5,5-Diphenylhydantoin

2.47

log Kow = 2.47

2.2

Needles (alcohol)

White powder

less than 0.1 mg/mL at 66 °F (NTP, 1992)

Insoluble in cold water

One gram dissolves in about 60 ml alcohol, about 30 ml acetone. Soluble in alkali hydroxides.

Soluble in acetic acid; slightly soluble in ethyl ether, benzene, chloroform

In water, 32 mg/L at 22 °C

7.11e-02 g/L

563 to 568 °F (NTP, 1992)

295

295-298 °C

286 °C

Phenytoin appears as fine white or almost white crystalline powder. Odorless or almost odorless. Tasteless. (NTP, 1992)

Solid

Sensitive to light

A slight yellowing of the solution will not affect its potency. After being refrigerated, solution may form a precipitate which usually dissolves after being warmed to room temperature; however, do not use if the solution is not clear. /Phenytoin Sodium Injection USP/

Positive

2.44

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

8.33

pKa = 8.33

2310；2350；2365；2347；2308；2340；2360；2380；2306.8；2317.8；2299.2；2292；2335；2310；2385；2330

2369；2372.3；2339.4；2387.7

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]；H350 (31.9%): May cause cancer [Danger Carcinogenicity]；H351 (63.8%): Suspected of causing cancer [Warning Carcinogenicity]；H360 (95.7%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 138 reports by companies from 14 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

H402: Harmful to aquatic life [Hazardous to the aquatic environment, acute hazard]；H412: Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Hazard Traits - Carcinogenicity; Developmental Toxicity；Authoritative List - IARC Carcinogens - 2B; NTP RoC - reasonable; Prop 65；Report - regardless of intended function of ingredient in the product

Status: Active Update: 30-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/18601

Phenytoin: Does not have an individual approval but may be used under an appropriate group standard

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

SYMPTOMS: Symptoms of exposure to this compound include ataxia, nystagmus, fever, agranulocytosis, lupus erythematosus, epidermal necrolysis, pseudolymphoma, slurred speech, mental confusion, dizziness, insomnia, transient nervousness, headache, dyskinesias, chorea, dystonia, asterixis, polyneuropathy, nausea, vomiting, constipation, rash (scarlatiniform or morbilliform), dermatitis (bullous, exfoliative or purpuric), thrombocytopenia, leukopenia, granulocytopenia, pancytopenia with or without bone marrow suppression, macrocytosis, megaloblastic anemia, coarsening of the facial features, gingival hyperplasia, toxic hepatitis, respiratory depression, Stevens-Johnson syndrome, coma and death. Other symptoms include central nervous system effects such as depression and motor restlessness, allergic reactions, gastric distress, hirsutism and blood dyscrasias. Exposure can cause liver damage, kidney damage, adenopathy, aplastic anemia, pulmonary changes, lymph gland enlargement, cardiac irregularities, peripheral nerve damage, tremor, drug psychosis, rigidity and convulsions. Exposure can also cause motor twitchings, decreased coordination, enlargement of the lips, hypertrichosis, Peyronie's Disease, periarteritis nodosa, immunoglobulin abnormalities, dysarthria, hyperreflexia, lethargy, hypertension and circulatory depression. It may cause tenderness of the gums, rickets, reduced bone density, osteomalacia, polyarthropathy, hyperglycemia, erythema multiforme, hypotension, blurred vision, unsteady gait, facial changes, thickening of the skull, thickening of the heel pad, eosinophilia, hemolytic anemia, myasthenia gravis, acquired hemophilia, leukemia, pulmonary function loss, decreased sexual potency and fertility, and cholestasis. It may also cause lymphadenopathy, lymphoma including Hodgkin's disease, hallucinations, excitation, cardiac arrhythmias, cerebellar-vestibular effects, behavioral changes, increased frequency of seizures, gastrointestinal symptoms, vertigo, my；ACUTE/CHRONIC HAZARDS: This compound is harmful by ingestion, inhalation and skin absorption. It may cause irritation. When heated to decomposition it emits toxic fumes of carbon monoxide, carbon dioxide and nitrogen oxides. (NTP, 1992)

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

A REVIEW OF THE REPORTED RISKS OF PHENYTOIN DURING PREGNANCY.[ALBENGRES E, TILLEMENT JP; PHENYTOIN IN PREGNANCY: A REVIEW OF THE REPORTED RISKS; BIOL RES PREGNANCY PERINATOL 4(2) 71 (1983)]

DHHS/NTP; Toxicology & Carcinogenesis Studies of 5,5-Diphenylhydantoin in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 404 (1993) NIH Publication No. 94-2859

Strasnick B, Jacobson JT; J Am Acad Audiol 6 (1): 28-38 (1995). Teratogenic hearing loss /is reviewed/.

