XYLENE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) XYLENE
2) BENZENE, DIMETHYL-
3) DIMETHYLBENZENE
4) METHYL TOLUENE
5) VIOLET 3
6) XYLOL
7) NCI-c 55232
8) CAS 95-47-6 (o-xylene)
9) CAS 106-42-3 (p-xylene)
10) CAS 108-38-3 (m-xylene)
11) CAS 1330-20-7 (xylenes)

1.2.1) MOLECULAR FORMULA
1) C8-H10 C6H4(CH3)2

Available Forms Sources

1) The specific distribution of the various isomers depends in the raw material, but typically, 44 to 85% of the isomers are the meta-form (Baselt, 2000; HSDB , 2001).
2) Xylene may be contaminated with benzene; benzene toxicity may be seen if it constitutes more than 0.02 percent (200 ppm). Other impurities may include ethylbenzene or trimethylbenzene, toluene, phenol, thiophene, pyridine and pseudocumene (Cavender, 1994; Harbison, 1998; HSDB , 2001) NIOSH, 1975; Riihimaki & Cavender, 1987).
3) The grade of xylene is determined by the boiling point range and isomer content of the solvent. Typical available grades are nitration, 2, 3, 4, 5 and 10 degrees grade, and industrial grade (HSDB , 2001; Lewis, 1997).

1) Xylene is produced by fractional distillation of petroleum, coal tar, or coal gas, by catalytic reforming from petroleum followed by separation of p-xylene by continuous crystallization, and from toluene by transalkylation or dysproportionation (ACGIH, 1991; Budavari, 1996; Lewis, 1997).
2) When heated to decomposition, xylene emits acrid smoke and irritating fumes (Lewis, 2000).
3) It can be obtain via pyrolysis of gasoline, and is a by-prduct of coke manufacturing (HSDB , 2001).
4) Xylene was first isolated from a crude wood distillate. It is now manufactured from pseudocumene (Budavari, 1996).

1) Xylene is used as a solvent in paints, printing inks, varnishes, dyes, cements and cleaning fluids. Other uses include the manufacture of plastics, synthetic textiles, perfumes, insect repellants,epoxy resins, herbicides and pharmaceutical preparations (HSDB , 2001; Lewis, 1998).
2) It is the raw material for the production of benzoic acid, phthalic anhydride, isophthalic and terephthalic acids and their dimethyl esters, and it is used to sterilize catgut (Budavari, 1996).
3) It is commonly used as a safer replacement for benzene, in the synthesis of synthetic agents and it is a component of gasoline (HSDB , 2001).

a) Xylene can be back-blended into gasoline. It is an unrecovered component of gasoline (HSDB , 2001).
b) The following percentages of xylene are typically found in gasoline (Harbison, 1998):

1) Leaded: 5.6%
2) Unleaded: 6.6%
3) Super unleaded: 7.4%

4) Xylenes are also a component of aviation fuels (Lewis, 1997).
5) Laboratory exposure frequently occurs during the preparation of histology tissue specimens (Baselt, 2000).

a) Xylene is contained in Canada balsam used in oil-immersion microscopy, and it is used as clearing agent in the preparation of histological sections (Budavari, 1996).

6) Xylene is used as an indirect food additive for use only as a component of adhesives, and it is used as an indirect food additive polymer for use as a basic component of single and repeated use food contact surfaces. It is a solvent used in polysulfide polymer-polyepoxide resins (HSDB , 2001).
7) The most frequent harmful effects on the user's health occur during spray painting (Sandmeyer, 1981).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Xylene is an aromatic hydrocarbon consisting of a benzene ring with 2 methyl substituents. It is widely used as a solvent in paint, printing inks, varnishes, dyes, cement and cleaning fluids. Xylene is also found in gasoline and aviation fuels. It is used in the manufacture of plastics, synthetic textiles, perfumes, insect repellants, epoxy resins, herbicides and pharmaceutical preparations.
B) TOXICOLOGY: Xylene is an aromatic hydrocarbon solvent that causes CNS depression and is an irritant of skin and mucus membranes. It preferentially accumulates in the brain and fatty tissue after inhalation. It has a lower volatility, lower affinity for the CNS, and a lower acute toxicity compared to toluene or benzene.
C) EPIDEMIOLOGY: Hundreds of exposures to aromatic hydrocarbons are reported to poison centers every year and exposure is common in certain petrochemical industries but serious toxicity is rare.
D) WITH POISONING/EXPOSURE

