Azelaic acid

188.22

188.22

1101094

204-669-1

F2VW3D43YT

757406|19493

DTXSID8021640

C47407

Monoclinic prismatic needles|Yellowish to white crystalline powder|Leaflets or needles

D10AX03|D - Dermatologicals

29171390

74.6

1.6

White to slightly yellow Slightly Crystalline Powder or Flakes

1.251 g/cm³

106.5 °C

286.5 °C

215 °C

1.42808 (107.3ºC)

H2O: 2.4 g/L (20 ºC)

2-8°C

<1 mm Hg ( 20 °C)

6.5 (vs air)

Oral-rat LD50:>5000 mg/kg

Open flames burn with heat; burning produces irritating smoke

4.55(at 25 °C)

Henry's Law constant = 2.23X10-11 atm-cu m/mol at 25 °C (est)

4.55 (at 25 °C)|pKa = 4.55

137.38 Ų [M-H]- [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]|148.4 Ų [M+Na]+ [CCS Type: DT, Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]|139.9 Ų [M-H]- [CCS Type: DT, Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]|141.9 Ų [M+Na-2H]- [CCS Type: DT, Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]|142.1 Ų [M-2H+Na]-

Specific gravity: 1.0291 at 110.6 °C/4 °C|pK (25 °C): 4.53; 5.33|Liquid, specific gravity: 1.0026 at 20 °C/4 °C, mp: -3.9 °C, bp: 140 deg at 8 mm Hg /Dimethyl ester/|Hydroxyl radical reaction rate constant = 9.83X10-12 cu cm/molec-sec at 25 °C (est)

1

36/37/38

24/25-36-26

CM1980000

Xi

Ventilated, low temperature and dry; stored separately from oxidant

Reacts violently with oxidants

Stable. Combustible. Incompatible with bases, strong oxidizing agents. Readily biodegrades in soil and water with >70% DOC reduction after 28 days.

P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501

H315

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Reactive with oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl azelaic acid, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Azelaic acid is an indirect food additive for use only as a component of adhesives.

|Warning|H315 (47.96%): Causes skin irritation [Warning Skin corrosion/irritation]|P264, P280, P302+P352, P305+P351+P338, P321, P332+P313, P337+P313, and P362|Aggregated GHS information provided by 1151 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Personal Protection: Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves.|Personal Protection in Case of a Large Spill: Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist BEFORE handling this product.|Engineering controls: Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants below the exposure limit.

Slightly flammable to flammable in presence of heat.

SMALL FIRE: Use DRY chemical powder. LARGE FIRE: Use water spray, fog or foam. Do not use water jet.

Small spill: Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and dispose of according to local and regional authority requirements. Large spill: Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and allow to evacuate through the sanitary system.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants.

Skin: May cause mild skin irritation. Eyes: May cause mild eye irritation. Inhalation: May cause respiratory tract irritation.

1,7-Heptanecarboxylic acid was detected in automobile exhausts from a 1982 Toyota Corolla Model 1.8 Liter gasoline engine and a 1971 Mercedes Benz 220 Model 2.2 Liter diesel engine which was rebuilt in 1982, at 3.9 and 51 nmol/cu m, respectively(1).|1,7-Heptanecarboxylic acid was identified as a directly emitted component in gas and particulate phases of pinene photooxidation aerosol products over a forest area at concentrations of 2.59 (6AM-12PM), 0.69 (12PM-6PM), 0.22 (6PM-6AM) ng/cu m, respectively; in aerosols - 0.47 (6AM-12PM), 0.16 (12PM-6PM), 0.31 (6PM-6AM) ng/cu m, respectively(1).

SEDIMENT: 1,7-Heptanecarboxylic acid was detected in samples from a bog in the foothills of the western Sierra Nevada Mountains, CA at concentrations of 34 and 55 nmol/g, for the humic and fulvic fractions, respectively(1). The compound was detected, not quantified in sediment samples collected on Sept 28, 1990 from Dokai Bay, Japan(2).

