Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Naphthalene
2) Moth flake
3) Mothballs
4) Moth balls
5) Tar camphor
6) White tar
7) RCRA Waste Number: U165
8) Molecular Formula: C10-H8
9) NCI-c 52904
10) CAS 91-20-3
11) NAPTHALENE
12) NTM

1.2.1) MOLECULAR FORMULA
1) C10-H8

Available Forms Sources

A)

1) Naphthalene is sold in the following forms: scales, powder, balls, cubes, cakes, spheres, and flakes (Budavari, 2000; Lewis, 1997).
2) Grades are determined by melting point.

1) 95% Pure: 176 degrees F (CHRIS, 2002)
2) Crude grade: 74 degrees C (minimum) (Lewis, 1997); 165-176 degrees F (CHRIS, 2002)
3) Refined grade: less than 79 degrees C (Lewis, 1997)
4) Scintillation grade: 80-81 degrees C (Lewis, 1997)

B)

1) Naphthalene occurs naturally in the essential oils of the roots of Radix and Herba ononidis and crude oil (Bingham et al, 2001; Harbison, 1998).
2) It can be manufactured by crystallizing and separating the naphthalene fraction (Ashford, 1994).
3) Naphthalene can also be formed by boiling coal tar oils at temperatures between 200-250 degrees C, followed by crystallization and distillation (Lewis, 1997).
4) Naphthalene is derived from catalytic processing of petroleum or is isolated from cracked petroleum. Naphthalene may also be formed from coke-oven emissions and from high-temperature carbonization of bituminous coal (Bingham et al, 2001; Lewis, 1997).
5) Naphthalene is formed in cigarette smoke by pyrolysis, and is also a photodecomposition product of carbaryl, an agricultural pesticide (Bingham et al, 2001).

C)

1) Naphthalene is used as a chemical intermediate for production of indigo and other dyes as well as in naphthyl and naphthol derivatives, hydrogenated and halogenated naphthalenes, chlorinated naphthalene, "Tertalin," "Decalin," phthalic anhydride, and anthroquinone. It is also used in the manufacture of insecticides, fungicides, wood preservatives, tanning chemicals, synthetic resins, lubricants, lampblack, annointing oils, celluloid, and smokeless powder. It has been used commonly as a moth repellent and as an ingredient in air fresheners and toilet bowl deodorizers (ACGIH, 1991; Bingham et al, 2001; Harbison, 1998; HSDB , 2002; ILO , 1998; Lewis, 1997; OHM/TADS, 2002).
2) Naphthalene is also used in scintillation counters, as emulsion breakers, and in explosives. It has been used in veterinary medicine as a dusting powder, intestinal antiseptic, vermicide, and for lice control in poultry and livestock. Pharmaceutical uses for naphthalene include: a topical and intestinal antiseptic, a dusting powder for skin diseases, and a antihelminthic. Naphthalene is also used to make salicyclic acid in microbial production (ACGIH, 1991; Budavari, 2000; Bingham et al, 2001; Harbison, 1998; HSDB , 2002; ILO , 1998; Lewis, 1997; OHM/TADS, 2002; Ostlere et al, 1988).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Naphthalene is found in mothballs and coal tar. It is also used as a component of petroleum and in the manufacturing of dyes, resins, fuels, and solvents.
B) TOXICOLOGY: Naphthalene is metabolized in the liver to alpha-naphthol, which causes oxidant stress. Oxidant stress causes hemoglobin iron to go from ferrous (2+) to ferric (3+) state. This results in methemoglobinemia. Oxidant stress can also cause heme groups and globin groups to dissociate, precipitating in the erythrocytes thus forming Heinz bodies and producing hemolysis.
C) EPIDEMIOLOGY: Adult and pediatric exposures are uncommon and deaths or severe toxicity due to exposure are extraordinarily rare.
D) WITH POISONING/EXPOSURE

1) TOXICITY: LOCAL EFFECTS: Naphthalene exposure may cause irritation to the eyes, skin, and mucous membranes. Eye contact with the solid material may result in conjunctivitis, superficial injury to the cornea, and diminished visual acuity. Skin exposure may cause hypersensitivity dermatitis.
2) SYSTEMIC EFFECTS: MILD TO MODERATE TOXICITY: Mild toxicity causes nausea, vomiting, diarrhea, and headache. Restlessness may also develop.
3) SEVERE TOXICITY: Severe toxicity may cause lethargy, hemolysis, hemolytic anemia, methemoglobinemia, hyperkalemia, hepatomegaly, splenomegaly, dysuria, hematuria. Hemoglobinuria can also develop. In the most severe cases, seizures, coma, metabolic acidosis, renal failure, and acute lung injury may occur.

0.2.3)

A) Tachycardia may develop if hemolysis occurs. Hypotension and shock are rare, but may occur in patients with severe toxicity.

0.2.7)

A) Headache, restlessness, and lethargy may occur.
B) Seizures and coma have been rarely reported in patients and represent severe toxicity.

0.2.20)

A) Prenatal naphthalene exposure has been harmful to the unborn. Naphthalene can cause methemoglobinemia and/or hemolytic anemia, conditions considered especially dangerous to the unborn.
B) In-utero exposure causes cataracts in rats.

0.2.21)

A) Naphthalene and coal tar exposure have been associated with laryngeal and intestinal carcinoma.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Care is symptomatic and supportive. Treat nausea and vomiting with antiemetics.

B) MANAGEMENT OF SEVERE TOXICITY

1) Care is symptomatic and supportive. Treat symptomatic methemoglobinemia with methylene blue. Severe hemolysis may require transfusion.

C) DECONTAMINATION

1) PREHOSPITAL: INGESTION: Gastrointestinal decontamination is not recommended because of the risk for seizures and subsequent aspiration.
2) HOSPITAL: INGESTION: Administer activated charcoal if the patient is alert and able to protect the airway. Activated charcoal may be effective for many hours after a mothball ingestion because they dissolve slowly.

D) ANTIDOTE

1) None.

E) SEIZURES

1) Administer a benzodiazepine IV: DIAZEPAM: ADULT: 5 to 10 mg, repeat every 10 to 15 minutes as needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed OR LORAZEPAM: ADULT: 2 to 4 mg; CHILD: 0.05 to 0.1 mg/kg. Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adult) or 10 mg (children over 5 years of age). Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

F) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

G) ENHANCED ELIMINATION

1) Hemodialysis is NOT LIKELY to be effective; however, it has been used in supportive care.

H) PATIENT DISPOSITION

1) HOME CRITERIA: Older reports suggest that ingestion of one mothball may cause hemolysis. The vast majority of cases were clearly associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, patients with G6PD deficiency should be referred for evaluation. Asymptomatic healthy children with ingestion of a single mothball (or less) can be monitored at home.
2) OBSERVATION CRITERIA: Any patient with deliberate ingestion with known G6PD deficiency, or with symptoms, should be referred to a healthcare facility. A child ingesting more than one mothball should be referred to a healthcare facility. If laboratory findings are negative and the patient is asymptomatic during a 4 to 6 hour observation period, the patient may be discharged with instructions to return for a follow-up CBC and urinalysis for up to 5 days postingestion. Patients should be instructed to return if any gastrointestinal symptoms, pallor, dark or diminished urine output, or CNS symptoms develop.
3) ADMISSION CRITERIA: Children or adults with G6PD deficiency should be admitted for monitoring. Admit any patient with evidence of anemia, hemolysis, or hemoglobinuria, or those with persistent nausea or vomiting who are unable to tolerate food or liquids by mouth.
4) CONSULT CRITERIA: Please consult a medical toxicologist or a local poison control center for all exposures in patients exhibiting signs or symptoms of systemic toxicity or those patients requiring observation or admission.