Wasfi FA, et al; Med Sci Res 23 (8): 551-3 (1995). Teratogenic effects of phenytoin in the rat: an in vivo and an in vitro study.

For more Special Reports (Complete) data for PHENYTOIN (8 total), please visit the HSDB record page.

PHENYTOIN is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). This chemical is incompatible with strong oxidizers and strong bases. (NTP, 1992)

Acute Tox. 4 (100%)；Carc. 1B (31.9%)；Carc. 2 (63.8%)；Repr. 1B (95.7%)

Acute toxicity (Oral) - Category 4；Germ cell mutagenicity - Category 1B；Carcinogenicity - Category 2；Reproductive toxicity - Category 1A；Specific target organ toxicity - Single exposure - Category 1 (nervous system)；Specific target organ toxicity - Repeated exposure - Category 1 (nervous system, gingiva, liver, lymph node)

Hazardous to the aquatic environment (Acute) - Category 3；Hazardous to the aquatic environment (Long-term) - Category 3

Carcinogens, Mutagens, Teratogens

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

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.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital.；OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing. /Phenytoin Oral Suspension USP/

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. /Phenytoin Tablets (Chewable) USP/

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. /Extended Phenytoin Sodium Capsules USP/

For more Storage Conditions (Complete) data for PHENYTOIN (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.；STORAGE PRECAUTIONS: You should store this chemical under ambient temperatures and keep it away from oxidizing materials and bases. (NTP, 1992)

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.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for PHENYTOIN (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for PHENYTOIN (9 total), please visit the HSDB record page.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:；IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.；SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.；FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

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

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. (L1712)

Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin.

Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/

Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity.

Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, sulfonamide, trazodone, or trimethoprim may increase serum concentrations of phenytoin because of decreased metabolism, thereby increasing the effects and/or toxicity phenytoin. Dosage adjustments of the anticonvulsant may be necessary.

For more Interactions (Complete) data for PHENYTOIN (50 total), please visit the HSDB record page.

Prospective studies indicate that a fairly high proportion of patients taking phenytoin have transient serum aminotransferase elevations. These elevations are usually benign, not associated with liver histological abnormalities and usually resolve even with drug continuation. In addition, a higher proportion of patients have mild-to-moderate elevations in gammaglutamyl transpeptidase (GGT) levels, which is indicative of hepatic enzyme induction rather than liver injury. Marked aminotransferase elevations (>3 fold elevated) occur rarely.；Importantly, however, phenytoin is one of the most common causes of clinically apparent drug induced liver disease and acute liver failure. More than 100 cases of liver injury due to phenytoin (diphenylhydantoin) have been published and a characteristic clinical pattern (signature) of injury has been described. The estimated frequency ranges from 1 per 1000 to 1 per 10,000 and probably varies by race and ethnicity. The typical case arises after 2 to 8 weeks of therapy with initial onset of fever, rash, facial edema and lymphadenopathy, followed in a few days by jaundice and dark urine. The serum enzyme elevations can be hepatocellular, although mixed patterns are probably more common and rare cases are cholestatic. Eosinophilia, increased white counts and atypical lymphocytosis are also common. Autoantibody formation is rare. The clinical symptoms and signs can mimic acute mononucleosis or even lymphoma (pseudo-lymphoma syndrome). Almost all cases of phenytoin hepatotoxicity occur in the context of a systemic hypersensitivity syndrome and it is referred to often as the anticonvulsant hypersensitivity syndrome (HDS) or drug rash with eosinophilia and systemic symptoms syndrome (DRESS). Other manifestations can be Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, thrombocytopenia, neutropenia, nephritis, and pneumonitis. Most cases of liver injury are self-limiting and resolve within 1 to 2 months of stopping phenytoin. However, the liver injury can be severe and many fatal instances have been reported, phenytoin usually appearing in the top 10 causes of drug induced acute liver failure. In the typical case, however, recovery is usually complete.；Likelihood score: A (well known cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a log Kow of 2.47(2) and a regression-derived equation(3), indicates that phenytoin is expected to have moderate mobility in soil(SRC). Volatilization of phenytoin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.02X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Phenytoin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-10 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2007).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a log Kow of 2.47(2) and a regression-derived equation(3), indicates that phenytoin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.02X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 16(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2007).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phenytoin, which has an estimated vapor pressure of 1.2X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase phenytoin may be removed from the air by wet or dry deposition(SRC). Phenytoin does not absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Adverse effects potentially include the following:；* Rash；* Sedation；* Peripheral neuropathy；* Phenytoin encephalopathy；* Psychosis；* Locomotor dysfunction；* Hyperkinesia；* Megaloblastic anemia；* Decreased bone mineral content；* Stevens-Johnson syndrome；* Toxic epidermal necrolysis；* Immunoglobulin A deficiency；* Gingival hyperplasia；* Dress syndrome (drug reaction accompanied by eosinophilia and systemic symptoms)；* Cardiovascular collapse；* Hypotension；* Arrhythmias；* Hydantoin syndrome in newborns；* Purple glove syndrome

IDENTIFICATION: Phenytoin is an antiepileptic drug. Phenytoin is a white solid crystalline substance or a solid powder. It is odorless, and tasteless. It is soluble in water, alcohol and practically insoluble in chloroform, in ether and in methylene chloride. HUMAN EXPOSURE: Main risks and target organs: The intoxication usually manifests as mild central nervous system effects. More severe manifestations may be seen following massive overdose but fatalities are extremely rare. Summary of clinical effects: Onset of symptoms including lateral nystagmus, ataxia, and drowsiness occurs within 1 to 2 hours after ingestion and may persist for about 4 to 5 days. In more severe cases, horizontal nystagmus, coarse tremor and inability to walk may be observed. In very severe poisoning, conciousness is impaired but coma is rarely observed. Contraindications: Acute intermittent porphyria, hypersensitivity. Intravenous injection in patients with sino-atrial cardiac block, second- or third degree atrio-ventricular block, sinus bradycardia and Adam-Stokes syndrome. Caution is indicated in patients with uremia, hypoalbuminemia, liver function disorders and viral hepatitis. Routes of exposure: Oral: Most common route. Parenteral: Intravenously in status epilepticus. Absorption by route of exposure: Phenytoin is slowly, but almost completely absorbed from the gastro-intestinal tract; the rate of absorption is variable and its bioavailability can differ markedly with different pharmaceutical formulations. Large doses are more slowly absorbed. In severe oral poisoning, gastro-intestinal absorption may continue up to 60 hours. Administration of 100 mg orally to normal volunteers produced two peaks at 2.5 to 3.5 and 10 to 12 hours. Distribution by route of exposure: Phenytoin is widely distributed throughout the body and is extensively (87 to 93%) bound to protein. Plasma binding is almost exclusively to albumin; in individuals with normal plasma albumin concentration and in absence

Phenytoin displays its primary signs of toxicity on the nervous and cardiovascular systems. Overdose of oral phenytoin mainly causes neurotoxicity, whereas cardiovascular toxicity is the main side effect of parenteral administration.；Neurotoxicity；The neurotoxic effects are concentration-dependent and can range from mild nystagmus to ataxia, slurred speech, vomiting, lethargy, and eventually coma and death. The following is a generalized correlation of side effects with total plasma phenytoin concentrations (the value obtained via most laboratories):；* Below 10 mg/L: Rare side effects；* 10 to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze；* 20 to 30 mg/L: Nystagmus；* 30 to 40 mg/L: Ataxia, slurred speech, tremors, nausea, and vomiting；* 40 to 50 mg/L: Lethargy, confusion, hyperactivity；* Over 50 mg/L: Coma and seizures；Seizures are infrequent and usually occur at very high serum concentrations. The presence of seizures with phenytoin overdose should prompt the search for other causes.；Cardiac Toxicity；Phenytoin is a Class IB antiarrhythmic; its suppressant effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias as well as sinoatrial and atrioventricular blocks. These effects rarely occur with oral administration. However, in the intravenous form, the primary toxicity is believed to be from propylene glycol, which is a cardiac depressant; rapid infusions of phenytoin can lead to bradycardia, hypotension, and asystole. Care must be taken not to administer intravenous phenytoin at a rate faster than 50 mg per minute.；Other Toxicities；“Purple glove syndrome” is a rare side effect that can accompany the intravenous administration of phenytoin. The worsening limb edema and discoloration appear to result from the crystallization of phenytoin within the blood. When there is extensive skin necrosis and limb ischemia, this can lead to amputations.；Chronic Toxicity；Chronic intake of phenytoin can lead to megaloblastic anemia due to folate deficiency, peripheral neuropathy, or lupus-like syndrome. These are not commonly reported in acute overdoses.；Toxicokinetics；Due to its metabolism by the CP450 microsomal enzyme system, drugs that alter their function can place the patient at risk for toxicity by increasing the plasma phenytoin concentrations. These include amiodarone, cimetidine, cotrimoxazole, disulfiram, fluconazole, metronidazole, chloramphenicol, sodium valproate, 5-fluorouracil, and sulphonamides.；Management；There is no specific antidote for phenytoin toxicity; supportive care is the hallmark of treatment.

Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=57-41-0]

Phenytoin was detected in 5 treated sewage effluent samples collected from the Espanola sewage treatment plant in New Mexico from August and September 2000 and April 2001 at concentrations of 250 ng/L (ditch) and 300 ng/L (outfall)(1). The estimated amount of phenytoin in untreated wastewater in the United States is 2,700 ng/L(1).

Hazard Traits - Carcinogenicity; Developmental Toxicity；Authoritative List - IARC Carcinogens - 2B; NTP RoC - reasonable; Prop 65；Report - regardless of intended function of ingredient in the product

Status: Active Update: 30-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/18601

Phenytoin: Does not have an individual approval but may be used under an appropriate group standard

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

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

N03AB02

N - Nervous system；N03 - Antiepileptics；N03A - Antiepileptics；N03AB - Hydantoin derivatives；N03AB02 - Phenytoin

QN - Nervous system；QN03 - Antiepileptics；QN03A - Antiepileptics；QN03AB - Hydantoin derivatives；QN03AB02 - Phenytoin

N03AB02

Phenytoin is an anticonvulsant with a narrow therapeutic index. Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging. For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied). It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect. Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.

Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels. Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.

The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. Phenytoin blocks the voltage-dependant sodium channels of neurons and inhibits the calcium flux across neuronal membranes, thus helping to stabilize neurons. It also decreases synaptic transmission, and decreases post-tetanic potentiation at the synapse. Phenytoin enhances the sodium ATPase activity of neurons and/or glial cells. It also influences second messenger systems by inhibiting calcium-calmodulin protein phosphorylation and possibly altering cyclic nucleotide production or metabolism.

Phenytoin may act to normalize influx of sodium and calcium to cardiac Purkinje fibers. Abnormal ventricular automaticity and membrane responsiveness are decreased. Also, phenytoin shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential.

Exact mechanism is unknown. Phenytoin may act in the CNS to decrease synaptic transmission or to decrease summation of temporal stimulation leading to neuronal discharge (antikindling). Phenytoin raises the threshold of facial pain and shortens the duration of attacks by diminishing self-maintenance of excitation and repetitive firing.

Phenytoin's mechanisms of action as a muscle relaxant is thought to be similar to its anticonvulsant action. In movement disorders, the membrane stabilizing effect reduces abnormal sustained repetitive firing and potentiation of nerve and muscle cells.

A number of studies suggest that keratinocyte growth factor (KGF) plays a major part in reepithelialization after injury, via binding to the specific KGF receptor (KGFR). Several pharmacological agents, including the anti-epileptic drug phenytoin (PHT), have been widely used clinically to promote wound healing. Although the mechanism of action of PHT in this process is still not well understood, it is possible that the activity of PHT in wound healing is mediated via KGF and the KGFR. In the present study, using the enzyme-linked immunosorbant assay and flow cytometry we have shown that PHT increases KGF secretion and KGFR expression by more than 150% in gingival fibroblasts and epithelial cells, respectively. Moreover, semi-quantitative reverse transcriptase-polymerase chain reaction analysis showed that PHT also markedly increased both KGF and KGFR gene transcription by these cells.

Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average. Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.

Following oral administration, the plasma half-life of phenytoin averages about 22 hours, although the half-life has ranged from 7-42 hours in individual patients. The plasma half-life of phenytoin in humans following IV administration ranges from 10-15 hours.

Because phenytoin exhibits saturable, zero-order, or dose-dependent pharmacokinetics, the apparent half-life of phenytoin changes with dose and serum concentrations. this is due to the saturation of the enzyme system responsible for metabolizing phenytoin, which occurs at therapeutic concentrations of the drug. Thus, a constant amount of drug is metabolized (capacity-limited metabolism), and small increases in dose may cause disproportionately large increases in serum concentrations and apparent half-life, possibly causing unexpected toxicity.