URBAN/SUBURBAN: 1,7-Heptanecarboxylic acid exhibited seasonal variations in the atmosphere in Tokyo, Japan, as evidenced by concentrations ranging from 6.9 to 73 ng/cu m in samples collected from 1988-1989(1). 1,7-Heptanecarboxylic acid was detected in air samples from west Los Angeles, CA at concentrations of 0.12, 0.04, 0.07, 0.09, 0.11, 0.03, 0.02 and 0.15 nmol/cu m, on Jun 12, Jun 13-14, Oct 20-22, Oct 24, Oct 24-25, Oct 25-26, Oct 26-29 and Oct 29-30, 1984, respectively(2). It was detected in air samples from downtown Los Angeles, CA at concentrations of 0.27 and 0.13 nmol/cu m, on Oct 24 and Oct 24-25, 1984, respectively(2). 1,7-heptanecarboxylic acid was tested for in 12 air samples from various locations in southern California as part of that area's Children's Health Study (SCCHS) in 1995; concentrations of 0.9, 0.93, 0.35, 0.87, 0.76, 0.25, 1.07 ,1.28, 0.95, 0.92, 0.61 and 1.3 ng/cu m from an Alpine location, Atascadero, Lake Arrowhead, Lake Elsinore, Lancaster, Lompoc, Long Beach, Mira Loma, Riverside, San Dimas, Santa Maria and an Upland locations were reported(3). Sources quantified were gasoline-powered motor vehicle exhaust, diesel vehicle exhaust, wood smoke, vegetative detritus, tire wear and natural gas combustion(3). 1,7-Heptanecarboxylic acid was detected in 4 samples collected in winter and summer of 1992 in Tokyo, Japan at concentrations of 41, 46 ng/cu m (February 24-26), 43 and 48 ng/cu m (July 22-23)(4).|INDOOR: 1,7-Heptanecarboxylic acid was detected in air samples from a greenhouse in Los Angeles, CA at concentrations of 0.03 nmol/cu m, sampled on Dec 12, 1984; it was not detected on Dec 13, 1984(1).

1,7-Heptanecarboxylic acid was detected in dust samples from the UCLA Geology Building and from outside an apartment building in downtown Los Angeles, CA at concentrations of 121 and 94 nmol/g, respectively(1). Emissions were analyzed from fireplace combustion of Northeastern United States woods, specifically red maple (Acer rubrum), northern red oak (Quercus rubra), paper birch (Betula papyrifera), eastern white pine (Pinus strobus), eastern hemlock (Tsuga canadensis) and balsam fir (Abies balsamea); only red oak tested positive for 1,7-heptanecarboxylic acid at 0.41 mg/g organic carbon emitted(2).

practically nontoxic

Oral LD50 in rat: >5 g/kg

The cytotoxic effect of azelaic acid on murine melanoma cells in culture is due, at least in part, to an antimitochondrial action. ...The possibility that the addition of carnitine to the medium may increase the transport of azelaic acid into the mitochondria and thereby increase its cytotoxic effect /was investigated/. Using mitochondrial cross-sectional area measured from electron micrographs as a criterion for mitochondrial damage, /it was/ found that the addition of L-carnitine to the culture medium had no effect either alone or with a low (10-3 M) concentration of azelaic acid. At a high concentration (5 X 10-2 M) azelaic acid caused swelling and disruption of the mitochondria to such an extent that this was not increased by carnitine. At 10-2 M azelaic acid, however, some swelling of the mitochondria occurred which was significantly increased by the addition of carnitine. This indicates that carnitine-mediated transport of the diacid into the mitochondria had occurred. ...Carnitine may reduce the time or concentration needed for azelaic acid to have a toxic effect on the malignant melanocyte.|Chemotherapy for melanoma results in low response and must be reinforced with sensitizer compounds. We believed that azelaic acid (AZA) could modulate melanomas' resistance to antineoplastics. Therefore we tried to compare in vitro treatment with antineoplastics alone versus AZA treatment followed by antineoplastics. We carried out MTT assays to evaluate the cytotoxicity of melphalan, lomustine (CCNU), fotemustine, and 4-Hydroxyanisole (4-HA) on three melanoma lines (B16F10, SK-MEL-28, and SK-MEL-1), and the modulating effect of pretreatment with AZA (1 mM). AZA showed a dose-dependent antineoplastic activity on the three lines. Melphalan was the most active drug followed by CCNU, fotemustine, and 4-HA. The most sensitive line was B16F10 and the least sensitive was SK-meL-1. Previous treatment with AZA of B16F10 reinforced the effect of melphalan (2.5 times), CCNU (10 times), and fotemustine (14 times); whereas for SK-MEL-28 and SK-MEL-1, only the cytotoxicity of CCNU and fotemustine increased. An antagonist effect was produced by 4-HA on all three lines. We concluded that AZA enhances in vitro cytotoxicity of CCNU and fotemustine.