I) PITFALLS

1) Failure to recognize that hemolysis may be delayed. Patients who are discharged should be instructed to return if they develop red or brown urine or develop symptoms of methemoglobinemia.

J) PHARMACOKINETICS

1) Oral absorption is erratic. Naphthalene undergoes hepatic metabolism with renal excretion of metabolites.

K) DIFFERENTIAL DIAGNOSIS

1) Paradichlorobenzene exposure. All causes of methemoglobinemia or hemolysis such as a local anesthetic exposure or glucose-6-phosphate dehydrogenase (G6PD) deficiency.

0.4.3)

A) Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta2 agonist and oral or parenteral corticosteroids.

0.4.4)

A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed area thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) TOXICITY: LOCAL EFFECTS: Naphthalene exposure may cause irritation to the eyes, skin, and mucous membranes. Eye contact with the solid material may result in conjunctivitis, superficial injury to the cornea, and diminished visual acuity. Skin exposure may cause hypersensitivity dermatitis.
2) SYSTEMIC EFFECTS: MILD TO MODERATE TOXICITY: Mild toxicity causes nausea, vomiting, diarrhea, and headache. Restlessness may also develop.
3) SEVERE TOXICITY: Severe toxicity may cause lethargy, hemolysis, hemolytic anemia, methemoglobinemia, hyperkalemia, hepatomegaly, splenomegaly, dysuria, hematuria. Hemoglobinuria can also develop. In the most severe cases, seizures, coma, metabolic acidosis, renal failure, and acute lung injury may occur.

Vital Signs

3.3.1)

A) Tachycardia may develop if hemolysis occurs. Hypotension and shock are rare, but may occur in patients with severe toxicity.

3.3.3)

A) FEVER: Hyperthermia may occur following acute ingestion and is often seen in patients who develop hemolysis (Zuelzer & Apt, 1949; Abelson & Henderson, 1951; Mackell et al, 1951; Haggerty, 1956).

1) CASE REPORT: ADULT: The acute ingestion of 50 mL of an anointing oil containing naphthalene, in one adult patient, resulted in fever within 1 to 2 days (Ostlere et al, 1988).
2) CASE REPORT: PEDIATRIC: A 2-year-old child who had intermittently ingested naphthalene-containing toilet bowel deodorant cakes for a year presented with fever as part of an acute hemolytic reaction (Chusid & Fried, 1955).

3.3.4)

A) HYPOTENSION: Low blood pressure as a side effect is rare but has been reported with severe multiorgan system toxicity (Kurz, 1987; Kouri et al, 1993).

3.3.5)

A) TACHYCARDIA may develop following significant hemolytic anemia (Zuelzer & Apt, 1949).

Heent

3.4.2)

A) WITH POISONING/EXPOSURE

1) FLUSHING of the face has been described following acute ingestion (Gidron & Leurer, 1956)

3.4.3)

A) WITH POISONING/EXPOSURE

1) Toxicity has occurred from both vapor contact and from systemic absorption. The most common effects are irritation, lens opacities, and optic neuritis.
2) EXTERNAL/VAPOR EXPOSURE

a) IRRITATION from naphthalene vapor occurs at airborne concentrations of 15 ppm (Robbins, 1951; Grant & Schuman, 1993).
b) CHRONIC

1) BILATERAL OPTIC NEURITIS was described by Koelsch (1926) in a patient who worked with naphthalene for a prolonged period.
2) CHORIORETINITIS has been reported in exposed workers who had cataracts but no other symptoms (van der Hoeve, 1906).
3) LENS OPACITIES: Some industrial surveys revealed no eye abnormalities among workers exposed to naphthalene for years, but one study found 8 of 21 employees who were exposed to naphthalene fumes for 5 years developed lens opacities (Axenfeld, 1915)(Pika, 1944).

c) LACK OF EFFECT

1) CORNEAL DAMAGE: Vapors probably do not produce corneal damage in humans (Robbins, 1951; Grant & Schuman, 1993).

3) SYSTEMIC EXPOSURE

a) Effects in humans are scantily documented (Grant & Schuman, 1993).
b) CATARACT: A pharmacist was given 5 g of unpurified naphthalene over 13 hours in 1900. On awakening 8 to 9 hours later, he was nearly blind. A year later, he had nonprogressive zonular cataracts (Lezenius, 1902).

B) ANIMAL STUDIES

1) Documented effects in animals are well established (Grant & Schuman, 1993).
2) Naphthalene is routinely used by the systemic route to induce cataracts in rats and rabbits. Dosages are large with, for example, 0.5 to 1 g/kg/day used in rats (Nagata et al, 1995).
3) Rabbit eyes developed reversible local epithelial injury and slight turbidity of the underlying stroma when naphthalene crystals were applied (D'Asaro Biondo, 1933).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia and flow murmurs secondary to acute hemolysis have been reported (Zuelzer & Apt, 1949).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Dysrhythmias secondary to hyperkalemia from hemolysis and acute renal failure have been reported in severe poisoning cases (Kurz, 1987).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypovolemic shock developed in a 3-year-old child with a partial glucose-6-phosphate dehydrogenase (G6PD) deficiency who ingested an unknown quantity of naphthalene (Kouri et al, 1993).

Respiratory

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: PEDIATRIC: Respiratory distress developed in a 3-year-old child with a partial glucose-6-phosphate dehydrogenase (G6PD) deficiency who ingested an unknown quantity of naphthalene. Apnea and severe hypoxemia followed and the patient ultimately required mechanical ventilation (Kouri et al, 1993).
b) CASE REPORT: ADULT: Shortness of breath was observed in a 21-year-old pregnant woman with a history of nearly-daily mothball inhalation for recreational purposes prior to and during the past 3 months of pregnancy. She presented to the emergency department in early labor at 39 weeks gestation. Other symptoms included, nausea and vomiting and slurred speech. Laboratory analysis showed anemia and elevated liver enzymes. Mothball abuse was not known at the time of admission and all pregnancy-related causes for the abnormal findings were ruled out. She was treated with supportive therapy followed by an epidural anesthesia for labor and delivery, which proceeded without issue. No abnormal events were reported in the newborn (Kuczkowski, 2006).

B) HYPOXIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old woman presented with methemoglobinemia and hemolysis 40 hours after intentionally ingesting 12 mothballs. At presentation to the emergency department, her SpO2 was 82% with O2 at 100% via face mask. She appeared cyanotic, pale, and jaundiced. Her heart rate was 109 bpm; all other vital and neurologic signs were within normal limits. She was admitted to the intensive care unit. Treatment included urine alkalinization, RBC transfusions, IV methylene blue, N-acetylcysteine, ascorbic acid, and 45 hours of continuous venovenous hemofiltration. By day 4, cyanosis had improved and O2 saturation was greater than 95% via pulse oximetry. She was stable by day 5 and discharged to home on day 10 (Lim et al, 2009).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: PEDIATRIC: Acute lung injury (pulmonary edema) and severe hypoxemia developed in a 3-year-old child with a partial glucose-6-phosphate dehydrogenase (G6PD) deficiency who ingested an unknown quantity of naphthalene (Kouri et al, 1993).

