Glucono-delta-lactone

Other Names

(3R,4S,5S,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)oxan-2-one(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one1,2,3,4,5-Pentahydroxycaproic acid δ-lactone1,5-D-Gluconolactone1,5-Gluconolactone1,5-δ-Gluconolactone3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-oneD-(+)-Dextronic acid δ-lactoneD-AldonolactoneD-delta-GluconolactoneD-Gluconic acid delta-lactoneD-Gluconic acid lactoneD-Gluconic acid, δ-lactoneD-Gluconic acid-1,5-lactoneD-Gluconic δ-lactoneD-Glucono-1,5-lactoneD-Glucono-δ-lactoneD-threo-Aldono-1,5-lactoneD-δ-Gluconolactonedelta-D-Gluconolactonedelta-GluconolactoneDeltagluconolactoneE575FujigluconGDLGluconic Acid AnhydrideGluconic acid lactoneGluconic acid lactone (6CI)Gluconic acid, lactone, D- (7CI)Gluconic acid, δ-lactone, D-Gluconic acid, δ-lactone, D- (8CI)Gluconic delta-lactoneGluconic δ-lactoneGluconolactoneGluconolactone (USP)NSC 34393δ-D-Gluconolactoneδ-Gluconolactone

Synopsis

Glucono-delta-lactone (Gluconolactone, GDL): A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Classification

Glucono-delta-lactone (abbreviated GDL), also known as gluconolactone, is an inner ester of gluconic acid and is a naturally occurring ingredient. Its common names include gluconolactone, D-glucono-1,5-lactone, and GdL; its European food additive code is E575. Lactones are cyclic esters of hydroxycarboxylic acids containing a 1-oxacycloalkan-2-one structure. Glucono-delta-lactone is specifically the cyclic ester of the corresponding hydroxycarboxylic acid, D-gluconic acid.

The compound is also known by the designations "1,5-D-gluconolactone," "1,5-delta-gluconolactone," and "D-gluconic acid δ-lactone." It is a lactone (cyclic ester) or oxidized derivative of D-gluconic acid. Gluconolactone is a polyhydroxy acid (PHA) capable of chelating metals and may also scavenge free radicals.

Physical Form and Properties

Pure GDL is a white odorless crystalline powder. It is practically odourless and has a slightly sweet taste. GDL is pH-neutral, but hydrolyses in water to gluconic acid which is acidic, adding a tangy taste to foods, though it has roughly a third of the sourness of citric acid.

In aqueous solution, D-gluconic acid and glucono-delta-lactone exist in equilibrium via intramolecular esterification, which takes place spontaneously to form a six-membered ring. In the case of glucono-delta-lactone, there are three hydroxyl groups (–OH) and one methoxy group (–CH₂OH) attached to the ring structure. In aqueous solution, GDL rapidly dissolves and the lactone ring opens up and slowly hydrolyzes to gluconic acid, thus producing mild acidification. There is an equilibrium between D-gluconic acid (55%–66%) and the delta and gamma lactone forms.

Molecular Formula and Metabolic Fate

GDL is metabolized to 6-phospho-D-gluconate; one gram of GDL yields roughly the same amount of metabolic energy as one gram of sugar. At its thirtieth meeting, the JECFA Committee changed the ADI for glucono-delta-lactone to "not specified" on the basis of biochemical and metabolic data on glucono-delta-lactone and gluconic acid, noting that in an aqueous medium glucono-delta-lactone exists in equilibrium with D-gluconic acid. These compounds are intermediates in the oxidation of glucose through the pentose phosphate cycle. In the body, E575 rapidly converts into gluconic acid and is further metabolized in the liver. Its breakdown products are excreted naturally via the kidneys or used in energy metabolism.

2. Natural Sources and Occurrence

Glucono-delta-lactone occurs naturally in plants, fruits, wine (up to 0.5%), honey (up to 1%), and many fermented products. Gluconic acid is a mild organic acid with applications in the food industry. It is a natural constituent of fruit juices and honey and is used in the pickling of foods. Its inner ester, glucono-δ-lactone, imparts an initially sweet taste, which later becomes slightly acidic.