LD50 Rat oral >5000 mg/kg

Occurs in rancid oleic acid

1,7-Heptanecarboxylic acid's production and use in organic synthesis, lacquers, alkyd resins, polyamides, polyester adhesives, low-temperature plasticizers and in urethane elastomers(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 170(SRC), determined from a log Kow of 1.57(2) and a regression-derived equation(3), indicates that 1,7-heptanecarboxylic acid is expected to have moderate mobility in soil(SRC). The pKa of 1,7-heptanecarboxylic acid is 4.55(4), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the acid exists as an anion and anions do not volatilize. 1,7-Heptanecarboxylic acid is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.07X10-8 mm Hg(6). Biodegradation data were not available(SRC, 2008) but straight chain carboxylic acids are expected to readily biodergade(7).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 170(SRC), determined from a log Kow of 1.57(2) and a regression-derived equation(3), indicates that 1,7-heptanecarboxylic acid is expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.55(4) indicates 1,7-heptanecarboxylic acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2008) but straight chain carboxylic acids are expected to readily biodergade(8).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,7-heptanecarboxylic acid, which has a vapor pressure of 1.07X10-8 mm Hg at 25 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 1,7-heptanecarboxylic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 40 hrs(SRC), calculated from its rate constant of 9.8X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase 1,7-heptanecarboxylic acid may be removed from the air by wet or dry deposition(SRC). 1,7-Heptanecarboxylic acid does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of 1,7-heptanecarboxylic acid with photochemically-produced hydroxyl radicals has been estimated as 9.8X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 40 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 1,7-Heptanecarboxylic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). 1,7-Heptanecarboxylic acid does not contain chromophores that absorb at wavelengths >290 nm(2) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for 1,7-heptanecarboxylic acid(SRC), using a log Kow of 1.57(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of 1,7-heptanecarboxylic acid is estimated as 170(SRC), using a log Kow of 1.57(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,7-heptanecarboxylic acid is expected to have moderate mobility in soil. The pKa of 1,7-heptanecarboxylic acid is 4.55(4), indicating that this compound will almost entirely exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

A pKa of 4.55(1) indicates 1,7-heptanecarboxylic acid will almost entirely exist in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces or moist soil is not expected to be an important fate process(2). 1,7-heptanecarboxylic acid is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.07X10-8 mm Hg(3).

DRINKING WATER: 1,7-Heptanecarboxylic acid was identified as an ozone disinfection by-product in drinking water(1).|RAIN/SNOW/FOG: 1,7-Heptanecarboxylic acid was detected in 9 samples collected in 1992 in Tokyo, Japan in at concentrations of 4.56, 11.5 and 0.85 ug/L in snow/sleet samples (March 18); 4.71, 0.62 and 0.36 ug/L in rain (June 30); 0.58, 2.11 and 30.4 ug/L in rain (August 1)(1).