D) DISORDER OF RESPIRATORY SYSTEM

1) WITH POISONING/EXPOSURE

a) ANIMAL DATA: Systemic doses of naphthalene can cause acute injury to clara cells (non-ciliated mucus producing cells) in the respiratory tracts of mice (50 mg/kg), hamsters (800 mg/kg) and other animal species (Plopper et al, 1992). The injury appears to be related to cytochrome P-450 mediated oxidation of naphthalene. The importance of this phenomena in human naphthalene poisoning is unknown, but human lung tissue appears to actively metabolize naphthalene (Buckpitt & Bahnson, 1986).

Neurologic

3.7.1)

A) Headache, restlessness, and lethargy may occur.
B) Seizures and coma have been rarely reported in patients and represent severe toxicity.

3.7.2)

A) COMA

1) WITH POISONING/EXPOSURE

a) Coma is a rare finding in patients with severe multiorgan toxicity. Coma may develop several days after the onset of illness (Kurz, 1987; Siegal & Wason, 1986; Gidron & Leurer, 1956; Budavari, 1996).
b) CASE REPORT: A 3-year-old child with glucose-6-phosphate dehydrogenase (G6PD) deficiency became comatose after ingesting an unknown amount of naphthalene. Respiratory distress followed by apnea, hypovolemic shock, and renal failure were also present (Kouri et al, 1993).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures are rare, but have been reported in patients with severe multiorgan toxicity. Seizures may develop several days after the onset of illness (Kurz, 1987; Gidron & Leurer, 1956; Zuelzer & Apt, 1949).

C) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been described following acute oral and inhalational exposure (Praharaj & Kongasseri, 2012; ACGIH, 1986).
b) CASE REPORT: INHALATION: A 26-year-old woman living with her 4-year-old daughter used 300 to 500 mothballs in their home as a pesticide and to manage foul odors. The woman, her daughter, and visitors to their household all experienced headaches after being in the apartment. Seven relatives of the woman who were living in 2 separate households where mothballs were used in similar quantities also reported symptoms including headache. The headaches ceased in all family members and visitors when mothball use was discontinued (Centers for Disease Control (CDC), 1983).

D) DROWSY

1) WITH POISONING/EXPOSURE

a) Lethargy may occur after acute or chronic ingestion.

E) CLOUDED CONSCIOUSNESS

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: INHALATION: Confusion and malaise were included in symptoms reported among 9 family members living in 3 separate households using 300 to 500 mothballs in their homes as a pesticide and to manage foul odors (Centers for Disease Control (CDC), 1983).

F) SLURRED SPEECH

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Slurred speech was observed in a 21-year-old pregnant woman with a history of nearly-daily mothball inhalation for recreational purposes prior to and during the past 3 months of pregnancy. She presented to the emergency department in early labor at 39 weeks gestation. Other symptoms included, nausea and vomiting and shortness of breath. Laboratory analysis showed anemia and elevated liver enzymes. Mothball abuse was not known at the time of admission and all pregnancy-related causes for the abnormal findings were ruled out. She was treated with supportive therapy followed by an epidural anesthesia for labor and delivery, which proceeded without issue. No abnormal events were reported in the newborn (Kuczkowski, 2006).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea has been reported after both ingestion and inhalational exposure. Vomiting is common after ingestion (Gidron & Leurer, 1956; Zuelzer & Apt, 1949; ACGIH, 1986; Kouri et al, 1993).
b) INHALATION EXPOSURE

1) CASE REPORT: Nausea and vomiting was reported in a 21-year-old pregnant woman with a history of nearly-daily mothball inhalation for recreational purposes prior to and during the past 3 months of pregnancy. She presented to the emergency department in early labor at 39 weeks gestation. Other symptoms included shortness of breath and slurred speech. Laboratory analysis showed anemia and elevated liver enzymes. Mothball abuse was not known at the time of admission and all pregnancy-related causes for the abnormal findings were ruled out. She was treated with supportive therapy followed by an epidural anesthesia for labor and delivery, which proceeded without issue. No abnormal events were reported in the newborn (Kuczkowski, 2006).
2) CASE REPORT: A 26-year old woman living with her 4-year-old daughter used 300 to 500 mothballs in their home as a pesticide and to manage foul odors. The woman, her daughter, and visitors to their household all experienced nausea and vomiting after being in the apartment. Seven relatives of the woman who were living in 2 separate households where mothballs were used in similar quantities also reported symptoms including nausea and vomiting. Symptoms ceased in all family members and visitors when mothball use was discontinued (Centers for Disease Control (CDC), 1983).

B) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea may occur after acute ingestion (Gidron & Leurer, 1956; Zuelzer & Apt, 1949)

C) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) Abdominal pain may occur after acute ingestion (Gidron & Leurer, 1956; Zuelzer & Apt, 1949).
b) CASE REPORT: One patient ingested up to 50 mL of a naphthalene-containing oil which produced abdominal pain and diarrhea within 6 hours (Ostlere et al, 1988).
c) CASE REPORT: INHALATION: A 26-year old woman living with her 4-year-old daughter used 300 to 500 mothballs in their home as a pesticide and to manage foul odors. The woman, her daughter, and 7 relatives of the woman who were living in 2 separate households where mothballs were used in similar quantities reported symptoms including abdominal pain. Symptoms disappeared in all family members when mothball use was discontinued (Centers for Disease Control (CDC), 1983).

D) LOSS OF APPETITE

1) WITH POISONING/EXPOSURE

a) Anorexia has been reported after ingestion and inhalational exposure (ACGIH, 1986).

Hepatic

3.9.2)

A) HYPERBILIRUBINEMIA

1) WITH POISONING/EXPOSURE

a) Bilirubinemia has been described in newborns exposed to naphthalene (Cock, 1957; Schafer, 1951; Valaes et al, 1963).
b) Hemolysis with serum bilirubin concentrations over 30 mg/dL caused kernicterus in 8 of 21 infants exposed to blankets and clothing stored in naphthalene mothballs. Two of these children died (Valaes et al, 1963).
c) CASE REPORT: A 19-year-old woman presented to the emergency department with methemoglobinemia and hemolysis 40 hours after intentionally ingesting 12 mothballs. Hyperbilirubinemia was detected (total bilirubin of 84 mcmol/L and a highly elevated indirect bilirubin). Further analysis showed low serum haptoglobin (0.09 g/L) and elevated AST (98 units/L). She was admitted to the intensive care unit. Treatment included urine alkalinization, RBC transfusions, IV methylene blue, N-acetylcysteine (NAC), ascorbic acid, and 45 hours of continuous venovenous hemofiltration. She was stable by day 5 and discharged to home on day 10 (Lim et al, 2009).

B) LARGE LIVER

1) WITH POISONING/EXPOSURE

a) Jaundice and hepatomegaly are rare, but have been reported following acute exposure (Abelson & Henderson, 1951; MacGregor, 1954; Dawson et al, 1958; Zuelzer & Apt, 1949).

C) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) Centrilobular necrosis was reported in one case (Siegal & Wason, 1986)
b) CASE REPORT: PEDIATRIC: A 10-year-old Indian boy developed centrilobular hepatic necrosis after sniffing mothballs for 2 months (Siegal & Wason, 1986).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Hemolysis may cause acute tubular necrosis and renal failure (Chugh et al, 1977; Schafer, 1951; Kurz, 1987).
b) PEDIATRIC CASE REPORTS

1) CASE REPORT: A 6-day-old infant was exposed to diapers and blankets that had been stored in naphthalene. She developed hemoglobin deposits in the renal tubules (Schafer, 1951).
2) CASE REPORT: Acute renal failure developed in a 3-year-old child with a partial glucose-6-phosphate dehydrogenase (G6PD) deficiency due to hemolysis following ingestion of an unknown amount of naphthalene (Kouri et al, 1993).

