레티노산

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary.

Tretinoin Gel, USP: store below 30 °C (86 dg F). Tretinoin Cream, USP: store below 27 °C (80 °F).

Capsules: Store at 20 deg to 25 °C (68 deg to 77 °F).

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature -20 °C. Storage class (TRGS 510): Non Combustible Solids.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then dampen the solid spill material with toluene and transfer the dampened material to a suitable container. Use absorbent paper dampened with toluene t pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent-wash all contaminated surfaces with toluene followed by washing with soap and water solution. All exposed surfaces should be analyzed for contamination. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols.Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

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. Ensure that the local ventilation moves the contaminant away from the worker.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Mouse mammary gland organ culture technique was utilized to determine the effects of retinoids, including trans-retinoic acid, on the prolactin-induced structural differentiation of the mammary gland. Thoracic glands from BALB/C mice pretreated with steroids differentiate in 6 days into alveolar structures in presence of insulin and prolactin. Trans-retinoic acid inhibited prolactin-induced structural changes in the glands.

To determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated orally on gestation days 10 or 12 with 10 ml corn oil/kg containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (0-18 ug/kg), retinoic acid (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gestation day 18 and toxicity and teratogenicity assessed. Coadministration of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by retinoic acid at lower doses on gestation day 10 than on gestation day 12, but by 2,3,7,8-tetrachlorodibenzo-p-dioxin at lower doses on gestation day 12 than on gestation day 10. Sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hydronephrosis was similar on both gestation days 10 and 12. The limb bud defects were only observed when retinoic acid was administered on gestation day 10, not when given on gestation day 12. No other soft tissue or skeletal malformations were related to administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin or retinoic acid. No effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin was observed on the incidence or severity of limb bud defects induced by retinoic acid, nor did retinoic acid influence the incidence or severity of hydronephrosis induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gestation day 10 and 12, the dose-response curves for cleft palate induction were parallel, suggesting some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific.

Risk of pseudotumor cerebri (intracranial hypertension) is increased in patients receiving tretinoin. Concomitant use of other agents known to cause pseudotumor cerebri or intracranial hypertension, such as tetracyclines, may increase the risk of this condition in patients receiving tretinoin.

Concurrent use of hydroxyurea, which is cytotoxic to cells in S phase, and tretinoin, which induces cells to enter the S phase, may cause a synergistic effect leading to massive cell lysis. Bone marrow necrosis, sometimes fatal, has been reported in patients receiving hydroxyurea during tretinoin therapy. Although some clinicians have administered hydroxyurea in conjunction with tretinoin therapy to reduce leukocytosis, the safety and efficacy of this practice have not been established, and caution is recommended in the use of hydroxyurea in patients receiving tretinoin.

For more Interactions (Complete) data for all-trans-Retinoic acid (14 total), please visit the HSDB record page.

EC50; Species: Danio rerio (Zebra danio) embryo 4 hr post fertilization; Conditions: freshwater, static; Concentration: 0.000423622 mg/L for 5.8333 days; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra danio) embryo 4 hr post fertilization; Conditions: freshwater, static; Concentration: 0.002076048 mg/L for 2.8333 days; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra danio) embryo 4 hr post fertilization; Conditions: freshwater, static; Concentration: 0.233743176 mg/L for 0.8333 days; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra danio) embryo 4 hr post fertilization; Conditions: freshwater, static; Concentration: 0.003575249 mg/L for 1.8333 days; Effect: abnormal development /formulation/

For more Ecotoxicity Values (Complete) data for all-trans-Retinoic acid (10 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a structure estimation method(2), indicates that all-trans-retinoic acid is expected to be immobile in soil(SRC). The estimated pKa of all-trans-retinoic acid is 4.76(3), indicating that this compound will exist partially 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(4). Volatilization of the neutral species of all-trans-retinoic acid from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). However, adsorption to soil is expected to attenuate volatilization(SRC). all-trans-Retinoic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a structure estimation method(2), indicates that all-trans-retinoic acid is expected to adsorb to suspended solids and sediment(SRC). Volatilization of the neutral species from water surfaces is expected(3) based upon an estimated Henry's Law constant of 9.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 7 and 55 days, respectively(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The volatilization half-life from a model pond is about 14 years when adsorption is considered(4). An estimated pKa of 4.76(5) indicates all-trans-retinoic acid will exist partially 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(SRC). According to a classification scheme(6), an estimated BCF of 56(SRC), from its log Kow of 6.30(7) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), all-trans-retinoic acid, which has an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase all-trans-retinoic 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 1.3 hrs(SRC), calculated from its rate constant of 2.9X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase all-trans-retinoic acid is degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 1.5 hrs(SRC), calculated from its rate constant of 1.8X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase all-trans-retinoic acid may be removed from the air by wet and dry deposition(SRC). all-trans-Retinoic acid absorbs UV light at wavelength 351 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

According to the FDA drug labeling guidelines, the most common adverse effects in topically administered tretinoin are the following: pruritus, skin pain, skin/subcutaneous irritation, erythema, and pharyngitis. According to the FDA drug labeling guidelines for orally administered tretinoin, most patients experience drug-related toxicity, such as headaches, weakness, fever, and fatigue. Interruption of therapy is rarely required, as these adverse effects are typically temporary and reversible.

IDENTIFICATION AND USE: All-trans-Retinoic acid (tretinoin) indicated for topical application in the treatment of acne vulgari. Tretinoin capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia. HUMAN STUDIES: Cardiac failure occurred in 6% of patients receiving tretinoin, and cardiac arrest, myocardial infarction, stroke, and pulmonary hypertension each occurred in 3% of patients. There is a risk of arterial or venous thrombosis, involving any organ system, during the first month of tretinoin therapy. Thromboembolic events, including fatal pulmonary embolism, have been reported in patients receiving tretinoin. In one patient receiving tretinoin, fatal thromboembolism occurred during concomitant therapy with an antifibrinolytic agent. Bone marrow necrosis, sometimes fatal, has been reported in several patients receiving hydroxyurea during tretinoin therapy. Thrombocytosis has been reported rarely in patients receiving tretinoin. Rapidly evolving leukocytosis occurs in approximately 40% of patients receiving tretinoin. Retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (also known as APL differentiation syndrome), characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltrates, pleural and pericardial effusions, edema, hepatic failure, renal failure, and multiorgan failure, occurs in approximately 25% of patients receiving tretinoin for the treatment of APL. RA-APL syndrome occasionally has been accompanied by impaired myocardial contractility and episodic hypotension and can occur with or without concomitant leukocytosis. In severe cases, progressive hypoxemia requiring endotracheal intubation and mechanical ventilation may occur, and deaths secondary to progressive hypoxemia and multiorgan failure have been reported. ANIMAL STUDIES: There was no evidence of carcinogenic potential when tretinoin dosages of 0.025 mg/kg daily were administered topically to mice. When mice received 0.017 and 0.035% formulations of tretinoin applied topically, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice and dose-related hepatic tumors were observed in male mice. Experiments in vitro with cultured rat conceptuses have shown that tretinoin is a direct-acting dysmorphogen. Major defects involved the branchial arches and somites. Retinoid-induced malformations of the jaw, ears, face, skull, eyes, and heart in humans and rodents are well known. In mice that were administered a single oral dose of 100 mg/kg tretinoin on gestation days 9 or 11 and were killed on gestation day 17 skeletal defects (limbs) and cleft palate were present in 90% of the fetuses. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in rats at dosages exceeding 1 mg/kg daily. Bone anomalies also have been reported in rats when tretinoin 10 mg/kg daily was applied dermally. Topical tretinoin cream was associated with an increased incidence of cleft palate and hydrocephaly in rabbits. In rabbits treated with topical tretinoin an increased incidence of domed head and hydrocephaly was noted in some of the fetuses, typical of retinoid-induced fetal malformations in this species. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkey. When given subcutaneously to rabbits, tretinoin was teratogenic at a dosage of 2 mg/kg daily but not at 1 mg/kg daily. In vivo and in vitro (Ames) tests have not demonstrated that tretinoin is mutagenic. However, ingredients in the microsphere formulation of the drug have shown potential for genetic toxicity and teratogenesis. ECOTOXICITY STUDIES: In Japanese flounder, Paralichthys olivaceus, at 6-9 days post-hatching tretinoin induced the most severe deformity in all skeletons examined among retinoic acid isomers.

/AQUATIC SPECIES/ Previously reported ...characteristic deformities were induced by retinoic acid (RA) treatment of the Japanese flounder, Paralichthys olivaceus, at 6-9 days post-hatching (dph). To evaluate the toxic potency of nuclear retinoid receptors in induction of deformities by RA, ...the effects of retinoic acid isomers on postembryonic development of this species /were investigated/. Larvae were exposed to either 25 nM of all-trans RA (atRA), 9-cis RA (9cRA) or 13-cis RA (13cRA) at 6-9 dph. All RA isomers induced deformities in the lower jaw, caudal fin and vertebrae. In the lower jaw, growth retardation of the dentary was evident. In the vertebrae, the major abnormalities were hypertrophy of the centrum, central fusion, and an increase in the number of abdominal vertebrae. Caudal fin deformities included deformity of caudal bone complex and absence of the entire caudal fin. The absence of the hypural primordium at 12 dph was the first sign of abnormality in caudal fin development, and resulted in complete blocking of the caudal fin development. Among the RA isomers, atRA induced the most severe deformity in all skeletons examined. Retinoic acid receptor (RAR) expression was activated by atRA and 9cRA, and pitx2 expression was inhibited in the lower jaw by atRA and 9cRA. Vitamin D receptor (VDR) expression was specifically inhibited by atRA treatment, suggesting that RA inhibits the lower jaw growth by suppressing the expression of these genes. These results suggest that RA exerted toxic effects on the skeletal systems, mainly through the RAR pathway.

/AQUATIC SPECIES/ Retinoic signaling plays an important role in cell proliferation and differentiation. Disruption of retinoic signaling via excessive or deficient retinoic acid can cause teratogenic effects on developing embryos. Similar to retinoic acid, many xenobiotic environmental pollutants have been found to disrupt retinoic signaling through binding and eliciting agonistic activity on retinoic acid receptors. Currently, studies of retinoic acid or retinoic acid-like compounds in aquatic organisms have mainly focused on teratogenicity and few studies have explored their neurobehavioral toxicity. In the present study, the authors used retinoic acid as an example to explore the neurobehavioral toxicity associated with developmental exposure of retinoic acid-like compounds in zebrafish. The findings confirmed retinoic acid's teratogenic effects such as bent spine, malformed tail, and pericardial edema in developing zebrafish with a median effective concentration of 2.47 nM. Retinoic acid-induced cell apoptosis at 24 hr postfertilization was consistently found in the eye and tail regions of embryos. Spontaneous movement as characterized by tail bend frequency was significantly increased in zebrafish embryos following exposure to 2 nM and 8 nM retinoic acid. Relatively low-dose retinoic acid exposure of 2 nM led to fast locomotion behavior in the dark period and hyperactivity during light-dark photoperiod stimulation. The 2-nM retinoic acid exposure also led to alterations of neurobehavior- and optic nerve-related genes, with the transforming growth factor-Beta signal transduction inhibitor noggin (nog) and the spinal cord marker homeobox c3a (hox) being underexpressed and the retinal G protein-coupled receptor a (rgr), the photoreceptor cell marker rhodopsin (rho), and the short wave-sensitive cone pigment opsin 1 (opn1sw1) being overexpressed. Increased expression of opn1sw1 and rho was confirmed by whole-mount in situ hybridization. Whether the misexpression of these genes leads to the neurobehavioral changes merits further study. The findings demonstrated that low-dose retinoic acid exposure perturbed the visual system and optic nerve development and caused hyperactivity in developing zebrafish. /Retinoic acid/

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for all-trans-retinoic acid is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of all-trans-retinoic acid can be estimated to be 2.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that all-trans-retinoic acid is expected to be immobile soil. The estimated pKa of all-trans-retinoic acid is 4.76(3), indicating that this compound will exist partially 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(4).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tretinoin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Antineoplastic Agents Keratolytic Agents

MEDICATION

Synthetic Polymer MALDI Matrix Compounds

Use (kg; approx.) in Germany (2009): >10

For the the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant); For the topical treatment of acne vulgaris, flat warts and other skin conditions (psoriasis, ichthyosis congenita, icthyosis vulgaris, lamellar icthyosis, keratosis palmaris et plantaris, epidermolytic hyperkeratosis, senile comedones, senile keratosis, keratosis follicularis (Darier's disease), and basal cell carcinomas.); For palliative therapy to improve fine wrinkling, mottled hyperpigmentation, roughness associated with photodamage.

By oxidation of vitamin A aldehyde which may be obtained by oxidation of vitamin A.

R. Marbet, German patent 2061507; United States of America patent 3746730 (1971, 1973 both to Hoffmann-La Roche).

Oral: Capsules 10 mg, Vesanold (Roche)

Table: Tretinoin (Topical) Preparations [Table#3901]