDA determined that propylene glycol causes Heinz body formation in red blood cells in cats, reducing their oxygen-carrying capacity; propylene glycol is safe for dogs and is permitted in dog food as a humectant; the cat-specific prohibition reflects a well-documented species difference in susceptibility
• § 500.51 — Animal drug misbranding: among representations that render an animal drug misbranded are: (1) broad claims that the drug is safe and effective "when used as directed" without identifying specific use conditions; (2) failure to include adequate directions for use; (3) failure to state withdrawal periods for food animals; and (4) use of unsubstantiated efficacy claims; the misbranding rules parallel the human drug misbranding standards in Part 201 but are calibrated to the animal drug context
• § 500.52 — Prohibited vague claims: terms such as "tonic," "tone," "toner," and "conditioner" in animal drug or feed supplement labeling are regarded as implied drug claims; products using these terms are subject to new animal drug approval requirements unless the terms are limited to feed with an approved food additive petition or GRAS status
• § 500.55 — Prescription labeling exemptions: licensed veterinarians may be exempt from certain animal drug labeling requirements (particularly detailed directions for use) for drugs that are "commonly known to practitioners licensed by law to prescribe" the drugs — the animal drug analog to the human prescription drug labeling exemption in § 201.105; this allows prescription animal drugs to carry abbreviated labeling (the Rx symbol plus veterinarian instructions) without repeating full direction text available in professional references

Carcinogenic compounds in food-producing animals (Subpart E, §§ 500.80–500.92):

• § 500.80 — Scope: Subpart E implements the statutory framework for approving drugs that are carcinogenic — or produce carcinogenic metabolites — for use in food animals; the FD&C Act's Delaney Clause (21 U.S.C. § 360b(d)(1)(H)) prohibits approval of any new animal drug that induces cancer in test animals, but provides an exception when FDA determines there is "no residue" of the carcinogen in edible tissue at the time of slaughter — the "no residue" finding that triggers Subpart E
• § 500.82 — Definitions: key defined terms include: "sponsored compound" (the drug whose carcinogenicity is at issue); "marker residue" (the residue whose concentration in edible tissue is used to track depletion of the carcinogenic compound or metabolite); "target tissue" (the edible tissue — muscle, liver, kidney, or fat — where the marker residue is measured); and "regulatory method" (the validated analytical test used to confirm compliance with the no-residue standard at slaughter)
• § 500.84 — Conditions for approval: FDA will approve a carcinogenic compound for food-animal use only when: (1) chronic bioassay data establish the compound's carcinogenic potency; (2) a marker residue and target tissue have been identified; (3) a validated regulatory method can detect the marker residue at the safe concentration; and (4) withdrawal periods have been established to ensure edible tissues at slaughter contain no detectable residue by the regulatory method
• § 500.86 — Marker residue and target tissue: for each edible tissue, the sponsor must demonstrate depletion of the residue of carcinogenic concern to at or below the safe concentration (Sm — the concentration consistent with a negligible cancer risk); in the target tissue, the sponsor must also identify a practical marker residue and validate a monitoring method; the marker residue may be the parent compound, a metabolite, or a related chemical whose concentration tracks the depletion of the actual carcinogenic residue
• § 500.88 — Regulatory method: the sponsor must submit a validated analytical method that can detect the marker residue in the target tissue at the regulatory threshold; the method must be transferable to FDA laboratories and to USDA's Food Safety and Inspection Service (FSIS) for use in meat inspection programs; a drug may not be approved for food-animal use under Subpart E until the regulatory method is validated and transferred to FSIS for use in the national residue monitoring program

The Subpart E framework reflects the specific policy challenge created by the Delaney Clause's absolute prohibition on carcinogens in food. The compromise embodied in § 360b(d)(1)(H) — the "sensitivity of method" or "no residue" exception — was developed in response to the practical impossibility of eliminating all traces of widely used veterinary drugs. Diethylstilbestrol (DES), a synthetic estrogen once used as a growth promoter in cattle and poultry, was ultimately banned in 1979 after FDA was unable to validate a sufficiently sensitive method demonstrating "no residue" — making DES the most prominent casualty of the Delaney Clause's application to animal drugs. Modern veterinary drug approvals for carcinogenic compounds (e.g., certain antimicrobials used in aquaculture) follow the Subpart E pathway, establishing withdrawal periods and regulatory methods that are incorporated into FSIS's national residue sampling program at slaughter.

