PHENYTOIN

Phenytoin and ethotoin are used for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures. Phenytoin is also used for the prevention and treatment of seizures which may occur during or following neurosurgery (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info Dilantin(R) intravenous injection solution, 2011; Prod Info PEGANONE(R) oral tablets, 2009).
RECREATIONAL USE: There have been several reports in the literature of phenytoin being used as a recreational drug. Phenytoin was combined with crack cocaine and smoked (Jessen, 2004). In one case, a man ingested several crack cocaine rocks adulterated with phenytoin (Roldan, 2014). In one case, a young adult "sipped syrup" (phenytoin), smoked marijuana and drank alcohol to elicit a "high" and developed symptoms associated with phenytoin toxicity (Jessen, 2004).

FORMS

PHENYTOIN

Phenytoin 50 mg chewable tablet (Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
Phenytoin oral suspension in concentrations of 125 mg/5 mL (Prod Info Dilantin-125(R) oral suspension, 2011).
Phenytoin sodium extended-release capsules 30 mg and 100 mg (Prod Info DILANTIN(R) oral extended release capsules, 2011; Prod Info DILANTIN(R) extended capsule, oral, 2009).
Phenytoin sodium parenteral solution 50 mg/mL (Prod Info Dilantin(R) intravenous injection solution, 2011).

ETHOTOIN

Ethotoin is available as 250 mg scored tablets (Prod Info PEGANONE(R) oral tablets, 2009).

SOURCES

Phenytoin sodium covers various anticonvulsant preparations, most notably Dilantin(R). Generic phenytoin preparations often exhibit erratic kinetics. Calculations based on kinetic parameters for Dilantin Kapseals(R) will frequently be wrong with overdoses of generic phenytoin.

-CLINICAL EFFECTS

GENERAL CLINICAL EFFECTS

This management includes phenytoin and ethotoin, both in the hydantoin class of anticonvulsants; however, phenytoin will be the primary drug discussed. Fosphenytoin is covered in a separate management.

USES: Phenytoin is primarily used as an anticonvulsant, both for status epilepticus and for seizure prevention.

PHARMACOLOGY: Phenytoin stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during nerve impulse generation.

TOXICOLOGY: Phenytoin prolongs effective refractory period and suppresses ventricular pacemaker automaticity, thus shortening the action potential in the heart. The intravenous form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol at a pH of 12. This formulation can have its own toxicity secondary to cardiac toxicity of propylene glycol (mechanism unknown) and tissue necrosis from infiltration (secondary to the alkaline nature of the formulation).

EPIDEMIOLOGY: There are thousands of exposures reported to poison centers every year, as it is a widely used anticonvulsant. However, deaths are extremely rare and severe manifestations occur in only a minority of cases.

WITH POISONING/EXPOSURE

MILD TO MODERATE TOXICITY: Nausea and vomiting may develop early after overdose. Nystagmus, ataxia, and mild CNS depression are common.
SEVERE TOXICITY: Large oral ingestions can cause more severe CNS depression, coma, and, rarely, respiratory depression. Rapid infusion of the parenteral formulation (faster than 50 mg/min) can cause hypotension, bradycardia, AV conduction delays, and ventricular dysrhythmias which may be fatal. It is felt that the cardiotoxicity of the intravenous formulation of phenytoin is secondary to the diluent, propylene glycol, and not the phenytoin itself.

WITH THERAPEUTIC USE

Significant adverse effects seen from intravenous use of phenytoin include venous irritation and pain, and thrombophlebitis. Extravasation can cause tissue necrosis. Adverse effects unrelated to plasma phenytoin levels include hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, and systemic lupus erythematosus (SLE). Some rarely seen but important adverse reactions include blood dyscrasias, dyskinesias, hepatitis, lymphadenopathy, lymphoma, pseudolymphoma, SLE-like syndrome, Steven-Johnson Syndrome, and toxic epidermal necrolysis.
Phenytoin is a known teratogen. Fetal hydantoin syndrome is characterized by microcephaly, mental retardation, craniofacial abnormalities, and digital hypoplasia. It occurs in 10% to 30% of exposed pregnancies.

Editor's Note: An ERG guide with information appropriate to this material does not exist.