Oxidation of the aldehyde group on the C-1 of beta-D-glucose to a carboxyl group results in the production of glucono-δ-lactone (C₆H₁₀O₆) and hydrogen peroxide. Glucono-δ-lactone is further hydrolyzed to gluconic acid either spontaneously or by a lactone-hydrolyzing enzyme, while hydrogen peroxide is decomposed to water and oxygen by peroxidase. This enzymatic pathway — catalyzed by glucose oxidase — represents the biosynthetic route through which GDL arises in honey, wines, and other biological matrices.

3. Commercial Production

Glucono-delta-lactone is produced by direct crystallization from the aqueous solution of gluconic acid, which can be produced by the oxidation of D-glucose with bromine water, or with microorganisms, or with enzymes derived from these microorganisms. GDL is commercially manufactured from renewable carbohydrate sources by microbial fermentation followed by downstream processing. During the process, GDL is produced along with gluconic acid by glucose fermentation. The resulting product is a fine, white, crystalline powder freely soluble in water.

Organic-certified labeling requires that GDL must be produced by fermentation of glucose by naturally occurring microorganisms or enzymes. Production by oxidation of D-glucose with bromine water is specifically prohibited by the annotation for glucono-delta-lactone on the USDA National Organic List.

4. Traditional and Historical Use

GDL does not have a history of deliberate traditional use as an isolated medicinal or dietary supplement in ancient herbal traditions. Rather, its traditional relevance arises from the long history of its host foods — honey, wine, and fermented products — in which it is naturally present.

Tofu originated in ancient China some 2,000 years ago. Chinese legend ascribes its invention to Prince Liu An (劉安, 179–122 BC). Tofu and its production technique were introduced into Korea and then Japan during the Nara period, and it spread into other parts of East Asia as well. In ancient times, brine or gypsum was the major coagulant for tofu production. However, lactone tofu has been used in large-scale tofu production since the 1980s due to its softness, smooth texture, high water retention, and springiness.

GDL was discovered in France by Boutroux in 1898 while doing research on milk enzymes, and was first used as a tofu coagulant during the mid-1950s. By the 1970s it would begin to revolutionize the tofu industry in Japan. The 1950s saw the development of two new types of tofu: bagged lactone silken tofu (fukuroiri-dofu) and pressed silken tofu (softo-dofu). The former type, which used glucono-delta-lactone (GDL) as a coagulant, was patented in the mid-1950s and started to become popular in about 1958–59.

GDL is specifically used for silken or soft tofu because it coagulates rapidly, allowing silken tofu to be made inside the container without an air-gap, which prevents the silken tofu from breaking during transport. Prior to the invention of GDL and its use in silken or soft tofu, tofu makers could not reliably transport soft tofu.

5. Key Constituents and Active Compounds

GDL is a single, pure chemical compound rather than an extract containing multiple phytochemicals. Its primary biologically active form and metabolite is D-gluconic acid, into which it hydrolyzes in aqueous media. The functional properties of GDL derive from several interconnected chemical characteristics:

Polyhydroxy Acid (PHA) Classification

A new generation of AHAs called polyhydroxy acids (PHAs) was discovered that provide similar effects as AHAs but do not cause the sensory irritation responses that can limit the use of classical AHAs. PHAs provide additional humectant and moisturization properties compared with AHAs and can enhance stratum corneum barrier function, therefore increasing the skin's resistance to chemical challenge. Most PHAs also possess antioxidant properties.