How It Affects You

For livestock producers: withdrawal periods on veterinary drugs are legally binding conditions of approval under these regulations — treating an animal with an approved drug and then slaughtering it before the withdrawal period expires is a federal violation. USDA/FSIS tests a statistically determined sample of slaughtered animals for drug residues; violative residues (above tolerance) trigger a "retain and retest" order on subsequent shipments from the same establishment and can result in criminal referral and producer debarment from federal inspection programs.

For companion animal owners: the prohibitions on hexachlorophene, methylene blue for cats, and propylene glycol in cat food reflect FDA's ongoing monitoring of products in the companion animal market; if you see a product making claims that depend on these ingredients, it is likely operating outside the legal framework.

For veterinary drug manufacturers: the administrative rulings in Part 500 Subpart B operate as binding regulatory determinations — a product FDA has determined to be a non-GRAS food additive or a new animal drug cannot be marketed without prior approval regardless of whether it carries FDA-approved labeling or is sold as a dietary supplement. The Subpart E pathway for carcinogenic compounds requires significant preclinical work and FSIS coordination before approval.

Statutory Authority

This rule implements:

• 21 U.S.C. § 321 — FD&C Act definitions (drug, food additive, new animal drug, misbranding, adulteration)
• 21 U.S.C. § 360b — New animal drug approval (NADA) requirements; Delaney Clause exception for no-residue carcinogenic compounds (§ 360b(d)(1)(H))
• 21 U.S.C. § 348 — Food additive approval requirements; the prohibition on unapproved food additives in animal feed
• 21 U.S.C. § 409 — Color additive approval; gentian violet's treatment as a color additive/food additive in animal feed

Recent Rulemakings

• 86 FR 52410 (September 2021) — Updated the N-methyl-2-pyrrolidone (NMP) residue standard for cattle and swine (§ 500.1410), establishing that no NMP residues may be present in uncooked edible tissues; NMP is used as a solvent carrier in certain injectable veterinary drug formulations
• 77 FR 50593 (August 2012) — Revised labeling requirements for anthelmintic drugs (§ 500.25) to clarify withdrawal period disclosure requirements
• 67 FR 78174 (December 2002) — Guidance updates on the marker residue and regulatory method requirements under Subpart E, reflecting advances in analytical chemistry that have changed what "no detectable residue" means operationally

Implementing Regulations — Medicated Animal Feeds (21 CFR Part 558)

The FDA regulations governing specific approved new animal drugs for use in feeds are at 21 CFR Part 558 — New Animal Drugs for Use in Animal Feeds (63 sections across 2 subparts). Part 558 operates as FDA's approval catalog for medicated feed products — each section in Subpart B names a specific drug and specifies which feed manufacturers (by sponsor number) are authorized to produce medicated articles containing it.

The Type A/B/C framework (§ 558.3): Medicated animal feeds are organized into three tiers based on concentration and intended use:

• Type A medicated articles — high-concentration premixes (the starting material, not fed directly to animals; manufactured by FDA-licensed facilities)
• Type B medicated feeds — intermediate-concentration feeds made by diluting Type A articles (must meet labeling, dilution, and labeling requirements; if made from Category II Type A articles, a medicated feed mill license (§ 558.4) from FDA is required)
• Type C medicated feeds — low-concentration finished feeds ready to give to animals (the product producers actually put in feeders)