Equilibrium dialysis was used to assess human milk partitioning in vitro. At an 1,7-heptanecarboxylic acid concentration of 25 ug/mL, the milk/plasma distribution coefficient was 0.7 and the milk/buffer distribution was 1.0, indicating that passage of drug into maternal milk may occur. Since less than 4% of a topically applied dose is systemically absorbed, the uptake of 1,7-heptanecarboxylic acid into maternal milk is not expected to cause a significant change from baseline 1,7-heptanecarboxylic acid levels in the milk.

1,7-Heptanecarboxylic acid was detected in dust samples from the UCLA Geology Building and from outside an apartment building in downtown Los Angeles, CA at concentrations of 121 and 94 nmol/g, respectively(1). Emissions from fireplace combustion of Northeastern United States woods were analyzed, specifically red maple (Acer rubrum), northern red oak (Quercus rubra), paper birch (Betula papyrifera), eastern white pine (Pinus strobus), eastern hemlock (Tsuga canadensis) and balsam fir (Abies balsamea); only red oak tested positive for 1,7-heptanecarboxylic acid at 0.41 mg/g organic carbon emitted(2).

For the topical treatment of mild-to-moderate inflammatory acne vulgaris.|FDA Label

Azelaic acid 20% cream is used topically in the treatment of mild to moderate inflammatory acne vulgaris. The drug is not indicated in the treatment of noninflammatory acne vulgaris. Therapy of acne vulgaris must be individualized and frequently modified depending on the types of acne lesions that predominate and the response to therapy. Results of several studies indicate that topical azelaic acid 20% cream is more effective than vehicle placebo in the treatment of mild to moderate inflammatory acne and as effective as topical tretinoin or benzoyl peroxide. Limited data indicate that topical azelaic acid also may be as effective as oral tetracycline hydrochloride in the management of acne vulgaris. A decrease in the number of inflammatory lesions occurs in most patients within 1-2 months of topical azelaic acid therapy, although maximum benefit generally requires more prolonged treatment.|Azelaic acid 15% gel is used topically for the treatment of inflammatory lesions (papules and pustules) associated with mild to moderate rosacea in adults. In 2 clinical studies in adults with mild to moderate papulopustular rosacea, therapy with azelaic acid 15% gel (applied twice daily for 12 weeks) resulted in a 50-58% reduction in the number of papules and pustules compared with a 38-40% reduction in patients receiving vehicle alone. Patients were instructed to avoid spicy foods, thermally hot foods and drinks, and alcoholic beverages during the treatment period, as well as to use only very mild soaps or soapless cleansing lotion for facial cleaning. Azelaic acid 20% cream also has been used with some success in the treatment of papulopustular rosacea. /Use is not currently included in the labeling approved by the US Food and Drug Administration/|The physiopathologic mechanism of acne seems to be dependent on four main factors: a) sebum production and excretion; b) type of keratinization of the follicular channel; c) microbial colonization of the pilosebaceous unit and d) inflammatory reaction of the perifollicular area. Azelaic acid is effective in the treatment of acne because it possesses an activity against all of these factors. Azelaic acid is a competitive inhibitor of mitochondrial oxidoreductases and of 5 alpha-reductase, inhibiting the conversion of testosterone to 5-dehydrotestosterone. It also possesses bacteriostatic activity to both aerobic and anaerobic bacteria including Propionibacterium acnes. Azelaic acid is an anti-keratinizing agent, displaying antiproliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.|The effects of azelaic acid (AZA) on the epidermis of 47 individuals (12 with normal skin, 15 with seborrheic skin and 20 suffering from acne) and on in vitro cultured keratinocytes are reported. Topical application of a 20% AZA cream significantly improved the lesions of acne patients, but failed to induce clinically detectable changes in normal or seborrheic epidermis. Complementary investigations clearly showed that AZA treatment failed to induce specific changes in sebum composition, excretion rate, or in the size of sebaceous glands, but modified epidermal keratinization. Keratohyalin granules and tonofilament bundles were reduced in size and number, mitochondria were swollen and the rough endoplasmic reticulum of malpighian keratinocytes enlarged. The infundibular epidermis of acne individuals showed marked reduction of the horny layer thickness, widening of the horny cell cytoplasm, transitional corneal cells, normalization of filaggrin distribution, and the comedo contained few bacteria and spores. In vitro, AZA exerted marked time- and dose-dependent antiproliferative cytostatic effects on cultured keratinocytes, with a 50% inhibitory dose of 20 mM, decreased some keratinocyte proteins (highly soluble fractions S2, keratohyalin macroaggregate R2, and non-cross-linked fibrous protein S4) and a 95 kD and a 35 kD protein of the cytosolic fraction. Mitochondria were frequently damaged and the rough endoplasmic reticulum enlarged. Our results indicate that AZA is an antikeratinizing agent, displaying antiproliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.|For more Therapeutic Uses (Complete) data for 1,7-HEPTANEDICARBOXYLIC ACID (7 total), please visit the HSDB record page.