Chelation

The close proximity of the oxygen atoms within the chemical structure lends to its function as a highly efficient chelating agent. Chelating agents bind to positively charged metal ions in solution and prevent them from forming insoluble precipitates with other ions that may be present. Glucono-delta-lactone functions as a chelating agent over a wide pH range. It is efficient in forming stable chelates with divalent and trivalent metal ions such as calcium, copper, iron, aluminum, and other metals, reducing the adverse effects these metals can have on systems. By chelating free iron ions, glucono-delta-lactone blocks the formation of hydroxyl radicals, thereby serving as an antioxidant.

Antioxidant Activity

Polyhydroxy acids like glucono-delta-lactone are known for their antioxidant activity because of their ability to scavenge free radicals. GDL is a special lactone, as it is a human natural metabolite showing anti-oxidant properties, and revealing of its role in cardioprotection may help to discover new disease pathogenesis and find possible therapeutic targets.

Humectancy

Glucono-delta-lactone acts as a humectant, which means that it attracts water and increases hydration in products.

Controlled Acidification

GdL hydrolyzes slowly in water to form gluconic acid, leading to a gradual decrease in pH, which is beneficial for controlled acidification processes. Two main properties differentiate GDL from other acid leaveners: its slow and progressive hydrolysis and pH drop make it a slow-release acidifier; and due to its initial sweet taste, hydrolysis of GDL results in lower tartness than other acidifiers.

6. Mechanisms of Action

Protein Coagulation

The most widely used acid coagulant is glucono-δ-lactone, which can dissociate into gluconic acid in an aqueous solution to induce tofu curd formation. Kohyama et al. plotted the coagulation curves by dynamic viscoelastic measurements and compression tests, revealing that the coagulation process can be divided into two steps: protein denaturation by heat and hydrophobic coagulation promoted by GDL.

Stratum Corneum Modulation (Dermatological)

As an alpha hydroxy acid, glucono-delta-lactone is known to enhance stratum corneum desquamation, improve skin appearance, and prevent skin irritation. Gluconolactone exhibits antioxidant and moisturizing effects. It also presents soothing effects, protects elastin fibers from UV-induced degradation, and improves the function of the skin barrier.

Cardioprotective Signaling (Preclinical)

GDL treatment was strongly associated with activation of pro-survival extracellular signal-regulated kinase (ERK) signaling both in vivo and in vitro. Protein kinase C (PKC) emerged as the most promising target for GDL by computational prediction. PKCε, an important member of the PKC family, was activated after GDL treatment in heart, thereby leading to ERK activation and cardioprotection against ischemia/reperfusion injury. GDL acts as a potent activator of PKCε and, thus, provides cardioprotection against I/R injury via activation of ERK signaling.

Vaginal pH Restoration and Antimicrobial (Emerging)

In contact with vaginal fluid, GDL is hydrolysed to gluconic acid, which is weakly acidic, thereby restoring the vaginal pH to normal. This inhibits the growth of Gardnerella vaginalis. It has been shown that GDL-based compositions reduce the presence of biofilm of different Candida species and additionally have a cytotoxic effect on several Candida species.

7. Scientific Evidence by Area of Use

7.1 Dermatology: Photoaging and Skin Renewal

There have been numerous clinical studies conducted to evaluate the beneficial effects of the polyhydroxy acids (PHAs) in skincare. Although there is significant evidence that PHAs provide antiaging effects to skin, a direct comparison between alpha-hydroxyacids (AHAs) and PHAs for these effects had not been conducted historically.

A 12-week clinical study evaluated gluconolactone-containing products (PHAs) in comparison with glycolic acid-containing products (AHAs). Clinical grading of photoaging, as well as objective and subjective irritation, was conducted on the face at baseline and after 6 and 12 weeks of product use. Pinch recoil, silicone replicas of the crow's-feet area, and self-assessment of product efficacy and tolerance were also collected. Both regimens showed significant antiaging benefits to skin as measured by silicone replicas, clinical grading, and pinch recoil for skin resiliency.

PHAs have been found to be compatible with clinically sensitive skin, including rosacea and atopic dermatitis, and can be used after cosmetic procedures. PHAs such as gluconolactone or lactobionic acid may be used in combination with other products, ingredients, or procedures such as laser and microdermabrasion to provide additional benefits to therapy or to enhance the therapeutic effect.

A study evaluated skin parameters such as pH, transepidermal water loss (TEWL), and sebum levels before, during, and after a series of applications of 10% and 30% gluconolactone chemical peel in a split-face model. The study involved 16 female subjects. Three split-face procedures were performed using two concentrations of gluconolactone solution applied on two sides of the face.

Evidence strength: Human clinical evidence exists for topical gluconolactone in photoaged skin; multiple small randomized and split-face studies report improvements in skin texture, resiliency, and tolerability. Sample sizes are generally small (16–150 subjects), and most studies are industry-associated. Evidence is considered moderate in support of topical efficacy, particularly when compared to classical AHAs.

7.2 Dermatology: Acne Vulgaris

A double-blind clinical trial on 150 patients evaluated the efficacy and skin tolerance of gluconolactone 14% in solution in the treatment of mild to moderate acne when compared with vehicle (placebo) and 5% benzoyl peroxide lotion. Both gluconolactone and benzoyl peroxide had a significant effect in improving patients' acne by reducing the number of lesions (inflamed and non-inflamed). Furthermore, fewer side effects were experienced by patients treated with gluconolactone when compared with benzoyl peroxide.

Gluconolactone, an alpha-hydroxy acid, affects keratinization and reduces inflammatory lesions. Moreover, it has fewer side effects than benzoyl peroxide. In one formulation studied, active ingredients comprised glycolic acid 7%, salicylic acid 1%, and gluconolactone 2%.

Evidence strength: One well-designed double-blind trial with 150 patients (Hunt & Barnetson, 1992) provides meaningful comparative evidence against a standard treatment. Additional combination studies are smaller (e.g., 25 subjects). Topical gluconolactone appears clinically active in mild-to-moderate acne with a superior tolerability profile compared to benzoyl peroxide. Larger and more recent independent replication studies are limited.

7.3 Vaginal Dysbiosis: Bacterial Vaginosis and Vulvovaginal Candidiasis

Standard oral or vaginal antimicrobial treatments have high immediate cure rates but almost as high recurrence rates. A vaginal pessary (pHyph) containing glucono-delta-lactone and sodium gluconate restores normal pH and disrupts the associated biofilm. Clinical studies have investigated its performance for both treatment and recurrence prevention of bacterial vaginosis.

Twenty-four adult women with confirmed bacterial vaginosis received the investigational GDL-containing product for self-administration on days 0, 2, 4, and 6 and were assessed on day 7. Clinical cure was defined as absence of three of four Amsel's criteria (pH excluded) on day 7.

The pHyph vaginal pessary containing glucono-delta-lactone and sodium gluconate has been described in the scientific literature as a biofilm-disrupting agent for bacterial vaginosis. In pHyph, glucono-delta-lactone causes the acidity (pH value) in the vagina to decrease to normal. In a slightly acidic environment, yeast fungi do not cause vulvovaginal candidiasis to the same extent, and lactobacilli are also favored, which can also inhibit yeast fungi.

Evidence strength: Clinical investigation is early-stage. The published open-label human pilot study involved only 24 women. Registered clinical trials are ongoing. The mechanism (pH restoration, biofilm disruption) is biologically plausible, but large randomized controlled trials comparing GDL-based pessaries to standard antimicrobial therapy are not yet available. Evidence is preliminary.

7.4 Cardiovascular: Myocardial Ischemia/Reperfusion Injury

GDL has long been considered a free radical scavenger; however, its role in cardioprotection has only recently been explored. Using a mouse model of myocardial ischemia/reperfusion (I/R) injury and a model of hypoxia/reoxygenation (H/R) in neonatal rat cardiomyocytes, researchers explored the role of GDL in I/R injury. GDL (5 mg/kg, i.p.) attenuated myocardial I/R injury as evidenced by decreased infarct size, release of cardiac injury markers, and apoptosis. Additionally, GDL decreased reperfusion-induced arrhythmias and oxidative stress.