Veterinary Feed Directive (VFD) (§ 558.6): Antibiotics and other antimicrobial drugs used in animal feeds that FDA has designated as VFD drugs can only be fed to animals with a VFD issued by a licensed veterinarian. The VFD requirement — phased in under FDA's Guidance for Industry #213 (2013) and finalized in rules effective January 2017 — ended the practice of over-the-counter antibiotic use in livestock. Previously, farmers could purchase medicated feeds containing tetracyclines, penicillin, sulfa drugs, and other antibiotics without a prescription for "production purposes" (growth promotion). FDA concluded this practice contributed to antimicrobial resistance. After 2017, any medicated feed containing a VFD drug (e.g., chlortetracycline, oxytetracycline, tylosin, lincomycin) requires: (1) a veterinarian-client-patient relationship; (2) a written VFD order from the veterinarian; (3) the feed distributor to retain a copy; and (4) the producer to retain a copy. Key VFD drugs in Part 558:

• § 558.128 — Chlortetracycline (CTC): one of the oldest and most widely used livestock antibiotics; used in cattle, swine, and poultry for treatment and control of respiratory disease; all production-use claims withdrawn as of 2017; now VFD-only
• § 558.140 — Chlortetracycline + Sulfamethazine combination: combination product for cattle and swine; used to control bovine respiratory disease; VFD required
• § 558.115 — Carbadox: growth promoter/antibiotic for swine under 35 lbs; not a VFD drug (it is a non-antimicrobially important drug) but requires a 10-week withdrawal period due to carcinogenic metabolite concerns under Part 500 Subpart E; highly controversial — consumer groups have petitioned FDA to ban it; FDA maintains that the withdrawal period ensures no residues reach food

The FDA's Part 558 catalog reflects the ongoing tension between livestock production efficiency (medicated feeds historically improved feed conversion ratios and reduced disease mortality) and public health concerns about antimicrobial resistance. The 2017 VFD reforms were the most significant restructuring of livestock antibiotic use in decades; compliance requires the entire supply chain (drug manufacturer → feed mill → distributor → farmer) to maintain VFD paperwork. The National Animal Health Monitoring System (NAHMS) has tracked changes in antibiotic use patterns since implementation. Recent rulemaking: 86 FR 14822 (March 2021) — added monensin combination products to Part 558 Subpart B.

Implementing Regulations — Medicated Feed Mill Licensing (21 CFR Part 515)

21 CFR Part 515 — Medicated Feed Mill License (12 sections — the FDA licensing program for feed mills that manufacture Type B medicated feeds from Category II Type A medicated articles; authority: 21 U.S.C. § 360b(m)):

The feed mill license is triggered specifically when a facility wants to manufacture Type B medicated feeds from Category II Type A articles — those whose active ingredients may be carcinogenic, pose special safety risks, or require particular manufacturing controls. Category II status is assigned by FDA at the Type A article approval level. This licensing requirement separates the more controlled manufacturing process from routine Type C feed production, which does not require a separate license.

• § 515.10 — License application (Form FDA 3448): applications must include facility name and address, the Type A medicated articles to be used and the Type B feeds to be made from them, manufacturing process descriptions, quality controls, and labeling specifications; FDA evaluates whether the facility has adequate controls to ensure the medicated feed will be manufactured at the correct concentration and with appropriate identity, strength, quality, and purity
• § 515.11 — Supplemental license applications: after initial license approval, any change in the drugs to be used, the manufacturing process, or the facility requires a supplemental application; minor supplements (e.g., adding a new approved Type A article) may be approved on a shorter timeline than a full application
• § 515.20 — Approval: FDA must act on a license application within 90 days of filing; if FDA does not act within 90 days, the application is deemed approved; FDA may request additional information during the review period, which tolls the 90-day clock
• § 515.21 — Refusal to approve: FDA must refuse within 90 days if the application is incomplete, the facility lacks adequate manufacturing controls, or the proposed manufacturing would not result in a product meeting the applicable Type A article and Type B medicated feed standards; the applicant may appeal a refusal through the formal evidentiary hearing process under 21 CFR Part 16
• § 515.22 — Suspension and revocation: the Secretary (through FDA) may suspend a medicated feed mill license immediately if current evidence shows manufacturing presents a danger to health; revocation may occur through an informal hearing process after the licensee has had an opportunity to respond to FDA's concerns; both suspension and revocation may follow inspection-revealed manufacturing deviations, adulteration findings, or failure to follow the approved manufacturing process
• § 515.23 — Voluntary revocation: a licensee may voluntarily surrender a license by notifying FDA in writing; voluntary revocation removes the licensee from FDA's active registry and terminates authorization to manufacture under that license