B) ABNORMAL URINE

1) WITH POISONING/EXPOSURE

a) Dark brown, red, or pink urine is seen when significant hemolysis occurs (Ostrele et al, 1988) (Zuelzer & Apt, 1949).
b) CASE REPORT: A 19-year-old woman presented with methemoglobinemia and hemolysis 40 hours after intentionally ingesting 12 mothballs. At presentation to the emergency department her urine was dark brown in color and tested positive for RBCs with dipstick. Significant RBCs or casts were not detected with urine microscopy. Additionally, suprapubic abdominal tenderness was noted. She was admitted to the intensive care unit and treated with urine alkalinization, RBC transfusions, IV methylene blue, N-acetylcysteine, ascorbic acid, and 45 hours of continuous venovenous hemofiltration. By day 4, her urine was clear; renal function remained stable throughout her hospital stay. Her abdominal pain resolved spontaneously. She was stable by day 5 and was discharged to home on day 10 (Lim et al, 2009).

C) DYSURIA

1) WITH POISONING/EXPOSURE

a) Dysuria and urinary frequency may rarely occur (Nash, 1903); (Gosselin et al, 1984).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may develop in patients with acute renal failure secondary to hemolysis (Kurz, 1987; Kouri et al, 1993).

Hematologic

3.13.2)

A) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) Severe hemolytic anemia has been reported following acute ingestion, inhalation, or dermal absorption. Development of clinically recognized hemolysis may be delayed 1 to 5 days following exposure and is typically preceded by gastrointestinal symptoms (Newns, 1949; Mackell et al, 1951; Zuelzer & Apt, 1949; Kumar & Mohan, 1986; Kouri et al, 1993). The delayed presentation is due to required metabolism of naphthalene to its hemolysis-inducing metabolite, alpha- naphthol.

1) Hemolysis is more common in infants and patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, sickle cell anemia, or sickle cell trait (Zuelzer & Apt, 1949; Shannon & Buchanan, 1982; Zinkham & Childs, 1958; Kumar & Mohan, 1986; Kouri et al, 1993; Santucci & Shah, 2000).

b) BLOOD SMEAR: The typical presentation of self-limiting naphthalene-induced hemolysis includes anisocytosis, poikilocytosis, reticulocytosis, severe anemia, leukocytosis, and icterus (Anziulewicz et al, 1959; Kumar & Mohan, 1986).
c) Severe reactions may include Heinz body formation (Zuelzer & Apt, 1949; Valaes et al, 1963; Hanssler, 1964; Irle, 1964) and hemoglobinuria (Abelson & Henderson, 1951; Gidron & Leurer, 1956; Valaes et al, 1963).
d) GLUCOSE -6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY: Hemolytic anemia is most severe in individuals with G6PD deficiency. It may even occur after exposure to very small amounts of naphthalene (Dawson et al, 1958; Gross et al, 1958; Valaes et al, 1963; Sherer, 1965; Todisco et al, 1991). Methemoglobinemia is more common in G6PD deficient individuals (Valaes et al, 1963).
e) SICKLE CELL: Patients with sickle cell anemia or sickle cell trait appear to be at increased risk for developing hemolysis (Zuelzer & Apt, 1949).
f) PROSPECTIVE STUDY: No cases of hemolysis were reported in a prospective evaluation of 43 patients who had ingested naphthalene-containing mothballs (Kucharski et al, 1992).

1) About 50 percent of these patients (n=22) ingested less than one-half of a mothball. Those patients who may have ingested greater than one-half of a mothball were treated with ipecac-induced emesis (n=20) or charcoal (n=1). One patient presented with vomiting, which resolved.

g) PEDIATRIC CASE REPORTS

1) Hemolysis occurred 24 to 72 hours following ingestion in 3 children (Shannon & Buchanan, 1982). Hemolysis was reported in a 20-month-old child with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Melzer-Lange & Walsh-Kelly, 1989).
2) Two children, with G6PD deficiency, developed hemolysis following mothball ingestions and were inappropriately diagnosed with methemoglobinemia They were subsequently treated with methylene blue, which can also cause hemolysis in G6PD deficient individuals. Both patients recovered following discontinuation of the methylene blue and blood transfusions (Chun et al, 1998).
3) CASE REPORT: INFANTS: Significant hemolysis was reported in newborns having normal G6PD levels (Valaes et al, 1963) but naphthalene was not measured in blood or urine.

h) ADULT CASE REPORTS

1) The ingestion of 50 mL of a naphthalene-containing oil produced an acute hemolytic anemia four days later. G6PD levels were normal (Ostlere et al, 1988).

B) ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT/CHRONIC EXPOSURE: A 19-year-old teenage girl, with a history of impulsivity and angry outbursts, had a 6-year history of sniffing naphthalene moth balls because of its euphoric effect. During the period of abuse she would sniff the moth balls until she had a slight headache which was followed by periods of euphoria. Although no major physical effects occurred, anemia (hemoglobin level 7 g/dL) did develop and was associated with chronic naphthalene abuse after other possible sources were ruled out. Due to the potential long term physical risks from ongoing abuse, the patient decided to stop sniffing and experienced intense cravings for several days but did not resume naphthalene and remained chemical free (Praharaj & Kongasseri, 2012).

C) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Methemoglobinemia has been reported in infants and occurs more commonly in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals (Valaes et al, 1963).
b) CASE REPORT: A 19-year-old woman developed methemoglobinemia and hemolysis 40 hours after intentionally ingesting 12 mothballs. She reported giddiness and dark-colored urine a few hours after ingestion. At presentation her O2 saturation was 82% with O2 at 100% via face mask. She appeared cyanotic, pale, and jaundiced. Her heart rate was 109 bpm; all other vital and neurologic signs were within normal limits. Suprapubic abdominal tenderness was noted on examination. Urine was dark brown. Supportive treatment including urine alkalinization was initiated and she was admitted to the intensive care unit. An initial CBC result showed a Hgb of 8.6 g/dL, with HCT of 27.4% and neutrophil leukocytosis. Further laboratory analysis showed hyperbilirubinemia and low serum haptoglobin. An initial methemoglobin (MetHgb) level was 9.6% with a Hgb of 8.6 g/dL. On day 2, Hgb decreased to 7.5 g/dL and MetHgb increased to 13%. She was treated with 60 mg (1.5 mg/kg) IV methylene blue and 2 units of RBCs as well as 300 mg oral ascorbic acid and 1.2 g/day of N-acetylcysteine (NAC). On day 3, MetHgb was 7.8%, Hgb remained unchanged, and dark colored urine persisted. She received 2 more units of RBCs. Continuous venovenous hemofiltration (CVVH) was initiated and continued for 45 hours. On day 4, her urine was clear, cyanosis decreased, O2 saturation was greater than 95%, and alkaline diuresis was discontinued. On day 5, leukocyte count and total bilirubin normalized, Hgb stabilized at 9.8 g/dL, MetHgb dropped to 1.8% and CVVH was discontinued. During admission, blood glucose-6-phosphate dehydrogenase activity was confirmed, suggesting a diagnosis of thalassemia. Blood and urine testing was positive for naphthalene. She was transferred to a noncritical care unit on day 5 and discharged to home on day 10 (Lim et al, 2009).

D) APLASTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Aplastic anemia has been reported in one patient exposed to both naphthalene and paradichlorobenzene (Hardin & Baetjer, 1978).

E) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Leukocytosis commonly develops in patients with hemolysis (Zuelzer & Apt, 1949; Abelson & Henderson, 1951).
b) CASE REPORT: A 19-year-old woman presented to the emergency department with methemoglobinemia and hemolysis 40 hours after intentionally ingesting 12 mothballs. Neutrophil leukocytosis with WBC 26.6 X 10(3)/mcL and neutrophils 84.1% were detected in the emergency room. She was admitted to the intensive care unit and treated with RBC transfusions, IV methylene blue, N-acetylcysteine and ascorbic acid, and 45 hours of continuous venovenous hemofiltration. She was stable by day 5 and discharged to home on day 10 (Lim et al, 2009).

Dermatologic

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Erythema and dermatitis have been described and attributed to a hypersensitivity reaction (Key et al, 1977; Gosselin et al, 1984; Hathaway et al, 1996).

B) PALE COMPLEXION

1) WITH POISONING/EXPOSURE

a) Pallor may be seen secondary to hemolytic anemia (Siegal & Wason, 1986).

C) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Exfoliative contact dermatitis has been reported (Fanberg, 1940).

Immunologic

3.19.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) A chronic ingestion study in mice showed no immunotoxicity (Shopp et al, 1984).

Reproductive

3.20.1)

A) Prenatal naphthalene exposure has been harmful to the unborn. Naphthalene can cause methemoglobinemia and/or hemolytic anemia, conditions considered especially dangerous to the unborn.
B) In-utero exposure causes cataracts in rats.

3.20.2)

A) ANIMAL STUDIES

1) CATARACT

a) Naphthalene may induce cataracts in rats when used as an antiseptic (Zhikov & Atanasov, 1985).
b) Naphthalene retarded skull formation and cardiac development in rats (Bond & Niemeier, 1979), but was not considered a teratogen (Hardin, 1981). It caused cataracts in rats with prenatal exposure (Zhivkov & Atanasov, 1965) (Van Der Hoeve, 1913). It may inhibit sperm production in mice, rats, or guinea pigs (Matorova, 1982). Naphthalene required metabolic activation to be toxic to mouse embryos in vitro (Iyer et al, 1991).
c) A Russian study concluded that naphthalene was an embryotoxin and teratogen (Matorova & Chetverikova, 1981).

3.20.3)

A) ANEMIA HEMOLYTIC

1) Naphthalene may induce hemolytic anemia in newborns following maternal ingestion during pregnancy (Shopp et al, 1984; Zinkham & Childs, 1958; Anziulewicz et al, 1959).
2) An infant was born with hemolytic anemia to a mother who had eaten naphthalene during pregnancy (Zinkham & Childs, 1958). Maternal inhalation of naphthalene caused severe jaundice, anemia, and/or methemoglobinemia in 21 Greek newborns (Valaes et al, 1963). Some of these infants were deficient in glucose-6-phosphate dehydrogenase (G-6-PD), but others were not. Other cases of severe neonatal jaundice associated with naphthalene exposure have been reported in Nigeria (Familusi & Dawodu, 1985).

B) METHEMOGLOBINEMIA

1) Naphthalene can cause methemoglobinemia (Valeest, 1963).
2) A 15-year-old woman at 36 weeks gestation presented in preterm labor. On admission, she was diagnosed with hemolytic anemia of unknown etiology. Because of fetal distress, she was given oxytocin and delivered a hypotonic, cyanotic, and apneic male infant. Bag-mask ventilation prompted spontaneous breathing, but cyanosis persisted. Methemoglobin level was 11.3% (normal less than 1%). At 7 hours, he required mechanical ventilation, but was extubated to room air at 40 hours of age. At that time, his methemoglobin level had decreased to 4.8%. He was discharged home at 16 days of age in healthy condition. Upon questioning the family, it was discovered that an entire box of moth ball flakes (100% refined naphthalene) had spilt into a heating vent approximately 1 week prior to delivery. After exchange transfusion, naphthalene was not detected in the infants blood. No infant urine samples were available for analysis. However, an admission maternal urine sample was positive for a naphthalene metabolite (Molloy et al, 2004).

C) BILIRUBIN INCREASED

1) A 15-year-old woman (blood group O, Rh-positive) presented at 36 weeks gestation with preterm labor. She was given oxytocin for fetal distress and delivered a hypotonic, cyanotic and apneic male infant. Bag-mask ventilation prompted spontaneous breathing, but cyanosis persisted. The infant's blood type was O, Rh-positive with negative antibody screen; total bilirubin was 6 mg/dL. Total bilirubin continued to rise despite double phototherapy with super-blue light bulbs and reached 20 mg/dL. His bilirubin decreased to 10 mg/dL following a double-volume exchange transfusion. There was a subsequent rebound after transfusion to 14 mg/dL, but he was discharged home at 16 days of age in healthy condition. Upon questioning the family, it was discovered that an entire box of moth ball flakes (100% refined naphthalene) had split into a heating vent approximately 1 week prior to delivery. After exchange transfusion, naphthalene was not detected in the infants blood and no urine samples were available; however, a urine sample from the mother on admission detected a urinary metabolite of naphthalene (Molloy et al, 2004).

D) PERINATAL INHALATION EXPOSURE

1) MULTIPLE FETAL ANOMALIES: A 19-year-old woman with a history of substance abuse, including naphthalene abuse by inhalation, was seen for antenatal care at gestational age 7 weeks. An ultrasound revealed normal fetal cardiac activity. The patient was uncooperative in discussing her history of drug abuse and refused psychiatric care. At 15 weeks gestation, she was admitted with nausea and vomiting and an 8 kg weight loss was noted. Laboratory studies were normal. She once again refused to discuss questions related to naphthalene use. During this admission, a repeat ultrasound detected multiple fetal abnormalities including anencephaly and scoliosis. In addition, a fetal echocardiogram showed hypoplastic left ventricles and pleural effusion. Although counseled regarding the severe fetal abnormalities, the patient refused the option to terminate the pregnancy. Four weeks later there was an absence of fetal cardiac function. Autopsy confirmed multiple anomalies found during prenatal screening. Although the patient had no risk for fetal anomalies (ie, diabetes, advanced maternal age, infection or alcohol abuse), a cause and effect could not be determined in this case (Boynukalin & Baykal, 2014).
2) LACK OF FETAL EFFECT: A 21-year-old woman with a history of nearly-daily mothball inhalation for recreational purposes prior to and during the past 3 months of pregnancy presented to the emergency department in early labor at 39 weeks gestation. At presentation, shortness of breath, nausea and vomiting, and slurred speech were observed. Laboratory analysis showed anemia and elevated liver enzymes. Mothball abuse was not known at the time of admission and all pregnancy-related causes for the abnormal findings were ruled out. She was treated with supportive therapy followed by an epidural anesthesia for labor and delivery, which proceeded without issue. No adverse events to the newborn were reported (Kuczkowski, 2006).

E) PLACENTAL BARRIER

1) Naphthalene can cross the placenta (Anziulewicz et al, 1959). Fetal tissues contain enzymes which can metabolize naphthalene (Juchau & Namkung, 1974).

F) ANIMAL STUDIES

1) STILLBIRTH

a) There was a significant reduction of live pups per litter when pregnant mice were given a single dose just below the limits of adult lethality. Maternal deaths were significant (Plasterer et al, 1985).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS91-20-3 (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):

1) IARC Classification

a) Listed as: Naphthalene
b) Carcinogen Rating: 2B

1) 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.