There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexions, these patients should be monitored for early signs of hypopigmentation.|Topical therapy for rosacea aims to reduce inflammatory lesions and decrease erythema but can carry side effects such as stinging, pruritus, and burning. Metronidazole and azelaic acid gel 15% are U.S. Food and Drug Administration-approved for the treatment of rosacea. The current study was conducted to assess the cumulative irritation potential of 2 formulations of metronidazole 0.75% gel and 1% gel--and azelaic acid gel 15% over 21 days (N=36). Results of this study demonstrated a significantly greater potential for irritation from azelaic acid compared with metronidazole gel 0.75% (P<0.0001), which had significantly greater potential for irritation compared with metronidazole gel 1% (P=0.0054).|FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./|In patients using azelaic acid formulations, the following additional adverse experiences have been reported rarely: worsening of asthma, vitiligo depigmentation, small depigmented spots, hypertrichosis, reddening (signs of keratosis pilaris), and exacerbation of recurrent herpes labialis.|For more Drug Warnings (Complete) data for 1,7-HEPTANEDICARBOXYLIC ACID (6 total), please visit the HSDB record page.

Azelaic acid is a saturated dicarboxylic acid found naturally in wheat, rye, and barley. It is a natural substance that is produced by Malassezia furfur (also known as Pityrosporum ovale), a yeast that lives on normal skin. It is effective against a number of skin conditions, such as mild to moderate acne, when applied topically in a cream formulation of 20%. It works in part by stopping the growth of skin bacteria that cause acne, and by keeping skin pores clear. Azelaic acid's antimicrobial action may be attributable to inhibition of microbial cellular protein synthesis.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Drugs used to treat or prevent skin disorders or for the routine care of skin. (See all compounds classified as Dermatologic Agents.)