1) INHALATION: Low concentrations are irritating to mucous membranes. Xylene may cause reversible hepatic and renal toxicity. High vapor concentrations can cause initial CNS excitation followed by narcosis, olfactory changes, respiratory tract irritation, and acute lung injury. Severe exposures may be fatal due to respiratory arrest and/or ventricular dysrhythmias.
2) INGESTION: Minor ingestions can cause mucous membrane irritation, a burning sensation in the oropharynx and stomach and vomiting. Large ingestions can cause ventricular fibrillation, reversible hepatic and renal toxicity and CNS depression. Pulmonary aspiration can cause pneumonitis and acute lung injury.
3) DERMAL: Exposure to xylene liquid can cause defatting of the skin with irritation, dryness, erythema, and cracking. Blistering may occur if exposure or concentrated xylene is prolonged.
4) OCULAR: Exposure to high vapor concentrations of xylene can cause ocular irritation. Vacuolar keratopathy has occurred in a few workers with prolonged exposure to high vapor concentrations. Splash accidents produce transient superficial injury in most cases, though there are older reports of conjunctivitis and corneal burns following eye contact with liquid xylene.
5) CHRONIC: Exposure to xylene may cause a defatting dermatitis, reversible eye damage, dyspnea, confusion, dizziness, apprehension, memory loss, headache, tremors, weakness, anorexia, nausea, tinnitus, irritability, thirst, liver function test abnormalities, renal impairment, and anemia. Xylene contaminated with benzene has been associated with blood dyscrasias.

0.2.20)

A) There are few well-conducted studies of the reproductive effects of xylene exposure in humans. Very limited data suggest that toxicosis, miscarriage, hemorrhage during childbirth, and infertility may occur. There is evidence in experimental animals that xylene is embryotoxic, fetotoxic, and possibly teratogenic, usually at doses which cause maternal toxicity.
B) Human studies concerning the reproductive effects of xylene have limitations, in that exposures are usually to more than one solvent (benzene, toluene and other compounds are common), exposure data are often lacking and endpoints are not sufficiently specific.

0.2.21)

A) There is inadequate information concerning carcinogenic effects of xylene in humans. Non-Hodgkin's lymphoma has been potentially associated with exposure to solvents, including xylene. However, xylene is not regarded as a human carcinogen.
B) The EPA classifies xylenes as Group D (not classifiable as to human carcinogenicity), based on no human data and inadequate animal data (HSDB, 2002).

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients with mild to moderate toxicity should do well with standard decontamination and good supportive care. The most common exposure from xylene is from inhalation; removal of patient to fresh air and supportive treatment of systemic symptoms should result in complete recovery in most patients.

B) MANAGEMENT OF SEVERE TOXICITY

1) In patients with severe toxicity, patients may require more aggressive respiratory support, including intubation. In patients with hydrocarbon pulmonary aspiration, there is some evidence for the use of an artificial surfactant. Cardiac dysrhythmias can be treated with standard ACLS protocols; epinephrine and other sympathomimetics should be avoided as it may potentiate ventricular dysrhythmias.
2) INHALATION: Move patient to fresh air and monitor for respiratory distress. Administer oxygen and assist ventilation as needed. For patients with bronchospasm, give inhaled beta 2 agonists or corticosteroids as needed. Monitor fluid and electrolyte status. If patients develop dysrhythmias, treat with standard ACLS medications; epinephrine and other sympathomimetics should be avoided as it may potentiate ventricular dysrhythmias.
3) DERMAL: Remove contaminated clothing and wash exposed area thoroughly with soap and water. Barrier creams, protective gloves, and topical steroids may be required to prevent and treat dermatitis symptoms. Treat systemic effects as needed.
4) OCULAR: Irrigate exposed eyes with copious amounts of room temperature water or saline for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persists, a careful ophthalmologic exam, including slit lamp, should be performed.
5) PARENTERAL: Parenteral exposure to xylene is extremely rare; supportive care of resulting symptoms is the mainstay of treatment.