ACUTE CLINICAL EFFECTS

SUMMARY

This management includes phenytoin and ethotoin, both in the hydantoin class of anticonvulsants; however, phenytoin will be the primary drug discussed. Fosphenytoin is covered in a separate management.
PHARMACOLOGY: Phenytoin stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during nerve impulse generation.
TOXICOLOGY: Phenytoin prolongs effective refractory period and suppresses ventricular pacemaker automaticity, thus shortening the action potential in the heart. The intravenous form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol at a pH of 12. This formulation can have its own toxicity secondary to cardiac toxicity of propylene glycol (mechanism unknown) and tissue necrosis from infiltration (secondary to the alkaline nature of the formulation).
EPIDEMIOLOGY: There are thousands of exposures reported to poison centers every year, as it is a widely used anticonvulsant. However, deaths are extremely rare and severe manifestations occur in only a minority of cases.
MILD TO MODERATE TOXICITY: Nausea and vomiting may develop early after overdose. Nystagmus, ataxia, and mild CNS depression are common.
SEVERE TOXICITY: Large oral ingestions can cause more severe CNS depression, coma, and, rarely, respiratory depression. Rapid infusion of the parenteral formulation (faster than 50 mg/min) can cause hypotension, bradycardia, AV conduction delays, and ventricular dysrhythmias which may be fatal. It is felt that the cardiotoxicity of the intravenous formulation of phenytoin is secondary to the diluent, propylene glycol, and not the phenytoin itself.
ADVERSE EFFECTS: Significant adverse effects seen from intravenous use of phenytoin include venous irritation and pain, and thrombophlebitis. Extravasation can cause tissue necrosis. Adverse effects unrelated to plasma phenytoin levels include hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, and systemic lupus erythematosus (SLE). Some rarely seen but important adverse reactions include blood dyscrasias, dyskinesias, hepatitis, lymphadenopathy, lymphoma, pseudolymphoma, SLE-like syndrome, Steven-Johnson Syndrome, and toxic epidermal necrolysis. Phenytoin is a known teratogen. Fetal hydantoin syndrome is characterized by microcephaly, mental retardation, craniofacial abnormalities, and digital hypoplasia. It occurs in 10% to 30% of exposed pregnancies.

Phenytoin is an anticonvulsant and antiarrhythmic agent. Therapeutic serum levels are usually in the range of 10 to 20 mcg/mL (Prod Info Dilantin(R), phenytoin, 1994; Hvidberg & Dam, 1976a; Eadie, 1976; Vajda, 1970). The oral dose may vary from an initial intake of 100 mg/day (3 to 4 mg/kg/day), incremented at weekly or biweekly intervals up to 300 to 600 mg/day. Higher initial loading doses are sometimes used in order to achieve therapeutic serum levels more quickly (Prod Info Dilantin(R), phenytoin, 1994; AMA, 1983).

In acute oral overdose, peak serum levels may not occur for 2 to 7 DAYS following ingestion, and toxic serum levels may persist for 2 WEEKS (Wilson et al, 1979) Gill et al, 1978; Albertson et al, 1981).

Because most cases of exposure to phenytoin involve long-term therapy, true acute versus chronic toxicity may be difficult to distinguish. Signs and symptoms have been divided here into groups with a primary acute phase versus those of a more chronic nature or which would be known to require previous exposure (this division may be somewhat artificial).

While there can be interindividual variation, signs of toxicity generally occur at serum levels exceeding 20 mcg/mL. Nystagmus on lateral gaze can appear at levels about 20 mcg/mL, ataxia at 30 mcg/mL, and mental changes, dysarthria, and lethargy at levels of 40 mcg/mL and above (Kutt, 1964; Prod Info Dilantin(R), phenytoin, 1994) Jacobsen et al, 1986-87). Encephalopathy may occur with either therapeutic or toxic serum levels (Ambrosetto et al, 1977; (Prod Info Dilantin(R), phenytoin, 1994; AMA, 1983). However, toxicity has been absent in patients with serum levels as high as 50 mcg/mL (Prod Info Dilantin(R), phenytoin, 1994).

Appearance of phenytoin toxicity is more strongly associated with the serum level of free, or unbound, phenytoin than total phenytoin. In one study, 85.7% of cases of phenytoin toxicity had free concentrations greater than 8 mcmol/L, while only 42.9% had total phenytoin serum levels greater than 80 mcmol/L (Peterson et al, 1991).

Fatalities from phenytoin sodium overdose are rare, but have occurred (Laubscher, 1966). A dose of 2 grams was fatal in a 7-year-old boy, and also in a 4.5-year-old girl (Schmeiser, 1952; Laubscher, 1966). Ingestion of 3.2 grams was fatal in a 3-year-old boy (Petty et al, 1957).

Adult fatalities from ingestion have been suicides (Tichner & Enselberg, 1951; Coutselinis et al, 1975). Adults have survived ingestions in excess of 20 grams (Theil et al, 1961; Nauth-Misir, 1948).

Phenytoin is a CNS depressant. In acute overdose, it can induce nausea, vomiting, epigastric pain, loss of appetite, dizziness, ataxia (staggering gait), nystagmus, lethargy, diplopia, blurred vision, mydriasis, hyperactive tendon reflexes, tremor, hyperactivity, drowsiness, hallucinations, confusion, respiratory depression, apnea, and coma (HSDB , 1995) Laubscher, 1966). Other CNS effects from acute exposure include chronic movement disorders (Kurata et al, 1988);

Rapid IV phenytoin injection can produce cardiovascular toxicity, including hypotension, bradycardia, atrial and ventricular conduction abnormalities, ventricular fibrillation, and cardiac arrest (Prod Info Dilantin(R), phenytoin, 1994) Barron, 1976; Earnest et al, 1983; (Blumson & Seabrook, 1970) Goldschlager & Karliner, 1967; Gellerman & Martinez, 1967). Cardiotoxicity under these conditions may be due to PROPYLENE GLYCOL in the injectable solution, or to pre-existing heart conditions or interaction with other drugs.