Results demonstrated that GDL exerted cardioprotection against I/R injury, partly due to the activation of its potential target PKC and downstream pro-survival extracellular signal-regulated kinase (ERK) signaling.

Evidence strength: This is exclusively preclinical evidence — animal (mouse) and cell-culture models only. No human clinical trials evaluating GDL for cardiac protection have been published. Evidence at this stage is preliminary and cannot be extrapolated to human therapeutic use.

7.5 Antimicrobial / Food Preservation

The heat resistance of Clostridium sporogenes PA 3679 spores has been studied to establish the influence of acidification with glucono-delta-lactone (GDL) and citric acid on thermal resistance parameters. A reduction in heat resistance values was observed as the acidification level increased with both acidulants, although this effect was more evident at lower treatment temperatures studied. Citric acid was more effective for reducing the heat resistance of spores than GDL at all temperatures studied.

In conjunction with reducing compounds, GDL accelerates the rate of development of cure color in smoked meats, which considerably reduces the smoking time. The main function of curing accelerators is to accelerate color fixing or to preserve color of cured meat products during storage.

Evidence strength: Well-established in food science through decades of industrial and laboratory application. GDL's acidification properties in food matrices are clearly characterized. Not directly applicable as a dietary supplement for antimicrobial purposes in humans.

8. Body Systems and Health Areas Associated with GDL

Integumentary system (skin): Gluconolactone exhibits antioxidant and moisturizing effects. It also presents soothing effects, protects elastin fibers from UV-induced degradation, and improves the function of the skin barrier.
Metabolic/energy pathways: GDL and gluconic acid are intermediates in the oxidation of glucose through the pentose phosphate cycle.
Reproductive/urogenital system: The vaginal pessary pHyph, containing glucono-delta-lactone and sodium gluconate, disrupts biofilm formation and restores normal vaginal pH.
Cardiovascular system (preclinical): GDL is a human natural metabolite showing anti-oxidant properties relevant to cardioprotection in preclinical models.
Digestive/food coagulation: GDL dissociates into gluconic acid in aqueous solution to induce protein curd formation, most notably in tofu production.

9. Dosage Forms and Reported Dosages

Food and Food Processing Applications

GDL is commonly applied in fermented salami at levels between 3 and 12 g per kilogram of product.
GDL is commonly used with soy milk having high solids levels (10%–13% instead of 5%–10% in regular tofu).
The level of addition of glucono-delta-lactone to soya milk, when no other soybean curd coagulant is concomitantly used, is at least 0.1 to 10 percent relative to soya milk, and the use of glucono-delta-lactone in the range of 1 to 5 percent imparts a satisfactory acid taste to yoghurt-like foods.

Topical (Dermatological) Preparations

A 14% gluconolactone in solution was evaluated in a double-blind clinical trial for mild to moderate acne.
Gluconolactone chemical peel concentrations of 10% and 30% have been studied for evaluation of skin parameters including pH, transepidermal water loss, and sebum levels.
In one acne combination formulation studied, gluconolactone 2% was used alongside glycolic acid 7% and salicylic acid 1%.

Vaginal Pessary (Medical Device)

Pharmaceutical vaginal formulations for glucono-delta-lactone have been described with GDL present in amounts of 5 to 99 wt% of the formulation. According to one embodiment, the glucono-delta-lactone is present in an amount of 10 to 70 wt% of the formulation; another embodiment specifies 20 to 70 wt%.

Preclinical Cardioprotective Studies

In mouse models of myocardial ischemia/reperfusion injury, GDL was administered at 5 mg/kg intraperitoneally and attenuated myocardial injury as evidenced by decreased infarct size and release of cardiac injury markers.

Historical Human Observations (JECFA)

In historical JECFA-cited studies, the total daily dose of glucono-delta-lactone examined was 20–50 g; at these levels, laxative effects were noted.

