Allantoin, Glyoxyldiureide, Alantan, Allantol, 97-59-6

Allantoin, Glyoxyldiureide, Alantan, Allantol, 97-59-6

ALLANTOIN (C₄H₆N₄O₃)

1. Chemical Identity and Material Classification

• Chemical Name: Allantoin, 5-Ureidohydantoin, (2,5-Dioxo-4-imidazolidinyl)urea

• Synonyms: Glyoxyldiureide, Glyoxyldiurea, Alantan, Allantol, Alcloxa (with aluminum hydroxide), Allantoinresin, Cordianine, 5-ureidohydantoin

• CAS Number: 97-59-6

• EC Number (EINECS): 202-592-8

• Molecular Formula: C₄H₆N₄O₃

• Molecular Weight: 158.12 g/mol

• Chemical Class: Heterocyclic compound, urea derivative, imidazolidine derivative, purine metabolite

• HS Code: 2933.21

• UN Number: Not applicable (not classified as hazardous material)

2. Physical Properties

2.1 General Physical Properties

2.2 Solubility Properties

2.3 Particle Characterization

2.4 Hydrate Forms and Polymorphism

2.5 Hygroscopicity and Stability

3. Chemical Properties

3.1 Molecular Structure

• Structure: Urea derivative of hydantoin; contains an imidazolidine ring fused with a urea moiety.

• Molecular structure: N-(2,5-dioxo-4-imidazolidinyl)urea

• Functional groups: Urea group (–NH–CO–NH₂), imide groups (two –CO–NH–CO–), secondary amine.

• Biological origin: Allantoin is the end product of purine (uric acid) metabolism in most mammals (except humans and great apes, who excrete uric acid directly).

3.2 Tautomerism and pH Behavior

3.3 Thermal Properties

3.4 Chemical Reactivity

3.5 Allantoin Metal Salts (Allantoinates)

4. Commercial Grades and Specifications

5. Quality Specifications (Cosmetic/Pharmaceutical Grade – USP/Ph.Eur)

6. Production Methods

6.1 Chemical Synthesis (Oxidation of Uric Acid – Classical Method)

• Reaction: Uric acid (C₅H₄N₄O₃) + oxidizing agent → Allantoin + CO₂

• Process:

  1. Uric acid (from natural sources or synthesis) is suspended in water.

  2. An oxidizing agent (alkaline permanganate, lead dioxide, or potassium permanganate) is added.

  3. Uric acid is oxidized to allantoin with evolution of carbon dioxide.

  4. The solution is filtered, neutralized, and concentrated.

  5. Allantoin crystallizes upon cooling.

  6. Recrystallization from water yields pure allantoin.

• Yield: 80–90%

• Purity: 98–99%

• Note: This classical method has been largely replaced by more economical synthesis from glyoxylic acid and urea.

6.2 Chemical Synthesis (Glyoxylic Acid + Urea – Most Common Industrial Method)

• Reaction: Glyoxylic acid (C₂H₂O₃) + 2 Urea (CH₄N₂O) → Allantoin (C₄H₆N₄O₃) + 2 H₂O

• Process:

  1. Glyoxylic acid and urea are dissolved in water at 60–80°C.

  2. The reaction mixture is heated under reflux for several hours.

  3. Allantoin crystallizes as the reaction proceeds.

  4. The product is filtered, washed with cold water, and dried.

  5. Recrystallization from water yields high-purity allantoin.

• Yield: 85–95%

• Purity: ≥99%

• Advantages: Lower cost, high yield, no toxic by-products.

6.3 Natural Extraction (Plant Sources)

• Sources: Comfrey root (Symphytum officinale), wheat sprouts, chamomile, rice, sugar beet, tobacco seeds, horse chestnut, germinating seeds.

• Process:

  1. Plant material is dried and ground.

  2. Allantoin is extracted with hot water or alcohol.

  3. The extract is concentrated and purified by crystallization.

• Yield: Low (0.1–0.5% dry weight in comfrey root)

• Purity: 90–98%

• Applications: "Natural" cosmetics (certified organic/natural products).

• Note: Natural extraction is more expensive and less common than chemical synthesis.