Approximately 4% of the topically applied azelaic acid is systemically absorbed.|Azelaic acid is mainly excreted unchanged in the urine, but undergoes some ß-oxidation to shorter chain dicarboxylic acids.|...Azelaic acid (AA, C9 dicarboxylic acid)... when administered perorally to humans, at the same concentrations as the other /dicarboxylic acids/ (DA), it reaches much higher serum and urinary concentrations. Serum concentrations and urinary excretion obtained with intravenous or intra-arterial infusions of AA are significantly higher than those achievable by oral administration. Together with AA, variable amounts of its catabolites, mainly pimelic acid, are found in serum and urine, indicating an involvement of mitochondrial beta-oxidative enzymes. Short-lived serum levels of AA follow a single 1 hr intravenous infusion, but prolonging the period of infusion with successive doses of similar concentration produces sustained higher levels during the period of administration. These levels are consistent with the concentrations of AA capable of producing a cytotoxic effect on tumoral cells in vitro. AA is capable of crossing the blood-brain barrier: its concentration in the cerebrospinal fluid is normally in the range of 2-5% of the values in the serum.|Azelaic acid was the first dicarboxylic acid proposed as an alternative energy substrate in total parenteral nutrition. In this study, the pharmacokinetics of azelaic acid were investigated in 12 healthy volunteers, 7 receiving a constant infusion (10 g over 90 min) and 5 a bolus dose (1g). The 24 hr urinary excretion and plasma concentration in blood samples taken at regular intervals were assayed by gas-liquid chromatography. Experimental data were analysed by a 2-compartment nonlinear model that describes both tubular secretion and cellular uptake in Michaelis-Menten terms. A high value of urinary excretion (mean 76.9% of infused dose) and a mean clearance of 8.42 L/hr were found, suggesting the presence of tubular secretion. Estimating the population mean of the pharmacokinetic model parameters gave a maximal cellular uptake of 0.657 g/hr. The model predicts that 90% of the maximal uptake should be reached in the plateau phase of a constant infusion of 2.2 g/hr. The presence of extensive and rapid losses through urinary excretion, and the low estimated value of the maximal cellular uptake, indicate that azelaic acid is not suitable as an energy substrate for total parenteral nutrition.|Follicular concentrations of azelaic acid (AzA) were determined in vivo using a rapid, non-invasive method, after a single topical application of 20% (w/w) AzA cream, in order to establish whether the in vitro antimicrobial effects observed in previous studies are relevant in vivo. Preweighed amounts of 20% (w/w) AzA cream were applied over demarcated areas on the forehead and back of nine young adults, and samples were taken over a period of 5 hr. AzA was removed from the skin surface by washing with acetone, and follicular casts were collected using cyanacrylate gel. The samples were centrifuged to remove particulate matter, and the supernatants derivatized for analysis by HPLC. Although the results showed wide-ranging variability, the follicular concentration increased as the amount present on the surface declined. The maximum follicular concentrations of AzA attained ranged from 7.5 to 52.5 ng (micrograms of follicular casts)-1 and 0.5 to 23.4 ng/(ug of follicular casts) in samples taken from the back and forehead, respectively. Assuming an average density of follicular material of 0.9 g/mL, the mean maximum follicular concentration attained on the back was between 36 and 251 mmol/L, and on the forehead was between 2 and 112 mmol/L, and indicates that the concentration of AzA attained in follicular casts after a single topical application is comparable with the concentration required to inhibit the growth of Propionibacterium acnes and Staphylococcus epidermidis, in vitro.|Six healthy male volunteers received a single topical treatment with 5 g of an anti-acne cream containing 20% azelaic acid (AzA) onto the face, the chest and the upper back. One week later 1 g of AzA was given orally to the same subjects as aqueous microcrystalline suspension. Following the two treatments the renal excretion of the unchanged compound was measured. Analysis included ether extraction of the urine, derivatization of extract and HPLC with UV detection. After topical application 2.2 +/- 0.7%, and after oral administration 61.2 +/- 8.8% of the dose had been excreted unchanged with the urine. By comparing both amounts, the percutaneous absorption of AzA from the cream was assessed to 3.6% of the dermally applied dose.|For more Absorption, Distribution and Excretion (Complete) data for 1,7-HEPTANEDICARBOXYLIC ACID (7 total), please visit the HSDB record page.

Mainly excreted unchanged in the urine but undergoes some b-oxidation to shorter chain dicarboxylic acids.|Approximately 60% of an oral-dose is excreted unchanged in the urine within 12 hr, and it is partly metabolized by -oxidation. After 8 hr, 6% of the radioactivity from a tracer dose of [14C]azelaic acid to rats was recovered as 14CO2. Successive cleavage by -oxidation results in the formation of pimelic and glutaric acids and subsequently malonyl-CoA and acetyl-CoA. Thus, azelaic acid is incorporated into fatty acid biosynthesis and the citric acid cycle|Pimelic acid is largely excreted unchanged in humans and dogs; the extent varies with the dose. Some degree of -oxidation occurs with dicarboxylic acids and, results in the formation of dicarboxylic acids that have two fewer carbon atoms than the parent acid. Pimelic acid has been identified as a metabolite of azelaic acid in microorganisms.