Phenytoin acts by depressing spontaneous depolarization in the heart tissue and by stabilizing all neuronal membranes (HSDB , 1995).

A hypoglycemia reaction to phenytoin was reported in one case where the patient was also receiving zopliclone (Manto et al, 1996).

Phenytoin can form .OH radicals in vivo after single doses of 65 or 100 mg/kg; radical formation was inferred from detection of 2,3-dihydrobenzoic acid from acetylsalicylic acid. This is the first in vivo evidence that hydroxyl radical formation may be involved in the toxicity of phenytoin (Kim & Wells, 1996).

One case of cerebellar atrophy following a single acute episode of phenytoin intoxication has been reported (Kuruvilla & Bharucha, 1996).

DRUG INTERACTION

Phenytoin is an enzyme inducer and can alter the metabolism of other substances. This may have the effect of increasing the toxicity of other substances, if their metabolites are more toxic, or of decreasing the activity if the metabolites are less active.
Phenytoin can interact with many drugs and chemicals. Among these are:
ACETAMINOPHEN: Phenytoin increases its metabolism by more than 40% and decreases its half-life by approximately 25%. Patients may be at greater risk of acetaminophen toxicity when taking phenytoin concurrently (Miners et al, 1984).
ACETYLDIGOXIN: Phenytoin has been reported to increase the metabolism of DIGOXIN (Rameis, 1985). Patients on concurrent phenytoin therapy may be LESS sensitive to digoxin.
ASPIRIN: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
CHLORAMPHENICOL: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
CHLORDIAZEPOXIDE: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
CORTICOSTEROIDS: Phenytoin increases the hepatic metabolism and decreases effectiveness of dexamethasone, fludrocortisone, methylprednisolone, and prednisone (Keilholz & Guthrie, 1986; Petereit & Meikle, 1977; McLelland & Jack, 1978).
DOXYCYCLINE: Phenytoin results in a shorter half-life for doxycycline and lower serum levels (Neuvonen et al, 1975; Penttila et al, 1974).
ESTROGENS: Anticonvulsants may decrease the effect of estrogens by accelerating estrogen metabolism (Gilman et al, 1990; (Notelovitz et al, 1981; Hempel & Klinger, 1976; Janz & Schmidt, 1974).
FUROSEMIDE: Phenytoin may decrease the diuretic response to furosemide (Ahmad, 1974; Fine et al, 1977).
HALOPERIDOL: Anticonvulsants can significantly lower haloperidol blood levels (Linnoila et al, 1980).
HALOTHANE: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
METHYLPHENIDATE: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
ORAL CONTRACEPTIVES: Efficacy is diminished when taken in conjunction with phenytoin.
PHENYRAMIDOL: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996).
STREPTOZOCIN: Concomitant administration of phenytoin negated the cytotoxicity of streptozocin in one case (Koranyi & Gero, 1979).
VITAMIN D: Concomitant administration of phenytoin and vitamin D (cholecalciferol) caused a decrease in the activity of vitamin D (Anon, 1985).
WARFARIN: Increased toxicity is seen with phenytoin, due to enhancement of metabolism of the former into active metabolites (HSDB, 1996). These results are controversial (Hansten, 1984).

CHRONIC CLINICAL EFFECTS

Potentially fatal hypersensitivity reactions have occurred to phenytoin. Symptoms of PHENYTOIN SYNDROME include fever, malaise, rash, facial edema, erythroderma, toxic epidermal necrolysis, lymphadenopathy, hepatitis, anemia, pharyngitis, diarrhea, anorexia, nephritis, anemia, Stevens-Johnson syndrome, acute interstitial pneumonitis with fever, dyspnea, hypoxemia, and pulmonary infiltrates (HSDB , 1995; Tomsick, 1983; Schmidt & Kluge, 1983; Flowers et al, 1987) (Helmy & Tripplet, 1988). Symptoms generally appear within 2 to 3 weeks after initiation of therapy.

Phenytoin-induced lymphadenopathy can include benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease (Prod Info Dilantin(R), phenytoin, 1994; Choovivathanavanich, 1970; Oates & Tonge, 1971; Biechel, 1975).
One case of hypersensitivity reaction involved hepatitis, proximal arm weakness, severe myalgia, high serum creatine kinase, and myopathy (Harney & Glasberg, 1983). Hypersensitivity myocarditis has been reported as a rare complication (Fenoglio et al, 1981; Taliercio et al, 1985). Allergic dermatitis has been noted with repeated exposure to phenytoin (RTECS , 1995).
The hypersensitivity reaction to phenytoin has been reviewed (Flowers et al, 1987).