3.21.2)

A) Naphthalene and coal tar exposure have been associated with laryngeal and intestinal carcinoma.

3.21.3)

A) LACK OF INFORMATION

1) Human data are minimal.

B) GASTRIC CARCINOMA

1) One study followed 15 workers exposed to vapors of naphthalene and coal tar for a period of up to 32 years. Laryngeal carcinoma developed in 4 of these people (who also smoked) and neoplasms of the pylorus and cecum developed in two others (Wolf, 1978).

3.21.4)

A) ROUTE OF EXPOSURE

1) Naphthalene did not cause cancer in rats exposed by the oral or intraperitoneal routes (Schmahl, 1955), but did induce tumors when injected subcutaneously in rats (Knake, 1956). It caused leukemia in a skinpainting study in mice, but these results were confounded by the use of benzene as the solvent (Knake, 1956). Increased pulmonary alveolar adenomas were seen in mice exposed to 30 ppm of naphthalene for 6 hours/day for 6 months (ACGIH, 1992).
2) An NTP Toxicology and Carcinogenesis Study (US Dept Health & Human Services, 1992) concluded that under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm.

a) There was some evidence of carcinogenic activity of naphthalene in female B6C3F1 mice, based on an increased incidence of pulmonary alveolar/bronchiolar adenomas.
b) In both male and female mice, naphthalene caused an increased incidence, as well as, severity of chronic inflammation, metaplasia of the olfactory epithelium, and hyperplasia of the respiratory epithelium in the nose and chronic inflammation in the lungs.

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) In patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency or ingestions involving more than a single mothball, obtain a baseline CBC, electrolytes, G6PD level, liver enzymes and renal function tests, urinalysis and urine dipstick test for hemoglobinuria, and a type and screen.
B) Measurement of urinary metabolites (1-naphthol or mercapturic acid) may help to confirm the diagnosis but are not widely available or useful for chemical management. Urinary naphthol levels may be used to monitor industrial creosote exposure (naphthalene is the most abundant compound found in creosote vapor).
C) Abdominal radiographs may help differentiate between mothballs or other products which contain paradichlorobenzene (PDB) (densely radiopaque) from those which contain naphthalene (radiolucent or faintly radiopaque). Another distinguishing feature between naphthalene and PDB is that naphthalene will float in water while PDB will sink.
D) Ingestions of more than a single mothball should be followed for several days to rule out delayed hemolysis.

4.1.2)

A) HEMATOLOGIC

1) Obtain baseline CBC.
2) Monitor METHEMOGLOBIN levels in cyanotic patients.
3) In toxic patients, peripheral smears may show anisocytosis, poikilocytosis, and red cell fragmentation (Siegal & Wason, 1986).
4) Physicians may wish to screen blood smears for abnormalities for at least 1 week after exposure. This may be especially important in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, sickle cell anemia, or sickle trait (Siegal & Wason, 1986).

B) BLOOD/SERUM CHEMISTRY

1) BASELINE LEVELS: Glucose-6-phosphate dehydrogenase (G6PD) and liver enzymes and kidney function tests may be helpful.

4.1.3)

A) URINE METABOLITE LEVELS

1) Identification of urine metabolites (1-naphthol and mercapturic acids) may confirm a diagnosis (Summer, 1979)(Gosselin et al, 1984). Urinary naphthol has been used to monitor industrial exposure to creosote (Heikkila et al, 1997). Naphthalene is the primary component found in creosote, which is used for timber impregnation during the production of telegraph poles, railway sleepers, and timber for domestic use (Preuss et al, 2003).

B) URINALYSIS

1) Obtain baseline urinalysis (check for hemoglobinuria).

Radiographic Studies

A)

1) Mothballs and other products which contain paradichlorobenzene (PDB) instead of naphthalene may appear strongly radiopaque. Products which contain naphthalene may appear radiolucent or faintly radiopaque on abdominal radiographs. This is based on an in vitro study of household products and 1 case of PDB ingestion (Woolf et al, 1993; Goldfrank & Bania, 1994).

Methods

A)

1) Techniques used in forensic medicine for the detection and quantitation of naphthalene and its metabolites include (Snyder, 1987):

a) Thin-layer chromatography
b) High-performance liquid chromatography
c) Gas chromatography with mass spectrometry
d) High resolution proton magnetic resonance

2) DIFFERENTIATING PARADICHLOROBENZENE/NAPHTHALENE

a) SUMMARY: Differentiation is difficult because both paradichlorobenzene (PDB) and naphthalene are white crystalline solids at room temperature and have similar odors.
b) PHYSICAL APPEARANCE: Naphthalene is dry, while PDB has a wet and oily appearance (Peterson & Liner, 1975).
c) SPECIFIC GRAVITY: Distinguishing between camphor, naphthalene, and PDB mothballs can be done by testing whether they float or sink in a saturated solution of salt water (4 ounces of tepid water to which 3 heaping tablespoons of table salt has been added and stirred vigorously until the salt will not dissolve any more) (Fukuda et al, 1991; Koyama et al, 1991).

1) CAMPHOR mothballs float in both water and salt solution.
2) NAPHTHALENE mothballs sink in water but float in saturated salt solution.
3) PDB mothballs sink in both water and salt solution.
4) The above method successfully and rapidly distinguished 10 cases of naphthalene mothball ingestion from 638 cases of PDB mothball ingestion when poison center callers (mostly housewives) were instructed on its performance over the telephone (Koyama et al, 1991).

a) Composition of mothballs was later confirmed by gas chromatography.

d) SOLUBILITY: Paradichlorobenzene (PDB) is more soluble in turpentine than naphthalene. A mothball of PDB will usually dissolve within 30 to 60 minutes whereas about 0.25 of the naphthalene will be left (Winkler et al, 1985).
e) HEAT: Paradichlorobenzene produces a bright green color in a bunsen burner flame; Naphthalene does not.
f) MELTING POINT: PDB = 53 degrees C; NAPHTHALENE = 80 degrees C (Ambree, 1986). Placing a small piece of the mothball in a test tube heated to 60 degrees C in water bath may simplify the melting point test. PDB will liquefy within several minutes; naphthalene will remain intact (Reeves & Pendarus, 1986).
g) CHEMICAL TEST: If chloroform and ammonium chloride powder are added to PDB no color change occurs; naphthalene turns blue.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Children or adults with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be admitted for monitoring. Admit any patient with evidence of anemia, hemolysis, or hemoglobinuria, or those with persistent nausea or vomiting who are unable to tolerate food or liquids by mouth.

6.3.1.2) HOME CRITERIA/ORAL

A) Older reports suggest that ingestion of one mothball may cause hemolysis. The vast majority of cases were clearly associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, patients with G6PD deficiency should be referred for evaluation. Asymptomatic healthy children with ingestion of a single mothball (or less) can be monitored at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Please consult a medical toxicologist or a local poison control center for all exposures in patients exhibiting signs or symptoms of systemic toxicity or those patients requiring observation or admission.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with deliberate ingestion with known G6PD deficiency, or with symptoms, should be referred to a healthcare facility. A child ingesting more than one mothball should be referred to a healthcare facility.
B) If laboratory findings are negative and the patient is asymptomatic during a 4 to 6 hour observation period, the patient may be discharged with instructions to return for a follow-up CBC and urinalysis for up to 5 days postingestion. Patients should be instructed to return if any gastrointestinal symptoms, pallor, dark or diminished urine output, or CNS symptoms develop.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the risk of seizures and subsequent aspiration.