The observed half-lives in healthy subjects are approximately 45 minutes after oral dosing and 12 hours after topical dosing, indicating percutaneous absorption rate-limited kinetics.|The observed half-lives in healthy subjects are approximately 45 minutes after oral dosing and 12 hours after topical dosing,

The exact mechanism of action of azelaic acid is not known. It is thought that azelaic acid manifests its antibacterial effects by inhibiting the synthesis of cellular protein in anaerobic and aerobic bacteria, especially Staphylococcus epidermidis and Propionibacterium acnes. In aerobic bacteria, azelaic acid reversibly inhibits several oxidoreductive enzymes including tyrosinase, mitochondrial enzymes of the respiratory chain, thioredoxin reductase, 5-alpha-reductase, and DNA polymerases. In anaerobic bacteria, azelaic acid impedes glycolysis. Along with these actions, azelaic acid also improves acne vulgaris by normalizing the keratin process and decreasing microcomedo formation. Azelaic acid may be effective against both inflamed and noninflamed lesions. Specifically, azelaic acid reduces the thickness of the stratum corneum, shrinks keratohyalin granules by reducing the amount and distribution of filaggrin (a component of keratohyalin) in epidermal layers, and lowers the number of keratohyalin granules.|Azelaic acid, and other saturated dicarboxylic acids (C9-C12), are shown to be competitive inhibitors of tyrosinase (KI azelaic acid = 2.73 X 10(-3) M) and of membrane-associated thioredoxin reductase (KI azelaic acid = 1.25 X 10(-5) M). The monomethyl ester of azelaic acid does not inhibit thioredoxin reductase, but it does inhibit tyrosinase, although double the concentration is necessary compared with azelaic acid (KI azelaic acid monomethyl ester = 5.24 X 10(-3) M). Neither azelaic acid nor its monomethyl ester inhibit tyrosinase when catechol is used as a substrate instead of L-tyrosine. Therefore, the weak inhibitory action of azelaic acid on tyrosinase appears to be due to the competition of a single carboxylate group on this inhibitor for the alpha-carboxylate binding site of the L-tyrosine substrate on the enzyme active site. Based on the inhibitor constant on tyrosinase, at least cytotoxic levels of azelaic acid would be required for the direct inhibition of melanin biosynthesis in melanosomes if this mechanism is responsible for depigmentation in the hyperpigmentation disorders lentigo maligna and melasma. Alternatively only 10(-5) M azelaic acid is required to inhibit thioredoxin reductase. This enzyme is shown to regulate tyrosinase through a feedback mechanism involving electron transfer to intracellular thioredoxin, followed by a specific interaction between reduced thioredoxin and tyrosinase. Furthermore, the thioredoxin reductase/thioredoxin system is shown to be a principal electron donor for the ribonucleotide reductases which regulates DNA synthesis.|The exact mechanism of action of topically applied azelaic acid in the treatment of acne vulgaris has not been fully elucidated; however, the effect appears to result partly from the antibacterial activity of the drug. Azelaic acid inhibits the growth of susceptible organisms (principally Propionibacterium acnes) on the surface of the skin by inhibiting protein synthesis. In addition, the drug also may inhibit follicular keratinization, which may prevent development or maintenance of comedones. Azelaic acid usually is bacteriostatic in action, but may be bactericidal in high concentrations against P. acnes and Staphylococcus epidermidis. Azelaic acid also exhibits antiproliferative effects against hyperactive and abnormal melanocytes but does not exhibit an appreciable depigmenting effect on normally pigmented skin.