10. Safety Considerations

Regulatory Status

The U.S. Food and Drug Administration (FDA) has affirmed glucono-delta-lactone as Generally Recognized As Safe (GRAS) under 21 CFR 184.1318, permitting its use as a curing and pickling agent, leavening agent, pH control agent, and sequestrant. Glucono-delta-lactone (E575) is listed in Commission Regulation (EU) No 231/2012 as an authorised food additive categorized in "Additives other than colours and sweeteners." GDL is classified in class I with the use level "quantum satis," which means there is no specific limit in its uses.

The EFSA has initiated a re-evaluation of gluconic acid (E 574) and its derivatives, including GDL (E 575), to ensure their continued safety as food additives, with a call for data issued to support this process. GDL is currently part of their list of permitted food additives. It is an approved ingredient in Australia and New Zealand with code number 575.

Acceptable Daily Intake (ADI)

Glucono-delta-lactone was previously evaluated by the Committee at its tenth, eighteenth, and thirtieth meetings. At its thirtieth meeting, the Committee changed the ADI for glucono-delta-lactone to "not specified" on the basis of biochemical and metabolic data on glucono-delta-lactone and gluconic acid, noting that in an aqueous medium glucono-delta-lactone exists in equilibrium with D-gluconic acid. The JECFA determined that no Acceptable Daily Intake needs to be specified for gluconic acid and its derivatives due to their low risk under normal consumption. This means that when used as needed for technological purposes, the additive does not pose a health risk.

Toxicological Studies

Data from studies evaluated by the JECFA Committee showed no evidence for the carcinogenicity, teratogenicity, or genotoxicity of glucono-delta-lactone. In one study, rats were exposed via diet to 340 mg/kg-day of glucono-delta-lactone for 29 months and no adverse effects were noted. Additional studies indicated no adverse effects at the highest doses of glucono-delta-lactone tested, which ranged from 560 to 780 mg/kg-day. No adverse reproductive effects were noted at the highest doses tested, resulting in a No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg-day in reproductive studies.

A single long-term test at one level showed no evidence of carcinogenicity. Teratogenic tests have shown no abnormalities in four species.

Laxative Effects at High Oral Doses

The JECFA has evaluated GDL and determined it to be safe for use in food, noting that excessive consumption may lead to laxative effects. These effects are described in the JECFA monograph, citing a study of 16 patients in 1939. However, such effects occur only with doses far exceeding the technological norms.

Occupational Exposure

Occupational exposure to GdL may occur among workers involved in its manufacturing, processing, distribution, use, and disposal, potentially leading to higher exposure levels than the general population. Despite increased exposure in certain occupational settings, GdL exhibits a low-hazard profile, with no significant adverse health effects identified in these populations.

Skin Sensitization and Tolerability

PHAs such as gluconolactone provide skin-smoothing benefits without the sensory irritating side effects like stinging and burning that are associated with classical AHAs. PHAs have been found to be compatible with clinically sensitive skin, including rosacea and atopic dermatitis, and can be used after cosmetic procedures. This tolerability profile represents one of the primary pharmacological advantages of GDL over conventional alpha-hydroxy acids in topical dermatological preparations.

Drug and Nutrient Interactions

GDL's metal-chelating activity is a relevant consideration when it is present alongside mineral-rich foods or supplements. Glucono-delta-lactone functions as a chelating agent over a wide pH range and is efficient in forming stable chelates with divalent and trivalent metal ions such as calcium, copper, iron, aluminum, and other metals, reducing the adverse effects these metals can have on systems. At typical food-additive exposure levels, this chelation is considered technologically useful rather than clinically adverse. No clinically established drug interactions with GDL have been documented in the JECFA or EFSA evaluations reviewed.

References

Health Conditions

Health conditions that Glucono-delta-lactone may help support.

No conditions available.

Body Systems

Body systems that Glucono-delta-lactone may help support.

No body systems available.