6.5.2)

A) SUMMARY

1) Gastric lavage may be useful for ingestion of flakes, but effectiveness may be limited by naphthalene's poor water solubility. Information on activated charcoal is scant, but adsorption is thought to occur. Mothballs dissolve slowly; gastric decontamination should be considered even in patients presenting late after ingestion.

B) ACTIVATED CHARCOAL

1) Adsorption of naphthalene to activated charcoal is not reported in the toxicology literature. One in vitro study reports that naphthalene desorbs poorly from the charcoal used to trap volatile organic compounds in preparation for analysis by gas chromatography (Murray & Lockhart, 1988). This would suggest that activated charcoal may effectively adsorb naphthalene.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) 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).

1) 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).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) 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.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Care is symptomatic and supportive following a mild to moderate exposure. Treat nausea and vomiting with antiemetics. Following a severe exposure, treat symptomatic methemoglobinemia with methylene blue. Severe hemolysis may require transfusion.

B) MONITORING OF PATIENT

1) In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or ingestions involving more than a single mothball, obtain baseline CBC, electrolytes, G6PD level, liver enzymes and renal function tests, urinalysis and urine dipstick test for hemoglobinuria, and a type and screen.
2) Measurement of urinary metabolites (1-naphthol or mercapturic acid) may help to confirm the diagnosis but are not widely available or useful for clinical management. Urinary naphthol levels may be used to monitor industrial creosote exposure (naphthalene is the most abundant compound found in creosote vapor).
3) Abdominal radiographs may help differentiate between mothballs or other products which contain paradichlorobenzene (densely radiopaque) from those which contain naphthalene (radiolucent or faintly radiopaque). Another distinguishing feature between naphthalene and paradichlorobenzene is that naphthalene will float in water while paradichlorobenzene will sink.
4) Ingestions of more than a single mothball should be followed for several days to rule out delayed hemolysis.

C) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

E) HEMOLYSIS

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Diuretics may be needed. Some authors advocate urinary alkalinization to prevent renal deposition of red blood cell break down products in the renal tubules and resultant renal failure, but efficacy is not clear.
2) SODIUM BICARBONATE/INITIAL DOSE

a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.

3) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

4) CAUTION

a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.

F) TRANSFUSION

1) Severe anemia due to hemolysis may require blood transfusions (Gosselin et al, 1984).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
B) Consider discarding contaminated clothing, as washing does not easily remove naphthalene.

Enhanced Elimination

A)

1) Not routinely recommended, but exchange transfusion or hemodialysis may help enhance elimination.

B)

1) Hemodialysis has been used for supportive care, but is not routinely recommended.
2) CASE REPORT: One patient with renal failure due to naphthalene was treated with hemodialysis and survived (Agarwal et al, 1993).

C)

1) Has been used for supportive care in patients with severe hemolysis, but is not routinely recommended.

Abstracts

Case Reports

A)

1) INFANT

a) ROUTE OF EXPOSURE

1) DERMAL: A 6-day-old child was exposed to diapers and blankets that had been stored in naphthalene. She developed heart murmur, cyanosis, and jaundice, and died within 4 days. Autopsy revealed hematopoiesis in the heart, liver, spleen, and adrenal glands. There were hemoglobin deposits in the renal tubules as well (Schafer, 1951).

b) ROUTE OF EXPOSURE

1) INHALATION: Hemolysis following inhalation was reported in 21 Greek infants, 9 of whom did not have glucose-6-phosphate dehydrogenase (G6PD) deficiency. Eight developed kernicterus and 2 died. Two children developed methemoglobinemia (Valaes et al, 1963).

Range Of Toxicity

Summary

A)

Therapeutic Dose

7.2.1)

A) DISEASE STATE

1) ANTHELMINTIC - Formerly used at doses of 100 to 500 milligrams per dose as an anthelmintic (ACGIH, 1986).

Minimum Lethal Exposure

A)

1) The acute lethal dose for humans is estimated between to be 5 g to 15 g (ACGIH, 1991; OHM/TADS, 2002; Sittig, 1991).
2) One source reported 2 g to 15 g as lethal for adults (Clayton and Clayton, 1981).
3) There have been recorded instances where some individuals died after ingesting 2 g (ACGIH, 1991; HSDB , 2002).
4) The lowest recorded lethal dose for a man is 74 mg/kg (ACGIH, 1991).

B)

1) 100 mg/kg is a lethal dose for children (Snyder, 1987). As little as 1 moth ball can cause serious toxicity, including methemoglobinemia and death, particularly in patients with glucose-6-phosphate (G6PD) dehydrogenase deficiency (Lim, 2006).
2) CASE REPORT: A 6-year-old child died after ingesting 2 g of naphthalene over a 2-day period (Bingham et al, 2001).
3) CASE REPORT: A 6-year-old boy died after taking seven 250 mg/kg powders. The total dosage was about 80 mg/kg, over 2 days (Hayes & Laws, 1991; Hayes, 1982).

Maximum Tolerated Exposure

A)

1) ENVIRONMENTAL BURDEN

a) Naphthalene is released primarily into the air (90%) with small amounts being released into water (5%) and soil (3%). Consequently, inhalation is the primary route of exposure in the general population. Naphthalene is released into the atmosphere from combustion fuels, cigarette smoke, and moth repellants (Preuss et al, 2003).
b) AVERAGE DAILY NAPHTHALENE INTAKE FROM AIR: 1.127 mcg/kg/day for an adult weighing 70 kg and 4.515 mcg/kg/day for a child weighing 10 kg (Preuss et al, 2003).
c) AVERAGE DAILY NAPHTHALENE INTAKE FROM FOOD: 0.041 to 0.237 mcg/kg/day for adults and 0.204 to 0.940 mcg/kg/day for children (Preuss et al, 2003).
d) AVERAGE DAILY NAPHTHALENE INTAKE FROM SOIL: 0.235 mcg/kg/day for adults and 3.3 mcg/kg/day for children (Preuss et al, 2003).

2) INGESTION

a) A 33-year-old woman became seriously ill after ingesting 47 mg/kg within 2 days, but recovered (Hayes & Laws, 1991; Hayes, 1982).
b) Some individuals have survived after ingesting 6 g of naphthalene (ACGIH, 1991).
c) Two individuals attempted suicide by taking 6000 mg and 10,000 mg of naphthalene. Both people completely recovered (Hayes & Laws, 1991; Hayes, 1982).
d) PEDIATRIC: 250 mg to 500 mg of pure naphthalene (less than one mothball) may cause toxicity in a child with glucose-6-phosphate (G6PD) dehydrogenase deficiency (Gross et al, 1958; Haggerty, 1956).

3) INHALATION

a) CASE REPORTS: A 26-year-old woman living with her 4-year-old daughter used 300 to 500 mothballs in their home as a pesticide and to manage foul odors. Analysis of air samples collected from their apartment showed detectable levels of naphthalene at 20 parts per billion. Headache, nausea, vomiting, confusion, malaise, and abdominal pain were included in symptoms reported by the woman, her daughter, 7 other family members living in 2 other households (also using moth balls), and visitors. Symptoms ceased in all family members and visitors when mothball use was discontinued (Centers for Disease Control (CDC), 1983).

4) OCULAR

a) Airborne concentrations of 15 ppm may produce eye irritation (ACGIH, 1991; Grant & Schuman, 1993; Hathaway et al, 1996; HSDB , 2002; Robbins, 1951; Sittig, 1991).