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Azelaic acid was the first dicarboxylic acid proposed as an alternative energy substrate in total parenteral nutrition. In this study, the pharmacokinetics of azelaic acid were investigated in 12 healthy volunteers, 7 receiving a constant infusion (10 g over 90 min) and 5 a bolus dose (1g). The 24 hr urinary excretion and plasma concentration in blood samples taken at regular intervals were assayed by gas-liquid chromatography. Experimental data were analysed by a 2-compartment nonlinear model that describes both tubular secretion and cellular uptake in Michaelis-Menten terms. A high value of urinary excretion (mean 76.9% of infused dose) and a mean clearance of 8.42 L/hr were found, suggesting the presence of tubular secretion. Estimating the population mean of the pharmacokinetic model parameters gave a maximal cellular uptake of 0.657 g/hr. The model predicts that 90% of the maximal uptake should be reached in the plateau phase of a constant infusion of 2.2 g/hr. The presence of extensive and rapid losses through urinary excretion, and the low estimated value of the maximal cellular uptake, indicate that azelaic acid is not suitable as an energy substrate for total parenteral nutrition.|/HUMAN EXPOSURE STUDIES/ Six healthy male volunteers received a single topical treatment with 5 g of an anti-acne cream containing 20% azelaic acid onto the face, the chest and the upper back. One week later 1 g of azelaic acid was given orally to the same subjects as aqueous microcrystalline suspension. Following the two treatments the renal excretion of the unchanged compound was measured. Analysis included ether extraction of the urine, derivatization of extract and HPLC with UV detection. After topical application 2.2 +/- 0.7%, and after oral administration 61.2 +/- 8.8% of the dose had been excreted unchanged with the urine. By comparing both amounts, the percutaneous absorption of azelaic acid from the cream was assessed to 3.6% of the dermally applied dose.|/SIGNS AND SYMPTOMS/ Acute Potential Health Effects: Skin: May cause mild skin irritation. Eyes: May cause mild eye irritation. Inhalation: May cause respiratory tract irritation. Ingestion: May cause digestive tract irritation.|/ALTERNATIVE and IN VITRO TESTS/ The effects of zinc sulfate and azelaic acid on 5 alpha-reductase activity in human skin were studied using an in vitro assay with 1,2[3H]-testosterone as substrate. When added at concentrations of 3 or 9 mmol/L, zinc was a potent inhibitor of 5 alpha-reductase activity. At high concentrations, zinc could completely inhibit the enzyme activity. Azelaic acid was also a potent inhibitor of 5 alpha-reductase; inhibition was detectable at concentrations as low as 0.2 mmol/L and was complete at 3 mmol/L. An additive effect of the two inhibitors was observed. Vitamin B6 potentiated the inhibitory effect of zinc, but not of azelaic acid, suggesting that two different mechanisms are involved. When the three substances were added together at very low concentrations which had been shown to be ineffective alone, 90% inhibition of 5 alpha-reductase activity was obtained. If this inhibition is confirmed in vivo, zinc sulfate combined with azelaic acid could be an effective agent in the treatment of androgen related pathology of human skin.

azelaic acid

Topical: Cream: 20% Azelex (with propylene glycol) (Allergan), Finevin (with propylene glycol) (Berlex). Gel: 15% Finacea (with propylene glycol) (Berlex).

Adhesive manufacturing|Nonanedioic acid: ACTIVE|Nonanedioic acid, homopolymer: ACTIVE|XU - indicates a substance exempt from reporting under the Chemical Data Reporting Rule, (40 CFR 711).|Occurs in rancid oleic acid

Method: NIOSH 5019, Issue 2; Procedure: gas chromatography with flame ionization detection; Analyte: azelaic acid; Matrix: air; Detection Limit: 0.001 mg/sample.

Food additives -> Flavoring Agents|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Fatty Acyls [FA] -> Fatty Acids and Conjugates [FA01] -> Dicarboxylic acids [FA0117]|Cosmetics -> Buffering

Flavoring Agents