Feed mill licensing under Part 515 occupies a small but important niche in the medicated animal feed regulatory architecture. The vast majority of feed mills — those using only Category I Type A articles — do not need a Part 515 license; they are regulated under Part 558's general manufacturing standards. Part 515 licensees face heightened FDA oversight because the drugs they handle have greater safety sensitivity. Inspection of Part 515 facilities emphasizes concentration verification, cross-contamination controls between batches, and cleanup procedures — the same concerns that drove the Category II designation in the first place.

Implementing Regulations — Minor Use and Minor Species (MUMS) Drugs (21 CFR Part 516)

The Minor Use and Minor Species Animal Drug Safety and Effectiveness Act of 2004 (MUMS Act) created two new regulatory pathways for veterinary drugs that the commercial market would otherwise not support. These pathways are codified at 21 CFR Part 516 (59 sections across 4 subparts), implementing 21 U.S.C. § 360ccc-2.

Why MUMS exists: Before 2004, there were effectively no FDA-approved drugs for most "minor species" — the thousands of species kept as pets, raised in aquaculture, or managed as zoo or exotic animals. Ferrets, rabbits, birds, reptiles, ornamental fish, and many livestock species like goats, sheep, bison, and minor aquaculture species had virtually no approved veterinary drugs because the market was too small to justify the $50–100 million NADA approval cost. The same market failure affected "minor uses" in major species — treating a rare condition in cattle with a drug that only 10,000 animals per year would need. Without FDA approval, veterinarians used drugs off-label, with no validated dosing, no withdrawal-period data, and no assurance of safety in those species. MUMS created incentives and alternative pathways to address this gap.

Key definitions: "Minor species" means any animal species other than the seven major species — cattle, horses, swine, chickens, turkeys, dogs, and cats. Minor species include aquaculture species, zoo animals, companion animals beyond dogs and cats (ferrets, rabbits, guinea pigs, birds, reptiles, fish), and minor livestock (goats, sheep, bison, elk, llamas). "Minor use" means a use in a major species for a condition that affects a limited number of animals annually (defined thresholds vary by species — e.g., fewer than 1 million cattle or horses per year).

MUMS designation and 7-year exclusivity (Subpart B, §§ 516.11–516.80):

• § 516.12 — The core incentive: a drug designated as a MUMS drug by FDA receives 7 years of exclusive marketing rights after approval — comparable to the Orphan Drug Act's 7-year exclusivity for human drugs. During the exclusivity period, FDA will not approve or index another drug for the same minor use or minor species for the same indication. This exclusivity makes investment in MUMS drug development commercially rational despite the small market
• § 516.14 — Submission: requests for MUMS designation are submitted to FDA's Office of Minor Use and Minor Species Animal Drug Development (OMUMS) before the drug is approved; applicants must demonstrate that the drug is intended for a minor use or minor species and that there is no reasonable expectation that the U.S. sales would be sufficient to recover the development costs without the incentives
• § 516.20 — Required designation request elements: the drug name, the target species or use, the proposed indication and dosage, an explanation of why the use qualifies as minor, and a statement that the drug is not already covered by another MUMS designation for the same use; FDA has 90 days to act on a complete request
• § 516.40 — Open protocols: FDA may open a MUMS drug development to multiple sponsors, allowing cooperative development of drugs where the commercial incentive is insufficient even for a single sponsor; grants and technical assistance from FDA are available to MUMS-designated drug sponsors
• § 516.80 — Withdrawal of designation: FDA may withdraw MUMS designation if a drug is found to not qualify (e.g., the market proves larger than represented) or if another drug has already been approved for the same use, eliminating the need for the incentive

Index pathway for minor species (Subpart C, §§ 516.111–516.175):

The Index is the MUMS Act's most novel feature — it allows legally marketed unapproved new animal drugs for non-food minor species to be listed in an FDA-maintained catalog without going through the full NADA process:

• § 516.111 — Scope: the Index covers only minor species that are not food-producing animals; drugs for food-producing minor species (e.g., farmed catfish, minor aquaculture species intended for human consumption) still require full NADA approval due to residue concerns
• § 516.115 — Definitions: "Index" refers to the FDA Index of Legally Marketed Unapproved New Animal Drugs for Minor Species; "qualified expert panel" means a panel of specialists in veterinary medicine assembled and convened by the requestor to evaluate the drug's safety and efficacy for the proposed indexing
• § 516.129 — Content of indexing request: each request must cover one drug in one dosage form; must include data or information demonstrating the drug is safe for the target species and has a reasonable basis for effectiveness; the expert panel's written report evaluating the data is the centerpiece of the submission
• § 516.141 — Qualified expert panels: the requestor assembles and funds the expert panel; FDA reviews panel composition to ensure relevant expertise; the panel must evaluate the safety and effectiveness data and prepare a written report; FDA then reviews the panel report, not the underlying data directly — a significant departure from the NADA model where FDA reviews all raw data
• § 516.143 — Written report: the panel report must describe the basis for the panel's conclusions on safety (target animal safety and residue data for non-food species) and effectiveness, state any limitations of the evidence, and recommend conditions of use including dosing, route of administration, and contraindications
• § 516.155–516.175 — Index listing and post-market requirements: once indexed, the drug may be legally marketed for the indexed species and use without an approved NADA; the label must state "This drug is NOT FDA approved" and include a reference to the FDA Index; FDA maintains the public Index on its website; indexed status may be removed if post-market safety problems emerge

Conditional approval pathway (Subpart E, §§ 516.1011–516.1031):

Conditional approval is an interim approval mechanism for MUMS drugs — and now also for some canine drugs following COVID-era legal changes:

• § 516.1012 — Conditionally approved drugs include fuzapladib (a novel pancreatitis treatment for dogs, the first drug approved under FDA's expanded conditional approval authority) and other drugs where full effectiveness data is being gathered post-approval
• A conditionally approved drug must demonstrate: (1) reasonable expectation of effectiveness (rather than demonstrated effectiveness required for full NADA approval); (2) full target animal safety; and (3) clinical need — the drug provides a meaningful treatment option for a condition with inadequate alternatives
• Conditional approvals are renewable annually for up to 5 years; during the conditional approval period, the sponsor must continue collecting effectiveness data; if effectiveness is not demonstrated within 5 years, the conditional approval lapses

The MUMS Act's legacy is the proliferation of legal treatment options for animals that previously had none. The FDA Index now lists dozens of drugs for minor species from ferrets to ornamental koi. The 7-year exclusivity has attracted investment in drugs for economically important minor livestock — goats, sheep, minor aquaculture species — as well as high-value companion animals like birds and reptiles. For exotic animal practitioners and aquaculture veterinarians, Part 516 and the FDA Index represent the primary framework for legally available treatment options. Recent rulemaking: 89 FR 85426 (November 2024) — updated Index listing procedures; 88 FR 16546 (March 2023) — expanded conditional approval authority for canine and feline drugs following the Modernizing Animal Drug Approvals Act (MADA).

Pending Action