B)

1) A few hours after feeding rabbits one g/kg of naphthalene, mild toxicity was observed and a variety of changes occurred in the eye (Bingham et al, 2001; Grant & Schuman, 1993).
2) Subcutaneous doses of naphthalene at 820 mg/kg/day, did not have a tumorigenic effect on rats after more than 1000 days of observation (Clayton & Clayton, 1994).
3) There were no mortalities in a group of rats administered 2.5 g/kg of naphthalene (Bingham et al, 2001).
4) OCULAR (ACGIH, 1991):

a) Rabbits fed doses of 1 g/kg/day for up to 20 days showed browning of the lenses and eye humors, degeneration of the retina and cataract formation.
b) Cataracts developed in rabbits given oral doses of 2000 mg/kg/day for 5 days.

C)

1) Rats feed 10 g of naphthalene once a day for 6 days/week for over 700 days showed no signs of toxicity or carcinogenic activity (ACGIH, 1991).
2) Male mice exhibited no adverse effects in the testes after a diet of naphthalene at 133 mg/kg/day or 267 mg/kg day for 90 days (ACGIH, 1991). Female rats had reduced spleen weights at 133 mg/kg, otherwise, no ill effects were noted (Hayes & Laws, 1991).
3) Mice administered 200 mg/kg/day for 5 days/week for 13 weeks by gavage had no observed effects (HSDB , 2002).
4) Fifty mg/kg of naphthalene for 5 days/week for 13 weeks dispensed to rats by gavage did not cause any observed effects (HSDB , 2002).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) NAPHTHALENE METABOLITE CONCENTRATION

a) Exposure to naphthalene may be determined by measuring urine metabolites 1-naphthol and/or 2-naphthol (Preuss et al, 2003).

1) In 983 smoking and non-smoking, non-occupationally exposed individuals, the median naphthalene metabolite levels in urine were 4.4 mcg 1-naphthol/L urine and 3.4 mcg 2-naphthol/L urine, respectively (Preuss et al, 2003).
2) SMOKERS: Urine naphthol concentrations are 2.5 to 14 times higher among smokers compared with non-smokers (Preuss et al, 2003).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Naphthalene

a) TLV:

1) TLV-TWA: 10 ppm
2) TLV-STEL: 15 ppm
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: Skin
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Hematologic eff; URT and eye irr; eye dam
d) Molecular Weight: 128.19

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Under Study

1) Naphthalene

a) TLV:

1) TLV-TWA:
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s):
d) Molecular Weight:

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS91-20-3 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Naphthalene
2) REL:

a) TWA: 10 ppm (50 mg/m(3))
b) STEL: 15 ppm (75 mg/m(3))
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH:

a) IDLH: 250 ppm
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS91-20-3 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Naphthalene

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Naphthalene
3) EPA (U.S. Environmental Protection Agency, 2011): C ; Listed as: Naphthalene

a) C : Possible human carcinogen.

4) 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: Naphthalene

a) 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.

5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Naphthalene
6) MAK (DFG, 2002): Category 2 ; Listed as: Naphthalene

a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.

7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Naphthalene

a) R : RAHC = Reasonably anticipated to be a human carcinogen

D) OSHA PEL Values for CAS91-20-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Naphthalene
2) Table Z-1 for Naphthalene:

a) 8-hour TWA:

1) ppm: 10

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 50

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) ACGIH, 1991 CHRIS, 2002 Clayton & Clayton, 1994 Bingham et al, 2001 Hayes & Laws, 1991 Hayes, 1982 HSDB, 2002 ILO, 1998 Lewis, 2000 OHM/TADS, 2002 RTECS, 2002

1) LD50- (ORAL)HUMAN:

a) 2200 mg/kg (ILO, 1998)

2) LD50- (GAVAGE)MOUSE:

a) Male, CD-1, 533 mg/kg (HSDB, 2002)
b) Female, CD-1, 710 mg/kg (HSDB, 2002)

3) LD50- (INTRAPERITONEAL)MOUSE:

a) 150 mg/kg

4) LD50- (ORAL)MOUSE:

a) 316 mg/kg
b) 533 mg/kg (Bingham et al, 2001; Lewis, 2000)
c) Male, 533 mg/kg (Hayes & Laws, 1991)
d) Female, 710 mg/kg (Hayes & Laws, 1991)

5) LD50- (SUBCUTANEOUS)MOUSE:

a) 969 mg/kg -- tremors
b) 5.1 g/kg (ACGIH, 1991; Bingham et al, 2001)

6) LD50- (INTRAPERITONEAL)RAT:

a) 590 mg/kg (OHM/TADS, 2002)

7) LD50- (ORAL)RAT:

a) Sprague-Dawley, 2.6 g/kg (Bingham et al, 2001; HSDB, 2002)
b) 490 mg/kg
c) 1.8 g/kg (ACGIH, 1991)
d) 1780 mg/kg (grade 2) (CHRIS, 2002; ITI, 1995)
e) Male, 2000 mg/kg (OHM/TADS, 2002)
f) Male, Sherman, 2200 mg/kg (Hayes & Laws, 1991; Hayes, 1982; HSDB, 2002)
g) Female, Sherman, 2400 mg/kg (Hayes & Laws, 1991; Hayes, 1982; HSDB, 2002; OHM/TADS, 2002)

8) LD50- (SKIN)RAT:

a) >2500 mg/kg
b) >20 g/kg (Bingham et al, 2001)

9) TCLo- (INHALATION)MOUSE:

a) 30 ppm for 6H/2Y-intermittent -- neoplastic agent by RTECS criteria, tumors of the respiratory system

Pharmacology Toxicology

Toxicologic Mechanism

A)

1) 1,2-dihyroxynaphthalene or 1,2-naphthoquinone combine with amino acids or irreversibly with the thio groups of lens protein to cause oxidant stress and/or lipid peroxidation. Brown precipitates are formed (Stekol, 1935)(Van Heyningen, 1980)(Wells et al, 1989).

B)

1) A major pathway of detoxification depends on glucuronide conjugation in the liver (Boyland & Wiltshire, 1953; Stekol, 1935) (Van Heyningen, 1980).
2) Toxicity may be increased in newborns due to the inability of the newborn liver to conjugate both naphthalene and bilirubin. This could explain the severity of hyperbilirubinemia in the presence of only moderate hemolytic anemia (Dawson et al, 1958).
3) In rats, naphthalene treatment produced enhanced hepatic peroxidation with reduced glutathione efflux from hepatocytes (Germansky & Jamall, 1988; Richieri & Buckpitt, 1988).

C)

1) Naphthalene does not cause hemolysis unless metabolized.
2) The oxidation products of naphthalene (alpha and beta naphtho-quinones) are responsible for hemolysis. These metabolites cause instability of erythrocyte glutathione in patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency (Zinkham & Childs, 1957a) 1958; (Dawson et al, 1958).

D)

1) The effects of naphthalene on morphology and cellular respiration suggest that it is capable of inhibiting mitochondrial function (Harmon & Sanborn, 1982).
2) Experimental animal studies have reported depletion of pulmonary glutathione and dose-dependent bronchiolar epithelial cell necrosis (Richieri & Buckpitt, 1988; O'Brien et al, 1989).

Physicochemical

Physical Characteristics

A)

B)

Molecular Weight

A)

Animal Toxicology

References

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FeedBack

NAPHTHALENE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography