ORTHO-CRESOL

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) ortho-Cresol
2) 2-Cresol
3) o-Cresol
4) o-Cresylic acid
5) 1-Hydroxy-2-methylbenzene
6) o-Hydroxytoluene
7) 2-Hydroxytoluene
8) o-Kresol
9) o-Methylphenol
10) o-Methylphenylol
11) 2-Methylphenol
12) o-Methylphenylol
13) Orthocresol
14) o-Oxytoluene
15) Phenol, 2-methyl-
16) o-Toluol
17) CAS 95-48-7
18) CRESOL, ORTHO

1.2.1) MOLECULAR FORMULA
1) C7 H8 O (Howard, 1989). CH3 C6 H4 OH (Lewis, 1997)

Available Forms Sources

1) Ortho-cresol is a colorless to white crystalline compound. It exists as a liquid above 88 degrees F (HSDB , 2000).
2) Ortho-cresol's odor has been described as sweet, tarry and phenolic (HSDB , 2000).

1) It is prepared from meta-toluic acid by fractional distillation from coal tar (Budavari, 1996; Lewis, 1997; Gosselin et al, 1984).
2) It is obtained from fractional distillation of tar acid (HSDB , 2000).
3) Ortho-cresol is a byproduct of naphtha crackling. It is recovered from spent caustic liquor which is used to wash petroleum distillates. It is then isolated by fractional distillation as mixed cresols or as higher purity grades (HSDB , 2000).
4) Ortho-cresol may be separated from crude cresols by repeated fractional distillation in VACVO (Clayton & Clayton, 1994).
5) Cresols are normal metabolites of protein metabolism and from decomposition of steroid hormones (IRPTC, 1985).
6) o-Cresol is a component of cigarette smoke (Dalhamn, 1968).

1) ortho-Cresol is a phenolic compound used as a disinfectant and solvent, as a chemical intermediate for phenolic and epoxy resins, sulfur chromium dyes, herbicides, magnet wire coatings, pharmaceuticals, as a fiber treatment agent, tanning agent, in photographic developers, as a fumigant, explosive, ore flotation agent, and metal degreasing agent (Budavari, 1996; EPA, 1985; ACGIH, 1986).
2) Cresols are ingredients in the British disinfectant Lysol, which is a synonym for 50 percent cresol and soap solution, B.P. The British Lysol product has been used in many attempted suicides (Gosselin et al, 1984).
3) Several products sold in the United Kingdom contained up to 100 percent cresol and have been used to treat symptoms of whooping cough, bronchitis, croup, and colds by inhaling the vapors after heating (Pegg & Campbell, 1985).
4) Ortho-cresol is used in making synthetic resins. It is also used in disinfectants and fumigants and as an industrial solvent (Budavari, 1996).

Overview

Life Support

Clinical Effects

0.2.1)

A) o-Cresol is corrosive to tissues and can cause serious burns. It is rapidly absorbed by all routes and can be fatal by any route of exposure. Systemic effects include profound CNS depression, seizures, hemolysis, methemoglobinemia, pulmonary edema, and lung, liver, pancreas, spleen, heart, and kidney damage. Metabolic acidosis may occur.
B) Skin contact is the main exposure route. Pain is followed by numbness; skin reddens, then blanches, blisters, and forms a scab. Skin contact can result in severe skin burns. Eye contact produces irritation, redness, corneal burns, keratitis, and possibly, in severe cases, blindness.
C) Inhalation produces coughing and labored, fast breathing; respiratory failure may result. Ingestion causes a burning pain in the mouth and throat, and abdominal pain, nausea, vomiting, bloody diarrhea and collapse. White necrotic lesions of the mouth, throat and stomach are also seen.
D) Other exposure symptoms include confusion, pallor, sweating, weakness, headaches, dizziness, tinnitus, shock (weak irregular pulse, shallow breathing, cyanosis, pallor), seizures, unconsciousness, collapse, coma and death from heart and lung failure. Kidney damage results in scant, dark, 'smoky' urine and impaired renal function.
E) Chronic exposure may produce allergic dermatitis, digestive disturbances, CNS effects, and liver and kidney damage. Effects may include vomiting, diarrhea, anorexia, difficulty swallowing, excessive salivation, diarrhea, loss of appetite, headache, fainting, dizziness, mental disturbances, skin rash, or death from severe damage to the liver or kidneys.