Phenytoin can also invoke autoimmune dysfunction. Acute arthritis developed in response to phenytoin in one elderly patient (Stalnikowicz et al, 1982). Phenytoin can also induce systemic lupus erythematosus and myesthenia gravis (Benton, 1962; Goldstein, 1963; Rallison, 1961; Lee, 1966; Jacobs, 1963; Adams et al, 1984).

Phenytoin can affect both cellular and humoral immunity. Reversible IgA deficiency is most common; levels fall within 3 to 6 months after initiation of therapy (Travin et al, 1989) (Basaran, 1994).

Reversible gingival hyperplasia (swelling of the gums) occurs in approximately 20% of patients receiving phenytoin in chronic therapy (HSDB , 1995) (Grant et al, 1988).

Effects on the blood include leukopenia, neutropenia, thrombocytopenia (with CIMETIDINE), agranulocytosis, eosinophilia, pancytopenia with abnormal immune function, and aplastic anemia (Tsan, 1976; Robins, 1962; Tomita et al, 1985; Menitove, 1981) (Wong et al, 1985a) (Yue et al, 1987).

Phenytoin is a CNS-active agent; many of the effects of chronic exposure involve the central nervous system. An unusual form of toxicity is PHENYTOIN ENCEPHALOPATHY, characterized by increasing seizures, EEG changes, alteration in mental function, and certain motor and sensory disturbances (VanDerLinde & Campbell, 1977) Shuttleworth et al, 1974; (Vallarta, 1974).

Other CNS effects include seizures, delusions, violent aggressive behavior, reversible choreoathetosis (abnormal or jerky movements, lip smacking, continuous tongue movements, slurred speech, ataxia, dysarthria and dystonic posturing), tardive dyskinesia (Ambrosetto et al, 1977; Arrellano-Isaac & Rivera-Calimlim, 1978; Chalhub & DeVivo, 1976; Zinsmeister & Marks, 1976; Luhdorf & Lund, 1977; Rasmussen & Kristensen, 1977; Rosenblum et al, 1974; Kooiker & Sumi, 1974; McLellan & Swash, 1974; Krishnamoorthy et al, 1983; Shuttleworth et al, 1974; Filloux & Thompson, 1987; DeVeaugh-Geiss, 1978).
Loss of mobility, slurred speech, abnormal EEGs, motor dysfunction, monoplegia, and peripheral neuropathy, have been reported with long-term phenytoin therapy (Selhorst, 1972; Lusins & Jutkowitz, 1972) (Abdulhadi et al, 1987). Extreme cases can involve irreversible cerebellar atrophy, degeneration, or necrosis (Baier et al, 1985) (Botez et al, 1985) (Cochat et al, 1987) (McLain et al, 1980) (Lindvall et al, 1984).
Neuromuscular disorders have been seen with long-term phenytoin therapy (Mochizuki, 1981). Abnormal eye movements can occur with phenytoin treatment. These include nystagmus (oscillating eyes) and ophthalmoplegia (inability to move eyes) (Anon, 1971; Daroff, 1977; Kutt, 1964; Sandyk, 1984). Phenytoin-induced chorea has been well described in the medical literature. In one case, unilateral chorea was linked to a structural lesion in the contralateral putamen, visualized by MRI, in a man who had been treated with 300 mg/day phenytoin for 30 years; the chorea ceased upon withdrawal of phenytoin (Shulman et al, 1996).
Development of peripheral neuropathy after chronic phenytoin therapy may be due to phenytoin-induced folate deficiency at the tissue or cellular level, but this has not been proven (So & Penry, 1981).

Up to 50% of institutionalized epileptics receiving anticonvulsant therapy (including phenytoin) develop osteomalacia or rickets with hypocalcemia and elevated alkaline phosphatase levels (Richens & Rowe, 1970; Hahn & Halstead, 1979; Eastwood et al, 1980; Morijiri & Sato, 1981; Ashworth & Horn, 1977). This may be due to lack of sunlight and/or induction of hepatic enzymes which inactivate vitamin D (Hoikka et al, 1982; Fogelman, 1982; Hunter et al, 1971; Zerwekh, 1982).

Elevated liver function tests in the absence of other signs of liver injury develop in approximately 25 to 30% of patients receiving chronic phenytoin therapy. Induction of potentially fatal hepatotoxicity, accompanied by fever, rash, eosinophilia, and leukocytosis, is a rare hypersensitivity reaction (Mullick & Ishak, 1980). Fatal hepatic necrosis has been reported in a patient who had received phenytoin for 1 month (Chien, 1970).

Interstitial nephritis accompanied by hepatomegaly, palpable spleen, lymphadenopathy, lethargy, fever, rash, eosinophilia, eosinophils in the urine, proteinuria, and a rise in serum creatinine, has developed within 5 to 30 days after initiation of phenytoin therapy, and may progress after discontinuation (Hoffman, 1981; Sheth, 1977). Phenytoin-induced interstitial nephritis is thought to develop by an immunologic mechanism (Hoffman, 1981). Reversible nephrotic syndrome has been seen in one case (Orlandini & Garini, 1989).

Other effects reported with chronic therapy include hyperglycemia, acute porphyria, cataracts, and respiratory failure (Fariss & Lutcher, 1971; Treasure & Toseland, 1971; Bazemore & Zuckermann, 1974) (Shuttleworth et al, 1974) (Mathers et al, 1987) (Mahatma et al, 1989).

Psychological changes may be an early sign of phenytoin toxicity (Larsen & Larsen, 1989). Effects noted are vegetative depression, organic mania, hallucinations, and confusion (Garrison & Henson, 1990; Dommisse, 1990; Grosz, 1956; Miller, 1988; Phelps et al, 1993). One case of toxic epidermal necrolysis involved 60 to 70% of the skin and left the patient with disabling ocular complications (Creamer et al, 1996).

WITHDRAWAL from phenytoin has induced psychotic symptoms including hallucinations, agitation, fear, and delusions (Demers-Desrosiers, 1978).

-FIRST AID

FIRST AID AND PREHOSPITAL TREATMENT

ACTIVATED CHARCOAL

PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

CHARCOAL DOSE

Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

ADVERSE EFFECTS/CONTRAINDICATIONS

Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

-RANGE OF TOXICITY

MINIMUM LETHAL EXPOSURE

GENERAL

ORAL: Estimates of the minimal lethal dosage are unreliable. Deaths are very rare even with massive acute oral overdosage and have been reported mostly with the relatively serious hypersensitivity reactions seen with chronic use. The lowest published lethal dose in a human child is 100 mg/kg (RTECS , 2001).

CASE REPORTS

PEDIATRIC

One 7-year-old boy who ingested 2 g phenytoin (100 mg/kg) presented comatose, but later developed vigorous motor activity, tetanic spasms, and Kussmaul respirations. He died 42 hours postingestion (Schmeiser, 1952).
A 4.5-year-old girl ingested 2 g phenytoin (160 mg/kg), and hyperactivity was the first sign of intoxication, but this progressed to ataxia, miosis, epigastric pain, and generalized pruritus. Later the ataxia worsened with the patient becoming lethargic and unresponsive and she lapsed into a coma. Eighty hours after the onset of symptoms the patient died (Laubscher, 1966).
A 3-year-old boy who ingested 3.2 g phenytoin (220 mg/kg) became lethargic, then comatose without reflexes. He experienced several minor seizures and died 34 hours postingestion (Petty et al, 1957).

ADULT

CHRONIC THERAPY: A 35-year-old man with a history of traumatic brain injury, epilepsy and pulmonary tuberculosis in a vegetative state developed severe cardiotoxicity (ie, junctional bradycardia, hypotension) after receiving phenytoin 200 mg twice daily for approximately 5 months. After transvenous pacing and intensive supportive care, the patient returned to baseline within 2 weeks (Su et al, 2009). The authors suggested that underlying metabolic derangements and a possible drug interaction (receiving an anti-TB agent) may have contributed to phenytoin toxicity in this patient.
ACUTE: Two adult men, a 37-year-old and an 18-year-old, were found dead in their homes after taking overdoses of phenytoin the previous evening. Phenytoin serum concentrations in each patient several hours postmortem were 45 mcg/mL and 48 mcg/mL, respectively (Coutselinis et al, 1975).

ROUTE OF EXPOSURE

INTRAVENOUS: Death may be seen after rapid intravenous administration of phenytoin from severe hypoperfusion with intractable shock, cardiac standstill, ventricular fibrillation, or respiratory arrest. These effects are nearly always rate related (Prod Info Dilantin(R) intravenous injection solution, 2011).

MAXIMUM TOLERATED EXPOSURE

GENERAL

Many cases of mild to moderately acute overdoses with phenytoin are reported. Also a few cases of acute overdose are reported in which patients survived ingestion of large amounts of oral phenytoin.

CASE REPORTS

ADULT

ORAL TOXICITY

There have been reports in the literature of adults ingesting between 4.5 g (Robinson, 1940; Black et al, 1987; Weichbrodt & Elliott, 1987; Blair et al, 1968; Miller et al, 2006; Theil et al, 1961; Grosz, 1956) up to 25 g of phenytoin (Nauth-Misir, 1948).
A 20-year-old epileptic male ingested 15 g of primidone and 12 g of phenytoin (17 mg/kg), and had a phenytoin plasma concentration of 130 mcg/mL approximately 96 hours after ingestion. Peritoneal dialysis was begun and phenytoin plasma concentrations decreased from 130 mcg/mL to 30 mcg/mL over a 12-hour period, with recovery of greater than 450 mg phenytoin in the dialysate. In this case, it appears that peritoneal dialysis contributed to the lowering of phenytoin plasma concentrations (Blair et al, 1968).
An 18-year-old pregnant epileptic ingested phenobarbital 2.4 grams and phenytoin 21.5 grams. At 138 hours postingestion the phenytoin concentration was 50 mcg/mL. Because of a lack of improvement in the patient's condition, she received hemodialysis for 6 hours. Phenytoin plasma concentrations dropped from 50 mcg/mL to 4 mcg/mL following dialysis. Although attempts to measure phenytoin in the dialysate were unsuccessful, it appears that dialysis contributed to the decrease in phenytoin concentrations (Theil et al, 1961).
A 15-year-old boy with absence seizures ingested 19.6 g of phenytoin. The peak phenytoin concentration occurred 2 days postingestion and was 100.8 mcg/mL (Mellick et al, 1989).
A 38-year-old man with a history of a right ganglia hemorrhage, seizures and diabetes mellitus ingested an unknown amount of alcohol and 10 g of phenytoin (133 mg/kg) and was initially alert and complaining of nausea and vomiting with evidence of ataxia. Serum phenytoin concentration peaked on day 15 at 90 mcg/mL. Despite aggressive supportive care including whole bowel irrigation (ileus developed and treatment was stopped) and charcoal hemoperfusion, the patient had persistently elevated phenytoin concentrations and progressing cerebellar toxicity. Phenytoin concentrations eventually dropped with the administration of multidose charcoal, but the patient was discharged to a rehabilitation center 100 days after admission with permanent cerebellar dysfunction (Craig, 2004).
A 32-year-old man presented to the ED with ataxia and nystagmus 1 hour after ingesting approximately 17.5 g of phenytoin. Despite decontamination with activated charcoal, the patient's serum phenytoin concentration peaked at 96 mg/L approximately 7 hours postingestion. Over the next several days, the patient was intubated, due to obtundation and a risk of aspiration following emesis. His phenytoin concentrations also fluctuated following hemodialysis and hemoperfusion sessions, although his clinical status remained unchanged. Gradually, his phenytoin concentration decreased and he was extubated. Over the next year, the patient continued to experience residual cognitive and functional impairment which slowly improved with rehabilitation (Miller et al, 2006).

INTRAVENOUS TOXICITY

INADVERTENT EXPOSURE: A peak phenytoin plasma concentration of 117 mg/L was reported in a 35-year-old woman after receiving a cumulative phenytoin intravenous dose of approximately 3150 mg over 48 hours. She developed symptoms of violent agitation, confusion, drowsiness with nystagmus, dysarthria and cerebellar ataxia. The patient recovered completely following several sessions of hemodialysis and hemoperfusion (Eyer et al, 2008).
Following a change in phenytoin oral dosing (100 mg 3 times per day) to the same dose given intravenously, phenytoin toxicity was reported in a 52-year-old man 5 days later. Neurologic findings, including mandibular tremor, encephalopathy and nystagmus (not related to his hydrocephalus) were reported, as well as a phenytoin serum concentration of 42 mcg/mL (Turkdogan et al, 2002).

PEDIATRIC

A 2.5-year-old boy ingested approximately 2.8 g phenytoin suspension (249 mg/kg). At 70 hours postingestion, the phenytoin plasma concentration was 112 mcg/mL. Peritoneal dialysis was begun and 16 hours later the concentration dropped to 75 mcg/mL. After 36 hours of dialysis the phenytoin serum concentration was 35 mcg/mL. However, analysis of the dialysis showed only "trace" phenytoin. The contribution of the dialysis to the lowering of the plasma concentrations in the patient is questionable based on the dialysate findings and the slow decrease in phenytoin concentrations (Tenckhoff et al, 1968).

OTHER

Severe phenytoin intoxication may result from altered protein binding associated with disease states. Agitation, lethargy, lack of response to deep pain, and bilateral clonus developed in a 25-year-old HIV positive woman while receiving a maintenance dose of phenytoin of 400 mg/day. Her total serum phenytoin concentration was 10.9 mcg/mL with a free phenytoin concentration of 4.9 mcg/mL (normal 1 to 2 mcg/mL) (Toler et al, 1990).

