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BHT (butylated hydroxytoluene)

Table of contents

Other Names

2,6-Bis(1,1-dimethylethyl)-4-methylphenol2,6-Bis(tert-butyl)-4-methylphenol2,6-di-Butyl-para-cresol2,6-Di-t-butyl-4-hydroxytoluene2,6-Di-t-butyl-4-methylphenol2,6-Di-t-butyl-p-cresol2,6-Di-tert-butyl-1-hydroxy-4-methylbenzene2,6-Di-tert-butyl-4-hydroxytoluene2,6-Di-tert-butyl-4-methylphenol2,6-Di-tert-butyl-p-cresol3,5-Di-tert-butyl-4-hydroxytoluene4-Hydroxy-3,5-di-tert-butyltoluene4-Methyl-2,6-bis(2-methyl-2-propanyl)phenol4-Methyl-2,6-di-tert-butylphenol4-Methyl-2,6-ditertbutylphenol4-Methyl-2,6-tert-butylphenolAntioxidant 264Antioxidant DBPCBHTButylated hydroxytolueneButylhydroxytolueneButylhydroxytoluenumDBMPDBPCDi-tert-butyl-p-cresolDi-tert-butyl-p-methylphenolDi-tert-butylcresolDi-tert-ButylparamethylphenolDibunolDibutylated hydroxytolueneDibutylhydroxytolueneE321p-Cresol, 2,6-di-tert-butyl-Phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl-

Synopsis

Butylated Hydroxytoluene (BHT)

1. Identity and Chemical Profile

Chemical Names and Nomenclature

BHT carries the IUPAC name 2,6-bis(1,1-dimethylethyl)-4-methylphenol and is a chemical derivative of phenol (C6H5OH). It is also formally known as 2,6-di-tert-butyl-4-methylphenol, 3,5-di-tert-butyl-4-hydroxytoluene, and dibutylhydroxytoluene. Its empirical formula is C15H24O, with a molecular weight of approximately 220.35 g/mol.

A large number of trade and commercial synonyms exist for BHT, including Ionol, Topanol, Dibunol, Antioxidant DBPC, Tenox BHT, Sustane BHT, and Dalpac, among others. On food labels it may appear as BHT, butylated hydroxytoluene, E 321, or INS 321.

Physical and Chemical Properties

Butylated hydroxytoluene is a white or light-yellow crystal with a melting point of 71°C, a boiling point of 265°C, a relative density of 1.048 (20/4°C), and a refractive index of 1.4859 (75°C). BHT is soluble in methanol, ethanol, isopropanol, mineral oil, acetone, petroleum ether, benzene, and various oils and fats. It is insoluble in water, 10% NaOH solution, glycerol, and propylene glycol. BHT is odorless with good thermal stability and is a lipophilic organic compound.

Origin: Synthetic Versus Natural Occurrence

BHT is primarily a synthetic antioxidant and food preservative widely used in different parts of the world. However, it is not exclusively a synthetic compound: phytoplankton, including the green algae Botryococcus braunii, as well as three different cyanobacteria (Cylindrospermopsis raciborskii, Microcystis aeruginosa, and Oscillatoria sp.), are capable of producing BHT as a natural product.

Synthesis

The chemical synthesis of BHT in industry has involved the reaction of p-cresol (4-methylphenol) with isobutylene (2-methylpropene), catalyzed by sulfuric acid. Alternatively, BHT has been prepared from 2,6-di-tert-butylphenol by hydroxymethylation or aminomethylation followed by hydrogenolysis.

Common Forms and Preparations

Food-grade BHT is not less than 99% (w/w) pure. BHT is encountered in a wide range of commercial contexts. As a synthetic antioxidant, it is added mainly to fat-containing foods, oils, cereals, potato products, chewing gum, flavor systems, and some food-contact materials. BHT can also improve the stability of pharmaceuticals, fat-soluble vitamins, and cosmetics. In the cosmetics industry, BHT is used in a wide range of cosmetic formulations as an antioxidant at concentrations from 0.0002% to 0.5%. BHT, the most frequently used synthetic phenolic antioxidant, is added to food, pharmaceuticals, and cosmetics, as well as used as an additive in rubber, plastics, mineral oil, and printing inks.

2. Historical and Regulatory Background

Discovery and Early Regulatory History

The phenolic antioxidant butylated hydroxytoluene (BHT) was patented in 1947 and received approval for use as a food additive and preservative by the Food and Drug Administration (FDA) in 1954. Since 1959, BHT has been generally recognized as safe (GRAS) for use in foods and is one of the most commonly used antioxidants in foods containing fats.

BHT does not have a tradition of use in historical pharmacopoeias, folk medicine systems, or classical herbal traditions. Its entire history of use is modern and industrial rather than ethnobotanical. The compound's application as a human dietary supplement emerged from its established role as a food additive antioxidant, and more recently from population-level self-experimentation documented in the scientific literature of the 1970s–1990s. There is no documented traditional (pre-modern) therapeutic use of BHT in any culture.

Current Regulatory Status

The FDA has requested information on the current uses and safety data for BHT in human food and as a food contact substance as part of a systematic post-market assessment process, conducting a post-market review of the safety of BHT in food considering the latest state of the science. FDA lists BHT as GRAS for use as an antioxidant in food generally, with the limitation that the total antioxidant content cannot exceed 0.02% of the total fat or oil content of the food (21 CFR 182.3173). BHT also has a prior-sanctioned use as an antioxidant when migrating from food packaging material, with a limit of addition to food of 0.005% (21 CFR 181.24).

Approximately 40 countries reportedly permit the use of BHT as a direct or indirect food additive. At the international level, BHT was evaluated by the EU Scientific Committee on Food (SCF) in 1989 and by JECFA in 1996. The SCF established an acceptable daily intake (ADI) of 0–0.05 mg/kg body weight per day based on thyroid, reproduction, and haematological effects in the rat, while JECFA allocated an ADI of 0–0.3 mg/kg body weight, based on effects in reproduction segments and hepatic enzyme induction seen in two separate two-generation studies in rats. In 2012, the European Food Safety Authority (EFSA) set an ADI of 0.25 mg/kg body weight per day, based on a NOAEL of 25 mg/kg body weight per day, citing reproductive effects and hepatic enzyme induction.

3. Key Constituents and Mechanisms of Action

Primary Mechanism: Free Radical Scavenging and Lipid Antioxidation

BHT behaves as a synthetic analog of vitamin E, primarily acting as a terminating agent that suppresses autoxidation — a process whereby unsaturated organic compounds are attacked by atmospheric oxygen. BHT stops this autocatalytic reaction by converting peroxy radicals to hydroperoxides. This radical chain-breaking action is the foundational mechanism underlying essentially all of BHT's documented industrial and proposed biological activities.

As a phenolic antioxidant, BHT can inhibit lipid peroxidation. It slows oxidation, helping fats and flavors resist rancidity during storage.

Antiviral Mechanism

BHT is a potent inactivator of lipid-enveloped viruses. The viral envelope structure is physically disturbed by BHT, thereby interfering with viral adsorption to host cells. This mechanism is highly specific: BHT's antiviral activity is essentially limited to viruses that possess a lipid-containing envelope. Non-enveloped viruses are not affected by this mechanism.

Ferroptosis Inhibition

Ferroptosis is a special kind of programmed cell death that involves dysregulated intracellular iron metabolism and uncontrolled lipid peroxidation, which together initiate intracellular ferroptotic signalling pathways leading to cellular suicide. BHT is an effective antioxidant that functions as a radical scavenger and has been reported to interfere with ferroptotic signalling. BHT prevents RSL3- and ML162-induced ferroptotic cell death in cultured human neuroblastoma cells (SH-SY5Y) in a dose-dependent manner, preventing the RSL3-induced oxidation of membrane lipids and normalising the RSL3-induced inhibition of the intracellular catalytic activity of glutathione peroxidase 4.

Metabolic Activation and Reactive Metabolites

BHT produces acute pulmonary toxicity in mice and can enhance the multiplicity of lung tumors in mice when chronically administered following a single dose of a carcinogen such as urethane. Evidence strongly indicates that the pulmonary effects of BHT are caused by one or more of its reactive metabolites, particularly the hydroperoxide or quinone methide products. The hydroperoxide metabolite BHT-OOH is later converted to free radicals by cytochrome P-450.

Oral studies demonstrate that BHT is metabolized, with major metabolites appearing as the carboxylic acid of BHT and its glucuronide in urine. An oxidized metabolite of BHT that is excreted in urine is 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT acid).

4. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

In contrast to butylated hydroxyanisole (BHA), BHT is cleared less rapidly from most species, with enterohepatic circulation being partly responsible for the delay.

The kinetics and metabolism of BHT in humans and rats have been directly compared. In one study, single oral doses of 200, 63, or 20 mg BHT/kg body weight were administered to rats and a single oral dose of 0.5 mg/kg body weight was ingested by human volunteers (non-smoking males). In humans, the mean plasma concentration–time profile after oral BHT intake was well below the BHT profiles observed for rats.