0.2.3)

A) Shock with a weak irregular pulse, hypotension, shallow respirations, hypothermia and respiratory failure may occur.

0.2.4)

A) Direct eye contact with o-cresol may cause serious eye damage and blindness. One case of blindness with optic atrophy occurred from the unusual route of intrauterine injection of Lysol in an attempt to induce abortion. Ingestion of o-cresol may produce burning pain in the mouth and throat and white necrotic lesions in the mouth.

0.2.5)

A) Cardiac damage, hemorrhage, necrosis and shock may occur.

0.2.6)

A) PULMONARY EDEMA and other signs of acute pulmonary edema may occur even from dermal exposure and not simply aspiration. Many fatalities have been caused by respiratory failure due to profound CNS depression.

0.2.7)

A) CNS depression and brain damage may occur.

0.2.8)

A) Gastrointestinal disturbances, abdominal pain, vomiting, bloody diarrhea and white necrotic lesions in the esophagus and stomach may occur.

0.2.9)

A) Hepatotoxicity, hemorrhage and necrosis of the liver may occur.

0.2.10)

A) Kidney damage can occur. Scanty, dark-colored, or "smoky" urine can occur. Female enamel-wire workers exposed to cresol and other substances experienced excessive menstrual bleeding and gynecological disorders.

0.2.11)

A) Mild acidosis has been reported after acute poisoning from phenol and could presumably occur with o-cresol.

0.2.13)

A) o-Cresol may induce methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia.

0.2.14)

A) o-Cresol is corrosive to the skin and may cause serious burns. In one case, an industrial worker fell into a vat containing a cresol derivative and suffered burns over 15% of his body and died from anuria and congestive heart failure.
B) Fatalities from dermal exposure to household disinfectants or inhalants containing o-cresol have occurred. Infants and children seem to be especially sensitive to o-cresol. Gangrene and allergic dermatitis may occur.

0.2.20)

A) Although o-cresol is not a confirmed human reproductive hazard at the present time, female enamel-wire workers exposed to cresol and other substances experienced excessive menstrual bleeding, gynecological disorders and increased birth defects. There is speculation that methemoglobinemia may be especially harmful to the fetus.

0.2.21)

A) o-Cresol induced small but significant sister chromatid exchanges in human fibroblasts. In mice, o-cresol induced skin and appendage tumors. o- Cresol was not mutagenic in bacteria but it did induce C-mitosis in onion root-tips.

0.2.22)

A) Predisposing medical conditions or chemical exposures may increase sensitivity to o-cresol.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
B) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
D) METHEMOGLOBINEMIA: 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.
E) 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.
F) 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.
G) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

H) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.

0.4.3)

A) INHALATION: 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 an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.

0.4.4)

A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Shock with a weak irregular pulse, hypotension, shallow respirations, hypothermia and respiratory failure may occur.

3.3.2)

A) Respirations may be shallow in patients with CNS depression or shock, or may be labored in patients with pulmonary edema (Gosselin et al, 1984).
B) RESPIRATORY FAILURE - Many fatalities are from respiratory failure resulting from profound CNS depression (Clayton & Clayton, 1994; Gosselin et al, 1984).

3.3.3)

A) HYPOTHERMIA has occurred in cases of severe acute overexposure to o-cresol (Bowman et al, 1984).

3.3.4)

A) HYPOTENSION - Symptoms of acute exposure to o-cresol may include shock with weak irregular pulse and hypotension (inferred from phenol) (Gosselin et al, 1984).
B) HYPERTENSION - Was reported in a case of massive dermal exposure to cresol (Lin & Yang, 1992).

3.3.5)

A) PULSE - Symptoms of acute exposure to o-cresol may include shock with a weak irregular pulse; (inferred from phenol) (Gosselin et al, 1984).

Heent

3.4.1)

3.4.3)

A) BURNS/BLINDNESS - o-Cresol may cause serious damage and blindness from direct contact with the eye due to its corrosive nature (Grant & Schuman, 1993; Sittig, 1985).

1) Lysol has caused burns of the human eye with hyperemia and swelling of the conjunctiva, and opacification and superficial vascularization of the cornea which only partially cleared after several months (Grant & Schuman, 1993).

B) OPTIC ATROPHY - One case of blindness with optic atrophy occurred from the unusual route of intrauterine injection of Lysol in an attempt to induce abortion. There was unconsciousness and edema of the brain, optic nerve, and chiasm (Grant & Schuman, 1993).
C) EFFECTS IN ANIMALS - Permanent opacification and vascularization have been produced by application of full-strength cresols to rabbit eyes (Grant & Schuman, 1993).

1) Only moderate injury occurred when a 33% solution was thoroughly rinsed off within 60 seconds (Grant & Schuman, 1993).
2) o-Cresol was a severe irritant to the eyes of rabbits at 105 mg in a standard Draize test (RTECS , 2001).

3.4.6)

A) BURNS/NECROSIS - Ingestion of o-cresol may produce burning pain in the mouth and throat and white necrotic lesions in the mouth (Gosselin et al, 1984).

Cardiovascular

3.5.1)

A) Cardiac damage, hemorrhage, necrosis and shock may occur.

3.5.2)

A) HYPOTENSIVE EPISODE

1) Symptoms of acute exposure to o-cresol may include shock with weak irregular pulse and hypotension (Gosselin et al, 1984).

B) CARDIOVASCULAR FINDING

1) CARDIAC DAMAGE - Degeneration of the myocardium with small hemorrhages in the epicardium and endocardium have been reported from exposure to o-cresol in humans (Clayton & Clayton, 1994).
2) Hemorrhage and necrosis of the heart have been caused by dermal exposure to o-cresol (Finkel, 1983).

C) HYPERTENSIVE EPISODE

1) Hypertension has been reported from chronic inhalation of cresol vapors in the workplace (Finkel, 1983), in a case of massive dermal exposure (Lin & Yang, 1992), and large ingestion (Wu et al, 1998).

Respiratory

3.6.1)

3.6.2)

A) ACUTE LUNG INJURY

1) Acute exposures to o-cresol can produce pulmonary edema with hemorrhages in the pleura (Proctor & Hughes, 1978; Clayton & Clayton, 1994).
2) Stertorous breathing, rales, rhonchi, frothing at nose and mouth, and other signs of acute pulmonary edema may occur (inferred from phenol). These symptoms may occur even from dermal exposure and may therefore not be due simply to aspiration (Gosselin et al, 1984; Lin & Yang, 1992).

B) ADULT RESPIRATORY DISTRESS SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT - A 42-year-old woman developed acute respiratory distress syndrome after dermal absorption of Lysol(R) solution from prolonged chemical contact. The patient was found unconscious on her bathroom floor after a fall and was lying in cleaning solution, which produced second degree burns on her back and right shoulder affecting about 10% of the total body surface area. No oral corrosive injury was present. Chest x-ray showed diffuse pulmonary infiltrates. The patient required mechanical ventilation with persistent high oxygen requirements. Despite high dose steroid therapy with gradual tapering, the patient developed ARDS-related pulmonary fibrosis. After approximately 3 months, the patient was weaned from the ventilator and was discharged to home with a tracheostomy, occasional home ventilation (to decrease workload) and awaiting lung transplantation (Liu et al, 1999).

C) APNEA

1) Many fatalities are from respiratory failure due to profound CNS depression (Clayton & Clayton, 1994).

Neurologic

3.7.1)

A) CNS depression and brain damage may occur.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

2) The systemic effects of o-cresol are primarily on the central nervous system (Clayton & Clayton, 1994).
3) CNS effects of acute exposure to o-cresol (some inferred from phenol) include headache, dizziness, ringing in the ears, weakness, dimness of vision, irregular and rapid respirations, weak pulse, profound fulminating CNS depression with coma, hypothermia, and respiratory arrest (Gosselin et al, 1984; Proctor & Hughes, 1978).
4) Fleeting excitement or confusion may be followed by the above signs of CNS depression. Seizures may occur in children (Gosselin et al, 1984).

B) TOXIC ENCEPHALOPATHY

1) BRAIN DAMAGE - Hemorrhage and necrosis of the brain have been caused by dermal exposure to o-cresol (Finkel, 1983).

C) CHRONIC POISONING

1) Chronic inhalation of the vapor has been associated with headache, tremors, and dizziness (Proctor & Hughes, 1978; Finkel, 1983).

3.7.3)

A) ANIMAL STUDIES

1) ENZYME ABNORMALITY

a) RATS - Some biochemical changes were seen in the brains of rats given o-cresol (0.3 g/L) in their drinking water for 20 weeks: increased RNA content, reduced glutathione concentration and azoreductase activity, increased acid proteinase and 2',3'-cyclic nucleotide 3'- phosphohydrolase activities in glial cells. These changes were inconspicuous (Savolainen, 1979).

Gastrointestinal

3.8.1)

A) Gastrointestinal disturbances, abdominal pain, vomiting, bloody diarrhea and white necrotic lesions in the esophagus and stomach may occur.

3.8.2)

A) GASTROENTERITIS

1) BURNS/NECROSIS - Gastroenteric disturbances can occur from acute exposures to o-cresol (Clayton & Clayton, 1994; Proctor & Hughes, 1978).
2) Ingestion may produce abdominal pain, vomiting, bloody diarrhea, and white necrotic lesions in the esophagus and stomach (Gosselin et al, 1984).
3) Upper GI bleeding was reported in a patient with dermal exposure (Lin & Yang, 1992).

B) CHRONIC POISONING

1) DIGESTIVE DISTURBANCES - Chronic exposure to o-cresol can produce digestive disturbances including vomiting and anorexia (Proctor & Hughes, 1978; Clayton & Clayton, 1994).

Hepatic

3.9.1)

A) Hepatotoxicity, hemorrhage and necrosis of the liver may occur.

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

2) HEPATOTOXICITY - Liver damage can occur from either acute or repeated exposure. Turbidity, inflammatory reactions, and fatty degeneration have been seen in humans (Clayton & Clayton, 1994).

B) HEPATIC NECROSIS

1) Hemorrhage and necrosis of the liver have been caused by dermal exposure to o-cresol (Finkel, 1983).

Genitourinary

3.10.1)

3.10.2)

A) NEPHRITIS

1) KIDNEY DAMAGE - Kidney injury can occur from either acute or repeated exposure to o-cresol. Parenchymatous and hemorrhagic nephritis have been reported in humans (Clayton & Clayton, 1994).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT - A 44-year-old man self-reported ingesting 300 mL (150 g) of a 50% saponated cresol solution and presented with corrosive gastrointestinal injury, transient CNS and respiratory depression, liver injury and acute renal failure. Following aggressive care including hemodialysis, the patient recovered completely(Wu et al, 1998).
b) CASE REPORT - Acute renal failure, with hematuria and anuria, developed several hours after dermal exposure over 40% of total body surface area (Lin & Yang, 1992).

2) Hemorrhage and necrosis of the kidney have been caused by dermal exposure to o-cresol (Finkel, 1983).

C) ANURIA

1) OLIGURIA/ANURIA - Scanty, dark-colored, or "smoky" urine can occur in cases of kidney damage. Moderately severe renal insufficiency may develop in cases where death is not immediate (inferred from phenol) (Gosselin et al, 1984).

D) BLACK URINE

1) WITH POISONING/EXPOSURE

a) SUMMARY: Black urine can be a prominent feature of cresol intoxication. Other potential differential diagnoses of black urine may include: hemoglobinuria, myoglobinuria, alkaptonuria, melanuria, porphyrinuria, and tyrosinuria (Liu et al, 2009).
b) CASE REPORT - A 45-year-old man developed black urine after ingesting an unknown amount of cresol. His hospital course was complicated by liver and renal function impairment, pneumonia and gastrointestinal symptoms. He recovered completely following supportive care (Liu et al, 2009).

E) MENORRHAGIA

1) GYNECOLOGICAL EFFECTS - Female enamel-wire workers exposed to cresol and other substances experienced excessive menstrual bleeding and gynecological disorders (Syrovadko & Malsheva, 1977).

3.10.3)

A) ANIMAL STUDIES

1) FERTILITY DECREASED FEMALE

a) RATS - Tricresol (mixture of the three isomers) prolonged the estrous cycle and reduced the number of primary follicles in the ovaries of rats inhaling 4 mg/m(3) for 4 months (IRPTC, 1985).