Carcinogenicity Ratings for CAS57-41-0 :

ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
EPA (U.S. Environmental Protection Agency, 2011): Not Listed
IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Phenytoin

2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
MAK (DFG, 2002): Not Listed
NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

Carcinogenicity Ratings for CAS630-93-3 :

ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
EPA (U.S. Environmental Protection Agency, 2011): Not Listed
IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
MAK (DFG, 2002): Not Listed
NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

TOXICITY AND RISK ASSESSMENT VALUES

EPA IRIS

EPA Risk Assessment Values for CAS57-41-0 (U.S. Environmental Protection Agency, 2011):

Not Listed

EPA Risk Assessment Values for CAS630-93-3 (U.S. Environmental Protection Agency, 2011):

Not Listed

TOXICITY VALUES

PHENYTOIN
- LD50- (INTRAVENOUS)DOG:
- LD50- (INTRAVENOUS)MOUSE:
- LD50- (ORAL)MOUSE:
- LD50- (INTRAVENOUS)RABBIT:
- LD50- (ORAL)RABBIT:
- LD50- (INTRAVENOUS)RAT:
- LD50- (ORAL)RAT:

-STANDARDS AND LABELS

WORKPLACE STANDARDS

ACGIH TLV Values for CAS57-41-0 (American Conference of Governmental Industrial Hygienists, 2010):

Not Listed

ACGIH TLV Values for CAS630-93-3 (American Conference of Governmental Industrial Hygienists, 2010):

Not Listed

AIHA WEEL Values for CAS57-41-0 (AIHA, 2006):

Not Listed

AIHA WEEL Values for CAS630-93-3 (AIHA, 2006):

Not Listed

NIOSH REL and IDLH Values for CAS57-41-0 (National Institute for Occupational Safety and Health, 2007):

Not Listed

NIOSH REL and IDLH Values for CAS630-93-3 (National Institute for Occupational Safety and Health, 2007):

Not Listed

OSHA PEL Values for CAS57-41-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

Not Listed

OSHA PEL Values for CAS630-93-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

Not Listed

OSHA List of Highly Hazardous Chemicals, Toxics, and Reactives for CAS57-41-0 (U.S. Occupational Safety and Health Administration, 2010):

Not Listed

OSHA List of Highly Hazardous Chemicals, Toxics, and Reactives for CAS630-93-3 (U.S. Occupational Safety and Health Administration, 2010):

Not Listed

ENVIRONMENTAL STANDARDS

EPA CERCLA, Hazardous Substances and Reportable Quantities for CAS57-41-0 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA CERCLA, Hazardous Substances and Reportable Quantities for CAS630-93-3 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA CERCLA, Hazardous Substances and Reportable Quantities, Radionuclides for CAS57-41-0 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA CERCLA, Hazardous Substances and Reportable Quantities, Radionuclides for CAS630-93-3 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA RCRA Hazardous Waste Number for CAS57-41-0 (U.S. Environmental Protection Agency, 2010b):

Not Listed
Editor's Note: The D, F, and K series waste numbers and Appendix VIII to Part 261 -- Hazardous Constituents were not included. Please refer to 40 CFR Part 261.

EPA RCRA Hazardous Waste Number for CAS630-93-3 (U.S. Environmental Protection Agency, 2010b):

Not Listed
Editor's Note: The D, F, and K series waste numbers and Appendix VIII to Part 261 -- Hazardous Constituents were not included. Please refer to 40 CFR Part 261.

EPA SARA Title III, Extremely Hazardous Substance List for CAS57-41-0 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA SARA Title III, Extremely Hazardous Substance List for CAS630-93-3 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA SARA Title III, Community Right-to-Know for CAS57-41-0 (40 CFR 372.65, 2006; 40 CFR 372.28, 2006):

Listed as: Phenytoin
Effective Date for Reporting Under 40 CFR 372.30: 1/1/95
Lower Thresholds for Chemicals of Special Concern under 40 CFR 372.28:

EPA SARA Title III, Community Right-to-Know for CAS630-93-3 (40 CFR 372.65, 2006; 40 CFR 372.28, 2006):

Not Listed

DOT List of Marine Pollutants for CAS57-41-0 (49 CFR 172.101 - App. B, 2005):

Not Listed

DOT List of Marine Pollutants for CAS630-93-3 (49 CFR 172.101 - App. B, 2005):

Not Listed

EPA TSCA Inventory for CAS57-41-0 (EPA, 2005):

Listed as: 2,4-Imidazolidinedione, 5,5-diphenyl-, monosodium salt

EPA TSCA Inventory for CAS630-93-3 (EPA, 2005):

Listed as: 2,4-Imidazolidinedione, 5,5-diphenyl-, monosodium salt

LABELS

NFPA

NFPA Hazard Ratings for CAS57-41-0 (NFPA, 2002):

Not Listed

NFPA Hazard Ratings for CAS630-93-3 (NFPA, 2002):

Not Listed

-PERSONAL PROTECTION

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

PROTECTIVE CLOTHING

CHEMICAL PROTECTIVE CLOTHING. Search results for CAS 57-41-0.

Specific recommendations and test data for this chemical were not found in the available manufacturers' product literature. A complete list of consulted manufacturers and references is presented below.

CHEMICAL PROTECTIVE CLOTHING. Search results for CAS 630-93-3.

Specific recommendations and test data for this chemical were not found in the available manufacturers' product literature. A complete list of consulted manufacturers and references is presented below.