After a single oral dose of [14C]BHT in the rat, 80–90% of the administered radioactivity was excreted within 4 days; in females about 40% of the dose was found in the urine and in males about 25%. Urinary excretion of (unconjugated) 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) accounts for only a small percentage of the administered dose in both rats and humans.

BHT does penetrate the skin, but the relatively low amount absorbed remains primarily in the skin.

5. Scientific Evidence by Area of Use

5.1 Antiviral Activity (Lipid-Enveloped Viruses)

The antiviral properties of BHT have been the subject of scientific investigation since the early 1980s, arising primarily from its known ability to disrupt lipid-containing structures.

Preclinical Evidence

Hairless mice cutaneously infected with herpes simplex virus type 1 (HSV-1) were treated topically with BHT, and the effectiveness of BHT in shortening the duration of infections was assayed under three conditions. Under all three conditions, BHT was found to be effective in reducing the clearance time of HSV-1 cutaneous lesions when applied topically to the infected area.

In a guinea pig model of genital herpes, the effect of topical treatment with BHT was evaluated in primary and recurrent genital herpes simplex virus type 2 (HSV-2) infection. Treatment with placebo, 5%, 10%, or 15% BHT was initiated 48 hours after viral inoculation and continued four times daily for 15 days. During primary infection, no differences in maximum lesion severity or titers of virus in lesions were observed; however, lesion duration was reduced in BHT-treated animals, resulting in a significantly smaller lesion score-day area under the curve. Treatment of the recurrent infection in either experiment failed to alter the number of recurrent episodes or days with lesions.

Human Clinical Evidence — Topical

BHT is a hydrophobic compound with in vitro activity against many enveloped viruses, including herpes simplex virus. The effect of topical therapy with 15% BHT in mineral oil on the course of recurrent herpes simplex labialis was examined in 30 patients in a double-blind, placebo-controlled pilot study in which treatment was initiated by the physician. Sixteen patients received BHT and 14 received the placebo mineral oil vehicle. The time from lesion onset to dry crust formation was slightly shorter among BHT recipients than among placebo recipients (2.0 and 2.4 days; P = 0.01). Duration of the vesicle-ulcer stages was likewise shorter (1.2 versus 2.0 days; P = 0.09), and lesion virus excretion appeared to be less in BHT subjects than in controls, but these differences were not statistically significant. There was no clinical or laboratory evidence of toxicity.

Evidence Assessment

The evidence for BHT's antiviral efficacy in humans is weak and preliminary. The single published human clinical trial (Freeman et al., 1985) was a small pilot study with only 30 participants, and the primary endpoints did not achieve statistical significance. There are no robust, large, randomized clinical trials showing that oral or systemic BHT reliably treats human herpes (HSV-1/HSV-2), shingles (VZV), or other lipid-enveloped viral diseases. No human trials for BHT against HIV or other lipid-enveloped viruses have been reported in the peer-reviewed literature.

5.2 Antioxidant and Anticarcinogenic Activity

Primary research studies in the 1970s–1990s reported both potential for increased risk and potential for decreased risk in the area of oncology.

Anticarcinogenic Evidence (Animal Studies)

In 1979, the National Cancer Institute determined that BHT was noncarcinogenic in a mouse model. Animal studies have demonstrated that BHT can inhibit chemically-induced carcinogenesis in certain tissue contexts: early rodent studies demonstrated that BHT inhibited cancer induction by specific chemical carcinogens (e.g., N-2-fluorenylacetamide) in rats.

A review of genotoxicity and carcinogenicity data concluded that the studies detailed experimental investigations which bear on cancer hazard assessment of exposure to humans, and concluded that BHT poses no cancer hazard and, to the contrary, may be anticarcinogenic at current levels of food additive use.

Pro-carcinogenic / Tumor-Promoting Evidence (Animal Studies)

BHT has been shown to have tumor promotion effects, to be anticarcinogenic, and to have no effect on other carcinogenic agents, depending on the target organ, exposure parameters, the carcinogen, and the animal tested. Specifically, BHT promoted urinary bladder carcinogenesis initiated by specific chemical carcinogens and thyroid carcinogenesis initiated by MNU, but inhibited ear-duct carcinogenesis initiated by DMBA.

The World Health Organization discussed a possible link between BHT and cancer risk in a 1986 report, concluding there is limited evidence for carcinogenicity from animal studies. A review report published in 2002 noted that BHT has shown anticarcinogenic effects, no effect, or tumor-promoting effects depending on animal species and target organ considered.

Human Epidemiological Evidence

In a study of the association between dietary intake of BHT and stomach cancer risk in the Netherlands Cohort Study, which started in 1986 among 120,852 men and women aged 55–69 years, there was no significant association.

Evidence Assessment

Taken as a whole, the carcinogenicity and anticarcinogenicity data for BHT are complex and context-dependent. Human epidemiological data are sparse. The large Dutch cohort study found no significant cancer signal at normal dietary exposure levels. Animal data are conflicting depending on species, dose, organ, and co-carcinogen, and cannot be directly extrapolated to human supplemental use. No human clinical trials have been conducted examining BHT as an anticarcinogenic supplement.

5.3 Neuroprotection and Alzheimer's Disease

In Vitro Evidence

BHT prevents RSL3- and ML162-induced ferroptotic cell death in cultured human neuroblastoma cells (SH-SY5Y) in a dose-dependent manner, preventing the RSL3-induced oxidation of membrane lipids and normalising the RSL3-induced inhibition of the intracellular catalytic activity of glutathione peroxidase 4. BHT prevented RSL3- and ML162-induced ferroptosis in SH-SY5Y human neuroblastoma cells at concentrations as low as 30 nM.

Animal Model Evidence

Recent studies have suggested that neuronal ferroptosis may play a major pathophysiological role in Alzheimer's disease. Researchers hypothesized that enteral administration of BHT as a radical scavenger might slow down or prevent the development of AD-related symptoms in an in vivo animal AD model. To test this hypothesis, they employed the rat model of streptozotocin-induced AD and administered BHT orally at a dose of 120 mg/kg body weight.

Evidence Assessment

The neuroprotective and anti-Alzheimer's evidence for BHT is preliminary and entirely preclinical. Published data (as of 2024) are limited to in vitro cell culture studies and a rat model of streptozotocin-induced neurodegeneration. No human clinical trials have been conducted. The doses used in the rat study (120 mg/kg body weight) are substantially above any regulatory ADI and cannot be extrapolated to human application.

6. Body Systems and Health Areas of Association

  • Lipid and cardiovascular system: BHT is primarily studied as an inhibitor of lipid peroxidation. Its antioxidant action preserves the integrity of polyunsaturated fatty acids in both foods and biological membranes.
  • Antiviral / immune system: BHT is a potent inactivator of lipid-enveloped viruses by physically disturbing the viral envelope structure and interfering with viral adsorption to host cells.
  • Respiratory system: BHT produces acute pulmonary toxicity in mice, and also enhances the multiplicity of lung tumors in mice when chronically administered following a single dose of a carcinogen such as urethane. These effects are species-specific and mediated by reactive metabolites.
  • Hepatic system: At acute doses of 0.5 to 1.0 g/kg, some renal and hepatic damage was seen in male rats. Short-term repeated exposure to comparable doses produced hepatic toxic effects in male and female rats.
  • Nervous system (neuroprotection): BHT is under preclinical investigation as a ferroptosis inhibitor with potential relevance to neurodegenerative diseases, particularly Alzheimer's disease (see Section 5.3 above).
  • Endocrine system: A recent opinion by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) hypothesizes a role for BHT in endocrine disruption, based on observations in mostly rat studies where changes to thyroid physiology are observed. Enzymatic induction of cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism, however, a causal relationship has not been proven. The current assessment using newer approaches concludes that no mechanistic link to thyroid dysfunction has been confirmed in animals treated with BHT.
  • Reproductive system: The most sensitive toxicological endpoints of BHT are hepatic enzyme induction and reproductive effects.

7. Dosage Forms and Reported Dosages

BHT is encountered in multiple forms relevant to both food additive and supplement contexts:

  • Food additive: FDA allows BHT as GRAS as an antioxidant in food generally, with the total antioxidant content not exceeding 0.02% of the total fat or oil content of the food (21 CFR 182.3173).
  • Cosmetics/topical: BHT is used in a wide range of cosmetic formulations as an antioxidant at concentrations from 0.0002% to 0.5%.
  • Topical antiviral (clinical trial): A 15% BHT in mineral oil preparation was tested for topical therapy for recurrent herpes simplex labialis in a double-blind pilot study.
  • Topical antiviral (preclinical): Treatment with 5%, 10%, or 15% BHT was tested in guinea pig genital herpes models, initiated 48 hours after viral inoculation and continued four times daily for 15 days.
  • Oral (human pharmacokinetic study): A single oral dose of 0.5 mg/kg body weight was used in a human pharmacokinetics study involving non-smoking male volunteers.
  • Oral (animal Alzheimer's study): BHT was administered orally at a dose of 120 mg/kg body weight in a rat streptozotocin-induced Alzheimer's disease model.
  • Regulatory ADI: The EU SCF established an ADI of 0–0.05 mg/kg body weight per day. JECFA allocated an ADI of 0–0.3 mg/kg body weight per day. EFSA set an ADI of 0.25 mg/kg body weight per day in 2012.

8. Safety Considerations and Interactions

General Acute Toxicity

Butylated hydroxytoluene toxicity is generally considered to be low. There are few studies on the effects of BHT on humans, with most identifying metabolic products of BHT. Studies with laboratory animals indicate that BHT may exert both detrimental and beneficial effects. For example, BHT ameliorates the toxicity and carcinogenicity of several chemical and physical agents, yet potentiates the toxicity and carcinogenicity of others. Furthermore, while BHT may exert a positive effect on lifespan, it exerts negative effects on the lungs, kidneys, myocardial cells, liver metabolism of lipids, and clotting factors, and is a potential behavioral and developmental teratogen.

Pulmonary Toxicity

BHT produces specific pneumotoxicity in type I cells of the alveolar epithelium in mice, but not rats, when administered by the intraperitoneal route, and chronic administration to mice results in loss of type II alveolar epithelial cells resulting in pulmonary fibrosis. Both acute and chronic toxicities are attributed to the metabolic formation of a reactive BHT quinone methide. These effects have been documented in rodents; their relevance to oral human exposure at food additive levels has not been established.

Hepatic and Reproductive Effects

At acute doses of 0.5 to 1.0 g/kg, some renal and hepatic damage was seen in male rats. Short-term repeated exposure to comparable doses produced hepatic toxic effects in male and female rats. The most sensitive toxicological endpoints of BHT are hepatic enzyme induction and reproductive effects.

Endocrine Disruption Concerns

BHT is suspected of being an endocrine disruptor by the French authority (MSCA France, 2017), and a targeted assessment of this is under development. This concern is based on observations in mostly rat studies where changes to thyroid physiology are observed; enzymatic induction of cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism, however, a causal relationship has not been proven. The EFSA ANS Panel reviewed the toxicology of BHT in 2012 in the context of these discrepant evaluations. The EFSA Panel concluded that BHT is not of concern with respect to genotoxicity and that any carcinogenicity would be thresholded.

Skin and Inhalation Concerns

Exposure of the user to BHT via inhalation is likely in occupational settings; however, panels have not been able to conclude on the potential inhalation toxicity of the additive. BHT is also identified as a skin and eye irritant, and no firm conclusions can be drawn on the potential of the additive to be a skin sensitiser.

Reactive Metabolites and DNA Effects

BHT can inhibit lipid peroxidation; however, its metabolites have been reported to cause DNA strand breaks in cultured cells and DNA breaks between nucleosomes — a typical feature of apoptosis. Evidence strongly indicates that these effects are caused by reactive metabolites, particularly the hydroperoxide (BHT-OOH) or quinone methide products, with the former being converted to free radicals by cytochrome P-450.

Drug and Additive Interactions

In rats, the simultaneous administration of BHT (200 mg/kg body weight) and butylated hydroxyanisole (BHA, 200 mg/kg) significantly decreased the absorption of BHT from the gastrointestinal tract in the first few hours after treatment. In human female volunteers, no alterations in plasma BHT or BHA profiles were seen after the simultaneous ingestion of BHT (0.25 mg/kg body weight) and BHA (0.25 mg/kg). More broadly, the interactions between BHT and specific medicines are not fully characterized in the peer-reviewed human literature.

Consumer Exposure Context

Because of its wide dispersive use and its potential relevance for human health, BHT was included in the human biomonitoring cooperation between the German Federal Ministry for the Environment and the German Chemical Industry Association. Assessments have found that consumer exposure to BHT from tissues and products of animals fed BHT as a feed additive ranged from 1% to 3% of the acceptable daily intake, and concluded that this is of no concern for the safety of consumers.

Reports on BHT toxicity and side effects have been somewhat contradictory. The overall picture from regulatory bodies is that BHT is acceptable at current dietary exposure levels, but ongoing post-market review activity by the FDA (as of 2025–2026) reflects continued scientific scrutiny.

References

Health Conditions

Health conditions that BHT (butylated hydroxytoluene) may help support.

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Body Systems

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