Acid-Base

3.11.1)

A) Mild acidosis has been reported after acute poisoning from phenol and could presumably occur with o-cresol.

3.11.2)

A) ACIDOSIS

1) Mild acidosis has been present after acute poisoning from phenol and could presumably occur with o-cresol (Gosselin et al, 1984).

Hematologic

3.13.1)

A) o-Cresol may induce methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia.

3.13.2)

A) METHEMOGLOBINEMIA

1) HEMOLYSIS/METHEMOGLOBINEMIA - o-Cresol may induce methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia (Gosselin et al, 1984).
2) In most cases the methemoglobin formation appears to be secondary to red blood cell lysis (Larcan et al, 1974). However, there has been at least one case where methemoglobinemia occurred in the absence of extensive hemolysis (Chan et al, 1971).

B) PANCYTOPENIA

1) Pancytopenia and anemia refractory to blood transfusions were reported after dermal exposure to cresol (Lin & Yang, 1992).

3.13.3)

A) ANIMAL STUDIES

1) ANIMAL STUDIES

a) RABBITS - Inhaling cresol was associated with decreased hemoglobin, lower red blood cell count, and thrombocytopenia and leukopenia (Laux, 1934).

Dermatologic

3.14.1)

3.14.2)

A) CHEMICAL BURN

1) CORROSIVE/BURNS - o-Cresol liquid or aerosol is corrosive to the skin and may cause serious burns. There may be no immediate sensation with prickling and intense burning after a few moments, followed by a loss of feeling due to subcutaneous nerve damage. Affected skin shows wrinkling, erythema, white or brown discoloration, and softening (Sittig, 1985; Finkel, 1983; Gosselin et al, 1984; Proctor & Hughes, 1978).
2) CASE REPORT - One fatality has been reported from industrial exposure. A worker fell into a vat containing a cresol derivative, suffered burns over 15% of his body, and died from anuria and congestive heart failure (Finkel, 1983).
3) CASE SERIES - There have been some fatalities from dermal exposure to household disinfectants or inhalants containing o-cresol. Infants and children appear to be especially sensitive to dermal exposure (Finkel, 1983; Arthur, 1972; Green, 1975).

B) GANGRENE

1) Gangrene may follow dermal exposure (Sittig, 1985; Proctor & Hughes, 1978) because of extensive chemical cauterization of skin, nerves, and blood vessels.

C) DERMATITIS

1) ALLERGIC DERMATITIS - Skin rash (allergic dermatitis) may develop after prolonged or repeated contact with low concentrations of o-cresol (Sittig, 1985; Proctor & Hughes, 1978).
2) Some persons are hypersensitive to the dermatological effects of o-cresol (Proctor & Hughes, 1978; Clayton & Clayton, 1994).

D) DISCOLORATION OF SKIN

1) There is a rare condition called OCHRONOSIS associated with prolonged skin contact with cresols. Symptoms include a darkening of the skin, conjunctiva, and cartilage of the nose and ears (Proctor & Hughes, 1978).

3.14.3)

A) ANIMAL STUDIES

1) RASH

a) RABBITS - o-Cresol was a severe irritant of the skin in rabbits at 524 mg/24 in a standard Draize test (RTECS , 2001).

Immunologic

3.19.2)

A) DERMATITIS

1) ALLERGIC DERMATITIS - Skin rash (allergic dermatitis) may develop after prolonged or repeated contact with low concentrations of o-cresol (Sittig, 1985; Proctor & Hughes, 1978).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) POSSIBLE BIRTH DEFECTS - Female enamel-wire workers exposed to cresol and other substances experienced excessive menstrual bleeding, gynecological disorders, and increased birth defects (Syrovadko & Malsheva, 1977). o-Cresol is not a confirmed human reproductive hazard at the present time.

3.20.3)

A) CONGENITAL ANOMALY

B) METHEMOGLOBINEMIA

1) There has been some speculation that methemoglobinemia may be especially harmful to the fetus.
2) Infants, who would have had high levels of residual fetal hemoglobin, were especially sensitive to cyanosis induced by aniline in laundry marking dyes used on diapers (Rayner, 1986).
3) Fetal hemoglobin is more easily oxidized to methemoglobin than the adult form, and infants have impaired ability to reduce methemoglobin back to normal hemoglobin (Ross & Desforges, 1959). These two factors result in theoretically higher levels of methemoglobin in the fetus than in the mother exposed to the same conditions.
4) Theoretically the fetus would be most sensitive during the last trimester, when its demand for oxygen is greatest. Effects of methemoglobinemia on the fetus would be expected to be similar to those known to be produced by carbon monoxide: CNS dysfunction and delayed neuromotor development in the absence of overt structural malformations. There are no known cases of prenatal effects from methemoglobinemia in humans, however.
5) In one study, slightly higher levels of methemoglobin were found in women who aborted or threatened to abort in the first trimester (Schmitz, 1961).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of o-cresol exposure during lactation.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS95-48-7 (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) Not Listed

3.21.2)

3.21.4)

A) SKIN HYPERTROPHY

1) MICE - o-Cresol was neoplastic by RTECS criteria for inducing skin tumors in mice when applied to the skin; lowest effective dose was 4800 mg/kg/12W (RTECS , 2001).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor methemoglobin levels if cyanosis is present.
B) Black urine can be a prominent finding of creosol intoxication.
C) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
2) Liver function tests may be indicated but hyperbilirubinemia is generally due to hemolysis (from phenol) (Gosselin et al, 1984).

B) HEMATOLOGIC

1) If cyanosis is present, monitor methemoglobin levels.
2) Monitor hemoglobin, hematocrit, urinalysis, plasma free hemoglobin, and possibly other tests for hemolysis if this condition is suspected.

4.1.3)

A) URINARY LEVELS

1) Cresols are normally present in human urine. This should be taken into account in determining elevated levels (Clayton & Clayton, 1994).

B) URINALYSIS

1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
2) Urinalysis which is positive for blood, but contains few or no RBC's can be an early indication of hemolysis.

C) URINE COLOR CHANGE

1) Black urine can be a prominent finding of creosol intoxication (Liu et al, 2009).

4.1.4)

A) OTHER

1) MONITORING

a) Medical surveillance for chronic exposure should include preplacement and annual physical examinations emphasizing the liver, kidneys, respiratory system, and skin (Proctor & Hughes, 1978). Attention should also be given to possible neurological and gastrointestinal disturbances.
b) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.

2) PULMONARY FUNCTION TESTS

a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Radiographic Studies

1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

1) o-Cresol vapors can be monitored in the air by absorption onto silica, workup with acetone and analysis by gas chromatography according to NIOSH Methods, Set L (Sittig, 1985).
2) o-Cresol can be measured in air by absorption in dilute alkali and colorimetric determination with diazotized p-nitroaniline. Alternatively it can be absorbed in spectrograde alcohol and determined directly by UV spectrophotometry (Clayton & Clayton, 1982).
3) o-Cresol can be measured in urine by extraction with ether followed by distillation at 100 degrees C. After reaction with 4-aminoantipyrine to separate the o- and m- isomers from p-cresol and phenol, o-cresol can be separated from the m- isomer by paper chromatography (Clayton & Clayton, 1982).

1) Fatal concentrations from ingestion of a solution containing phenol and o-cresol were determined simultaneously using gas chromatography/mass spectrometry. Extractions from the stomach contents were obtained by gel permeation with cyclohexane/dichloromethane, by solid phase extraction from urine samples and by deproteinization with acetonitrile from blood samples. The phenol and o-cresol concentrations found were 115.0 mcg/g and 5.0 mcg/g in the stomach contents, 58.3 mcg/mL and 1.9 mcg/mL in the blood, and 3.3 mcg/mL and 20.5 mcg/mL in the urine, respectively (Boatto et al, 2004).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

Monitoring

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Do NOT induce emesis.

6.5.2)

A) EMESIS

1) Do NOT induce emesis.

B) NASOGASTRIC TUBE

1) INDICATIONS: Consider insertion of a small, flexible nasogastric tube to aspirate gastric contents after large, recent ingestion of caustics. The risk of worsening mucosal injury (including perforation) must be weighed against the potential benefit.
2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric emptying.
b) AIRWAY PROTECTION: Alert patients - place in Trendelenburg and left lateral decubitus position, with suction available. Obtunded or unconscious patients - cuffed endotracheal intubation. COMPLICATIONS:

1) Complications of gastric aspiration may include: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach (Vale, 1997). Combative patients may be at greater risk for complications.

6.5.3)

A) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

B) IRRITATION SYMPTOM

1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
2) If severe burns are present and either perforation or bleeding occur, surgical consultation should be obtained.

C) LABORATORY TEST

1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
2) Monitor methemoglobin levels in cyanotic patients.

D) AIRWAY MANAGEMENT

1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation may be required.

E) 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, 2009; 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).

F) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

G) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

H) 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.

I) HEMOLYSIS

1) If significant hemolysis occurs, transfusion therapy may be necessary.
2) Monitor and maintain a good urine output.

a) Urine alkalinization with sodium bicarbonate may help prevent renal damage from RBC breakdown products.

J) HYPOTHERMIA

1) Carefully monitor rectal temperature in cases of significant exposure.
2) Warming measures should be undertaken if hypothermia occurs.

K) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.

L) MALIGNANT HYPERTENSION

1) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

2) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

3) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

4) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

5) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

7) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

8) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

M) ENDOSCOPIC PROCEDURE

1) There is little information regarding the use of endoscopy, corticosteroids or surgery in the setting of concentrated ortho cresol ingestion. The following information is derived from experience with other corrosives.
2) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
3) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
4) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)

5) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):

a) Advancing across the cricopharynx under direct vision
b) Gently advancing with minimal air insufflation
c) Never retroverting or retroflexing the endoscope
d) Using a pediatric flexible endoscope
e) Using extreme caution in advancing beyond burn lesion areas
f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).

6) GRADING

a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
b) Grade 0 - Normal examination
c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.

7) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
8) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
9) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).

N) CORTICOSTEROID

1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
8) STUDIES

a) ANIMAL

1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).

b) HUMAN

1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
2) META ANALYSIS

a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).

3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).

a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).

6) ADVERSE EFFECTS

a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).

O) SURGICAL PROCEDURE

1) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
2) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
3) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).

a) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).

4) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
5) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
6) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).

a) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).

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.

6.7.2)

A) IRRITATION SYMPTOM

1) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
2) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).

a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.

1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).

3) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
4) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
5) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

B) ACUTE LUNG INJURY

C) AIRWAY MANAGEMENT

D) OBSERVATION REGIMES

1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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).

6.8.2)

A) SUPPORT

1) As severe irritation or burns may occur, prolonged initial flushing and early ophthalmologic consultation are advisable.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) Like phenol, small amounts of water can dilute the cresol and expand the involved area, increasing the penetration and risk of systemic toxicity. Decontamination should consist of copious (deluge) quantities of water, or repeated sponging with polyethylene glycol 300 or 400. The PEG should be removed with soap and water following decontamination (Lin & Yang, 1992).

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

B) SKIN ABSORPTION

1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
2) Pulmonary edema and fatalities have occurred following dermal exposure.

C) ACUTE LUNG INJURY

D) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) If renal failure occurs, treatment with hemodialysis may be required.

1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

1) One fatality has been reported from industrial exposure. A worker fell into a vat containing a cresol derivative, suffered burns over 15 percent of his body, and died from anuria and congestive heart failure (Finkel, 1983).
2) Of two patients who had swallowed Lysol, one developed methemoglobinemia, reduced red cell glutathione, and large solitary Heinz bodies. The other had methemoglobinemia and multiple small Heinz bodies but no frank hemolysis (Chan et al, 1971).
3) Massive intravascular Heinz-body hemolytic anemia and bizarre-looking erythrocytes were seen in a 52-year-old man who had swallowed approximately 100 ml of penetrating oil containing 85 percent kerosene, 12 percent cresol, and 2 percent surfactant. Immediate erythrocytaphresis and forced diuresis successfully resolved the conditions (Cote et al, 1984).
4) A 32-year-old man who had swallowed more than 25 mL of a vaporizer solution containing 90 percent cresols developed dyspnea, tachycardia, respiratory failure, and systolic hypotension 12 to 24 hours after exposure. Total serum phenols were 9 mg/100 mL, with no free phenol detected. Oxygenation became increasingly difficult and the patient died of myocardial failure and fulminating pulmonary edema on the fourth day in spite of hemodialysis and forced diuresis to remove the phenol. No methemoglobin was found but occasional Heinz bodies were seen (Arthurs et al, 1977).
5) A 23-year-old man who swallowed brake fluid composed of kerosene and cresol developed intractable hypoxia which proved fatal (Faure et al, 1973).
6) A 74-year-old woman institutionalized for depression died from drinking an unknown quantity of Lysol. No injury was evident to the mouth, throat, or upper two-thirds of the esophagus. The lower third of the esophagus and the entire stomach lining were bleached white. Brown discoloration of the face and mouth were evident.