-PHYSICAL HAZARDS

FIRE HAZARD

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

FLAMMABILITY CLASSIFICATION

NFPA Flammability Rating for CAS57-41-0 (NFPA, 2002):

Not Listed

NFPA Flammability Rating for CAS630-93-3 (NFPA, 2002):

Not Listed

FIRE CONTROL/EXTINGUISHING AGENTS

Editor's Note: An ERG guide with information appropriate to this material does not exist.

NFPA Extinguishing Methods for CAS57-41-0 (NFPA, 2002):

Not Listed

NFPA Extinguishing Methods for CAS630-93-3 (NFPA, 2002):

Not Listed

EVACUATION PROCEDURES

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

AIHA ERPG Values for CAS57-41-0 (AIHA, 2006):

Not Listed

AIHA ERPG Values for CAS630-93-3 (AIHA, 2006):

Not Listed

DOE TEEL Values for CAS57-41-0 (U.S. Department of Energy, Office of Emergency Management, 2010):

Not Listed

DOE TEEL Values for CAS630-93-3 (U.S. Department of Energy, Office of Emergency Management, 2010):

Not Listed

AEGL Values for CAS57-41-0 (National Research Council, 2010; National Research Council, 2009; National Research Council, 2008; National Research Council, 2007; NRC, 2001; NRC, 2002; NRC, 2003; NRC, 2004; NRC, 2004; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; United States Environmental Protection Agency Office of Pollution Prevention and Toxics, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; 62 FR 58840, 1997; 65 FR 14186, 2000; 65 FR 39264, 2000; 65 FR 77866, 2000; 66 FR 21940, 2001; 67 FR 7164, 2002; 68 FR 42710, 2003; 69 FR 54144, 2004):

Not Listed

AEGL Values for CAS630-93-3 (National Research Council, 2010; National Research Council, 2009; National Research Council, 2008; National Research Council, 2007; NRC, 2001; NRC, 2002; NRC, 2003; NRC, 2004; NRC, 2004; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; United States Environmental Protection Agency Office of Pollution Prevention and Toxics, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; 62 FR 58840, 1997; 65 FR 14186, 2000; 65 FR 39264, 2000; 65 FR 77866, 2000; 66 FR 21940, 2001; 67 FR 7164, 2002; 68 FR 42710, 2003; 69 FR 54144, 2004):

Not Listed

NIOSH IDLH Values for CAS57-41-0 (National Institute for Occupational Safety and Health, 2007):

Not Listed

NIOSH IDLH Values for CAS630-93-3 (National Institute for Occupational Safety and Health, 2007):

Not Listed

CONTAINMENT/WASTE TREATMENT OPTIONS

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

SMALL LEAK/SPILL

Editor's Note: An ERG guide with information appropriate to this material does not exist.

LARGE LEAK/SPILL

Editor's Note: An ERG guide with information appropriate to this material does not exist.

-PHYSICAL/CHEMICAL PROPERTIES

MOLECULAR WEIGHT

Phenytoin: 252.26

Ethotoin: 204.2

Mephenytoin: 218.3

DESCRIPTION/PHYSICAL STATE

Phenytoin is a powder with a bitter, soapy taste (HSDB , 1991; Budavari, 1996).

Ethotoin is a white crystalline powder which is practically insoluble in water (S Sweetman , 2001).

Mephenytoin is a white crystalline powder with 1 part soluble in 1400 parts of water (S Sweetman , 2001).

FREEZING/MELTING POINT

MELTING POINT

MELTING POINT

295 to 298 degrees C (Budavari, 1996)

SOLUBILITY

IN WATER

Practically insoluble in water (USP, 1989)

OTHER/PHYSICAL

DISSOCIATION CONSTANT

pKa = 8.3 (Baselt, 1982)

-REFERENCES

GENERAL BIBLIOGRAPHY

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40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.

49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.

62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.

65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.

67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.

68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.

69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.

AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.

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Ambrosetto G, Tassinari CA, & Baruzzi A: Phenytoin encephalopathy as probable idiosyneratic reaction: case report. Epilepsia 1977; 18:405-408.

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Anseeuw K, Mowry JB, Burdmann EA, et al: Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup. Am J Kidney Dis 2016; 67(2):187-197.

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Arya R, Gulati S, Kabra M, et al: Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology 2011; 76(15):1338-1343.

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Baier WK, Beck U, & Hirsch W: CT findings following diphenylhydantoin intoxication. Pediatr Radiol 1985; 15:220-221.

Ballek RE, Reidenberg MM, & Orr L: Inhibition of diphenylhydantoin metabolism by chloramphenicol. Lancet 1973; 1:150.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.

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Product Information: DILANTIN KAPSEALS(R) extended oral capsules, phenytoin sodium extended oral capsules. Parke-Davis, New York, NY, 2007.

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Information to evaluate chemical incidents

Information to evaluate chemical incidents