6.4 Biosynthesis (Fermentation)

• Microorganism: Bacillus subtilis, Escherichia coli (engineered), or other uricase-producing microorganisms.

• Process: Fermentation of purine-rich substrates.

• Commercial availability: Limited; primarily research scale.

7. Mechanism of Action (Functional Mechanisms)

7.1 Keratolytic (Skin Exfoliation) Mechanism

• Increased water content of the stratum corneum: Allantoin is a hygroscopic molecule that binds water in the outermost skin layer.

• Softening of keratin: By increasing hydration, allantoin softens the keratin protein matrix of the stratum corneum.

• Promotion of desquamation: Softened corneocytes (dead skin cells) are more easily shed from the skin surface.

• Result: Gentle exfoliation without irritation (unlike alpha-hydroxy acids or retinoids). Keratolytic effect is mild – allantoin is considered a desquamating agent rather than a strong exfoliant.

7.2 Skin Conditioning and Moisturizing Mechanism

• Humectant effect: Allantoin attracts and retains water in the skin due to its multiple polar groups (amide, urea, imide).

• Film-forming: Forms a thin, invisible, non-occlusive film on the skin that reduces transepidermal water loss (TEWL).

• Smoothing effect: Fills microscopic gaps between corneocytes, creating a smoother skin surface.

• Result: Improved skin hydration, softer feel, reduced roughness.

7.3 Wound Healing and Cell Proliferation Mechanism

• Fibroblast stimulation: Allantoin has been shown to stimulate fibroblast proliferation (in vitro and in vivo studies).

• Collagen synthesis: Increases collagen deposition in healing wounds (animal models).

• Granulation tissue formation: Promotes the formation of healthy granulation tissue.

• Epithelialization: Accelerates re-epithelialization (migration of keratinocytes over the wound bed).

• Anti-inflammatory effect: Reduces inflammation in the wound site (modulates prostaglandin synthesis, though mechanism not fully elucidated).

• Result: Faster wound closure, improved healing quality, reduced scarring.

7.4 Anti-irritant / Soothing Mechanism

• Membrane stabilization: Allantoin stabilizes cell membranes, reducing the release of inflammatory mediators (histamine, prostaglandins, leukotrienes).

• Reduction of erythema: Clinically shown to reduce skin redness (erythema) in irritant contact dermatitis.

• Calming effect on sensitive skin: Reduces stinging and burning sensations associated with sensitive skin.

• Result: Soothes irritated skin, reduces redness and inflammation.

7.5 Keratinization Regulation Mechanism (Skin Barrier Function)

• Normalization of keratinocyte differentiation: Allantoin helps regulate the process of keratinocyte maturation and cornification.

• Prevention of hyperkeratosis: Reduces excessive thickening of the stratum corneum (useful in conditions like psoriasis, calluses, and corns).

• Result: Smoother, more even skin texture; reduced scaling.

7.6 Anti-inflammatory Mechanism (General)

• Inhibition of inflammatory mediators: Allantoin inhibits the production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in some cell models.

• Antioxidant activity: Allantoin has weak antioxidant properties (scavenges free radicals, particularly hydroxyl radicals).

• Result: Reduced inflammation in conditions such as acne, sunburn, dermatitis, and minor wounds.

7.7 Oral Care Mechanism (Gingivitis, Stomatitis)

• Mucosal healing: Promotes healing of oral mucosal lesions (aphthous ulcers, stomatitis, gingivitis).

• Anti-inflammatory effect in oral mucosa: Reduces inflammation in gingival tissue.

• Keratinization regulation: Helps normalize oral epithelial keratinization.

• Result: Reduced pain from mouth ulcers, faster healing, improved gingival health.

8. Applications

8.1 Cosmetics and Personal Care – Largest Application (~80%)

8.2 Pharmaceutical Products (Topical)

8.3 Oral Care Products

8.4 Animal Health and Veterinary Products

8.5 Plant Tissue Culture and Agriculture

8.6 Industrial and Research Applications

9. Cosmetic Formulation Guide

9.1 Typical Concentration Ranges by Product Type

9.2 Solubilization Guide for Formulators

9.3 Compatibility with Other Ingredients

10. Toxicology and Safety

10.1 Acute Toxicity

10.2 Subchronic and Chronic Toxicity

10.3 Special Concerns and Considerations

10.4 GHS Classification (Generally Not Classified)

Signal word: None (generally not classified as hazardous)

Note: Allantoin is considered a very safe ingredient by major regulatory authorities (FDA, EFSA, CIR – Cosmetic Ingredient Review). It is listed in the FDA OTC (Over-the-Counter) monograph for skin protectant and wound healing products.