a) Autopsy revealed intense mucosal edema in the trachea and bronchi from inhaled necrotic tissue of the esophagus, congested lungs, necrotic and hemorrhagic stomach mucosa, small perforations in the gastric wall, a soft and almost black liver, and congested spleen, pancreas, and kidneys (Bruce et al, 1976).

7) Postal workers exposed to fumes for 4 days from mail contaminated with cresols, phenol, and methylene chloride developed headaches, nausea, vomiting, weakness, diarrhea, numbness of the hands and face, and exacerbation of asthma in one person (Pike, 1988).
8) A 46-year-old man spilled hot cresol solution over his upper trunk, covering 40% of total body surface area. Several hours later he developed hematuria and oliguria. Hemodialysis was started on the second day for renal failure. Complications over the first 10 days included hypertension, anemia, pancytopenia, and ARDS. Septic shock occurred on day 15. He recovered without need for skin grafting and was discharged 38 days after the injury (Lin & Yang, 1992).

1) A 12-month-old baby died after having about 20 mL of coal tar vaporizer fluid poured onto the top of the head. All internal organs smelled strongly of cresol. Hemorrhagic pulmonary edema, congested kidneys, bloodstained pleural effusions, swelling and congestion of the brain, and bloody urine were found on post-mortem examination. Blood contained 12 mg/100 mL cresols (Green, 1975).
2) A 3-year-old child died and an 18-month-old sustained extensive burns from having cresylene vaporizing fluid poured on them (Arthur, 1972).

Range Of Toxicity

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) POSTMORTEM BLOOD CONCENTRATIONS

a) ORAL EXPOSURE

1) Following ingestion of an unknown amount of solution, postmortem phenol and ortho-cresol concentrations in the blood of a 31-year-old male, were 58.3 mcg/mL and 1.9 mcg/mL, respectively (Boatto et al, 2004).

2) URINARY CONCENTRATIONS

a) A 45-year-old man ingested an unknown amount of cresol and had the following urine concentrations: para-cresol, meta-cresol and ortho-cresol, and phenol of 10,186, 11,015, 388 and 101 mg/g creatinine, respectively. He recovered completely with supportive care (Liu et al, 2009).

Workplace Standards

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) Cresol, all isomers

a) TLV:

1) TLV-TWA: 20 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: IFV, 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) IFV: Inhalable fraction and vapor.
c) 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): URT irr
d) Molecular Weight: 108.14

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 CAS95-48-7 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: o-Cresol
2) REL:

a) TWA: 2.3 ppm (10 mg/m(3))
b) STEL:
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 CAS95-48-7 :

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

2) EPA (U.S. Environmental Protection Agency, 2011): C ; Listed as: 2-Methylphenol

a) C : Possible human carcinogen.

3) 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
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: o-Cresol
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS95-48-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) References: RTECS, 2001

1) LD50- (ORAL)MOUSE:

a) 344 mg/kg

2) LD50- (ORAL)RAT:

a) 121 mg/kg -- Behavioral, lung, thorax, or respiration, gastrointestinal

3) LD50- (SKIN)RAT:

a) 620 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

1) The cresols appear to have a similar mode of action to phenol (Clayton & Clayton, 1994).
2) Phenols can denature and precipitate proteins. They are general cellular poisons and do not have any specific antidote once absorbed (Bowman et al, 1984).

Physicochemical

Physical Characteristics

Molecular Weight

Other

1) Cresol odor is recognized at 5ppm (Hathaway, 1996).

Animal Toxicology

References

General Bibliography

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ORTHO-CRESOL

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

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

General Bibliography