Phenytoin is extensively metabolized and is first transformed into a reactive _arene oxide intermediate_. It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions. The _arene oxide_ is metabolized to either a _hydroxyphenytoin_ or _phenytoin dihydrodiol_ metabolite, although the former accounts for about 90% of phenytoin metabolism. Interestingly, two stereoisomers of the _hydroxyphenytoin_ metabolite are formed by CYP2C9 and CYP2C19: _(R)-p-HPPH_ and _(S)-p-HPPH_. When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer. Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes. EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the _phenytoin dihydrodiol_ metabolite. _Hydroxyphenytoin_ can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a _phenytoin catechol_ metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a _glucuronide metabolite_ that can be eliminated in the urine. On the other hand, the _phenytoin dihydrodiol_ entity is only transformed to the _catechol_ metabolite. The _catechol metabolite_ can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a _phenytoin quinone_ (NQO1 can transform the quinone back to the catechol metabolite). Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin. This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.

The major route of metabolism of phenytoin is oxidation by the liver to the inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Because this metabolism is a saturable process, small increases in dosage may produce substantial increases in plasma phenytoin concentrations...

The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. The major inactive metabolite of phenytoin is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Phenytoin may be metabolized slowly in a small number of individuals due to genetic predisposition, which may cause limited enzyme availability and lack of induction.

... Oxidative metabolism of 1 of geminal phenyl rings of diphenylhydantoin ... 5-meta-hydroxyphenyl-(l) and 5-para-hydroxyphenyl-5-phenylhydantoin were detected in urine of man (approx ratio 1:12) ...

Phenytoin has known human metabolites that include (2S,3S,4S,5R)-6-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-3,4,5-trihydroxyoxane-2-carboxylic acid, 4-Hydroxyphenytoin, 5-(3,4-dihydroxycyclohexa-1,5-dien-1-yl)-5-phenylimidazolidine-2,4-dione, and 3'-HPPH.

Primarily hepatic. The majority of the dose (up to 90%) is metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). This metabolite undergoes further glucuronidation and is excreted into the urine. CYP2C19 and CYP2C9 catalyze the aforementioned reaction. Route of Elimination: Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Half Life: 22 hours (range of 7 to 42 hours)

6158TKW0C5

PHENYTOIN

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Mechanisms of Action [MoA] - Cytochrome P450 1A2 Inducers

Mechanisms of Action [MoA] - Cytochrome P450 2B6 Inducers

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP1A2.

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing. Phenytoin is completely absorbed. Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively. It should be noted that absorption can be markedly prolonged in situations of acute ingestion.

The majority of phenytoin is excreted as inactive metabolites in the bile. An estimated 1-5% of phenytoin is eliminated unchanged in the urine.

The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.

The clearance of phenytoin is non-linear. At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics. As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.

Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract. Bioavailability may vary enough among oral phenytoin sodium preparations of different manufacturers to result in toxic serum concentrations or a loss of seizure control (subtherapeutic serum concentrations)...

Absorption of phenytoin is slow and variable among products (poor in neonates) for oral admininstration, immediate for iv administration, and very slow but complete (92%) for intramuscular administration.

MEDICATION (VET)

MEDICATION

Antiepileptic drug useful in the treatment of epilepsy.

THERAP CAT: Anticonvulsant; antiepileptic

THERAP CAT (vet): Anticonvulsant

Use (kg; approx.) in Germany (2009): >2500；Use (kg) in USA (2002): 80000；Consumption (g per capita; approx.) in Germany (2009): 0.0305；Consumption (g per capita) in the USA (2002): 0.284；Excretion rate: 0.05；Calculated removal (%): 24.6

From benzil, urea and NaOH: BILTZ, BER 41, 1391 (1908); 44, 411 (1911) /Phenytoin sodium/

Prepared from benzophenone: H. R. HENZE, US PATENT 2,409,754 (1946 TO Parke Davis).

Oral: Suspension: 125 mg/5 mL Dilantin-125 (with alcohol <0.6%), (Pfizer), Phenytoin Oral Suspension (with <0.6% alcohol), (Actavis), Phenytoin Oral Suspension (with <0.6% alcohol), (Morton Grove), Phenytoin Oral Suspension (with <0.6% alcohol), (UDL), Phenytoin Oral Suspension (with <0.6% alcohol), (Vistapharm), Phenytoin Oral Suspension (with <0.6% alcohol), (Xactdose). Tablets, chewable: 50 mg Dilantin Infatabs, (Pfizer).

DILANTIN