10.5 NFPA Rating

11. Safety Precautions and Personal Protective Equipment (PPE)

Hazards:

• Combustible dust – may form explosive dust-air mixtures at high concentrations (though very low hazard).

• Dust may cause mechanical irritation to eyes and respiratory tract at high concentrations.

• Very low toxicity – no significant health hazards under normal handling conditions.

• Environmentally safe – readily biodegradable.

PPE (recommended – for dust handling):

• Respiratory protection: P1 or P2 dust mask (when handling large quantities of powder to avoid dust inhalation).

• Eye protection: Safety glasses with side shields (dust protection).

• Gloves: Not required for normal handling. Nitrile or latex gloves recommended for prolonged contact.

• Protective clothing: Laboratory coat or standard work clothing.

• Footwear: Closed-toe shoes.

Engineering controls:

• Local exhaust ventilation (LEV) for dust control during weighing and mixing.

• General room ventilation.

• Dust collection system for large-scale handling.

Storage conditions:

Firefighting:

• Fire class: Combustible dust (Class A). Allantoin burns like paper or wood.

• Extinguishing media: Water spray, dry chemical powder (ABC), CO₂, foam.

• Dust explosion hazard: Low but possible in high dust concentrations. Avoid creating dust clouds.

• Firefighting instructions: Firefighters should wear SCBA and full protective gear. Toxic decomposition products (ammonia, oxides of nitrogen) may be released.

First aid:

• Inhalation: Move to fresh air. No specific treatment required.

• Skin contact: Wash with water and soap. No specific treatment required.

• Eye contact: Rinse with water for several minutes. Remove contact lenses. Seek medical attention if irritation persists.

• Ingestion: Rinse mouth. Drink water. No specific treatment required. Seek medical attention if large amounts ingested.

Spill cleanup:

• Small spills: Sweep or vacuum (use dust-rated vacuum). Dispose of as non-hazardous waste.

• Large spills: Vacuum or wet-sweep to avoid dust generation. Place in labeled container.

• Do not flush large quantities down the drain (though allantoin is biodegradable).

• Disposal: Dispose of as non-hazardous waste. Incineration or landfill (non-hazardous).

12. Environmental Fate

13. Storage and Shelf Life

13.1 Storage Conditions

13.2 Shelf Life and Degradation

14. Transport Information

Transport note: Allantoin is not classified as a hazardous material for transport. Standard shipping regulations apply.

15. Synonyms and Common Names

• English: Allantoin, Glyoxyldiureide, Glyoxyldiurea, Alantan, Allantol, 5-Ureidohydantoin, (2,5-Dioxo-4-imidazolidinyl)urea, Urea (2,5-dioxo-4-imidazolidinyl), Alcloxa (with aluminum hydroxide)

• German: Allantoin, Glyoxylsäure-diureid

• French: Allantoïne, Glyoxyldiuréide

• Spanish: Alantoína, Glicoxildiureida

• Trade names: Alantan® (Pharma), Allantol® (Cosmetic), Dermactive® Allantoin, Symrise Allantoin (Symrise), Merck Allantoin (Merck), Clariant Allantoin (Clariant), Seppic Allantoin (Seppic)

16. Natural Sources of Allantoin

Note: Most commercial allantoin is produced synthetically (via glyoxylic acid + urea), not extracted from plants. "Natural" allantoin (extracted) is significantly more expensive and less common.

17. Allantoin vs. Other Keratolytic / Healing Agents – Comparison

18. Frequently Asked Questions (FAQs)

Q1: What is allantoin and what is it used for?
A1: Allantoin is a naturally occurring heterocyclic compound (a purine metabolite) widely used in cosmetics and pharmaceuticals for its skin-soothing, moisturizing, mild keratolytic (exfoliating), and wound-healing properties. It is commonly found in face creams, lotions, serums, sunscreens, wound healing ointments, toothpaste, and mouthwashes. Approximately 80% of allantoin production is used in cosmetics and personal care products.

Q2: Is allantoin safe for sensitive skin?
A2: Yes, allantoin is considered very safe and is widely used in products designed for sensitive skin. It has a very low incidence of allergic reactions (extremely rare, <0.01%) and is non-irritating at typical concentrations (0.1–0.5%). It is often added to products containing potentially irritating active ingredients (retinoids, AHAs, BHAs, benzoyl peroxide) to reduce irritation.

Q3: Does allantoin exfoliate the skin?
A3: Allantoin has a mild keratolytic (exfoliating) effect. It works by increasing water content in the stratum corneum (outer skin layer), softening keratin, and promoting gentle shedding of dead skin cells. It is not a strong exfoliant like glycolic acid or salicylic acid. Instead, it is considered a "desquamating agent" that provides very gentle, non-irritating exfoliation suitable for sensitive skin.

Q4: Can allantoin help heal wounds and scars?
A4: Yes. Allantoin has been shown to stimulate fibroblast proliferation, increase collagen synthesis, promote granulation tissue formation, and accelerate re-epithelialization. It is used in wound healing ointments (0.5–2.0%) for minor wounds, burns, pressure ulcers, and diaper rash. It may also improve the appearance of scars when used consistently over time.

Q5: Is allantoin natural or synthetic?
A5: Allantoin occurs naturally in plants such as comfrey root, wheat sprouts, and chamomile. However, most commercial allantoin is produced synthetically via reaction of glyoxylic acid and urea (chemical synthesis). Synthetic allantoin is chemically identical to natural allantoin. "Natural" extracted allantoin is significantly more expensive and less common, primarily used in certified organic/natural cosmetics.

Q6: Is allantoin safe during pregnancy and breastfeeding?
A6: Yes, allantoin is considered safe for topical use during pregnancy and breastfeeding. It is not absorbed systemically in significant amounts and has no known teratogenic or reproductive toxicity. However, as with any skincare product, consult a healthcare provider if you have specific concerns.

Q7: What is the difference between allantoin and urea?
A7: Both are keratolytic agents, but they have different properties:

• Urea is a stronger keratolytic (5–20% concentration) and a more effective humectant. Higher concentrations (>10%) can be irritating.

• Allantoin is milder, less irritating, has anti-inflammatory properties, and promotes wound healing more effectively than urea.

• They are often combined in formulations (e.g., 0.2% allantoin + 10% urea) for synergistic moisturizing and keratolytic effects.

Q8: Is allantoin approved by the FDA?
A8: Yes, allantoin is listed in the FDA OTC (Over-the-Counter) monograph as a skin protectant (up to 0.5%) and as a wound healing ingredient (up to 2.0%). It is also listed in the FDA Inactive Ingredients Database for topical pharmaceutical products. It is generally recognized as safe (GRAS) for use in cosmetics and topical pharmaceuticals.

Q9: Can allantoin be used in oral care products?
A9: Yes, allantoin is commonly used in toothpaste (0.1–0.5%), mouthwash (0.05–0.2%), and oral gels (0.5–1.0%) for soothing mouth ulcers (aphthous ulcers), reducing gingival inflammation, and promoting healing of oral mucosal lesions. It is safe for ingestion in small amounts.

Q10: How should allantoin be formulated in cosmetics?
A10: Allantoin is a water-soluble powder (0.5–0.7 g/100 mL at 25°C). For higher concentrations, dissolve in hot water (60–70°C) where solubility increases to ~6 g/100 mL. Add to the water phase of the formulation. Avoid prolonged heating >80°C (risk of hydrolysis). Works best at pH 4–8. Allantoin is compatible with most cosmetic ingredients except strong acids (pH <3) and strong bases (pH >9).

19. Summary Table – Key Specifications at a Glance

*This TDS is prepared in compliance with ISO 11014-1 format and is intended for cosmetic formulators, pharmaceutical scientists, dermatologists, oral care product developers, veterinary professionals, and procurement personnel. Certificates of Analysis (CoA), Safety Data Sheets (SDS), and sample validation reports are available upon request.*