C) DECONTAMINATION

1) PREHOSPITAL: GI decontamination is not indicated due to the potential for aspiration. Remove contaminated clothing and wash exposed areas with soap and water. Irrigate exposed eyes with normal saline or water for at least 15 minutes.
2) HOSPITAL: GI decontamination is not indicated due to the potential for aspiration. Remove contaminated clothing and wash exposed areas with soap and water. Irrigate exposed eyes with normal saline or water for at least 15 minutes.

D) AIRWAY MANAGEMENT

1) Airway management can be an issue for patients with severe respiratory distress or CNS depression, so severe exposure may require early intubation.

E) ANTIDOTE

1) There is no specific antidote for xylene exposure.

F) ENHANCED ELIMINATION

1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization or multiple dose activated charcoal for xylene exposure. Hemodialysis or hemoperfusion is unlikely to be helpful, as peak blood concentrations of xylene occur very quickly after exposure and the xylene quickly redistributes throughout the body.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with inadvertent ingestions of small quantities of hydrocarbons can remain at home. Eye and skin exposures with only minor irritation can be managed at home after washing or irrigation.
2) OBSERVATION CRITERIA: Any patient with symptoms greater than minor irritation, and any deliberate exposure should be sent to a healthcare facility for evaluation and treatment.
3) ADMISSION CRITERIA: Patients who remain symptomatic should be admitted until they are clearly improving or asymptomatic. Patients with significant CNS depression, dysrhythmias, or pulmonary toxicity should be admitted to an ICU.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with significant symptoms. Consult a pulmonologist or intensivist for patients with significant pulmonary toxicity.

H) PITFALLS

1) Epinephrine and other sympathomimetics may precipitate refractory dysrhythmias.

I) TOXICOKINETICS

1) Xylene is rapidly absorbed following inhalation (60% absorbed, peak concentrations 15 to 30 min) or ingestion (peak concentration 1 to 2 hours). It is less well absorbed through intact skin. The main metabolic pathway is through the cytochrome p450-dependent monooxygenase system to the corresponding 0-, m-, or p-toluic acid. The corresponding toluic acid is then excreted in the form of a glycine conjugate as 0-, m- or p-methyl hippuric acid. Approximately, 72% to 95% of absorbed xylene is excreted in the urine within 18 hours as hippuric acid. The initial half-life in blood is 0.5 to 1 hour while the terminal half-life is 20 to 30 hours.

J) PREDISPOSING CONDITIONS

1) Patients at the extremes of age or associated comorbid conditions (such as asthma or chronic obstructive pulmonary disease) may be more sensitive to xylene exposures.

K) DIFFERENTIAL DIAGNOSIS

1) A toluene ingestion can appear similar, but is usually more severe. Other hydrocarbon exposures may share similar features of a xylene exposure.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) CASE REPORT: Severe hypothermia was reported in one case after massive exposure to xylene vapors (Morley et al, 1970). The worker was possibly exposed for 18.5 hours to estimated xylene vapor concentrations of 10,000 ppm.

Heent

3.4.3)

A) IRRITATION

1) VAPORS

a) A 15 minute exposure to vapor concentrations of greater than 400 ppm produced a sensation of mild eye irritation in 4 of 6 volunteers, but did not produce eye discomfort at lower concentrations (Carpenter et al, 1975).
b) Some persons may experience ocular discomfort at vapor concentrations of 200 ppm (Grant & Schuman, 1993).

2) LIQUID

a) Splashes in human eyes generally cause transient superficial injury. Recovery is rapid (Grant & Schuman, 1993). An older publication reported conjunctivitis and corneal burns from eye contact with xylene (Sandmeyer, 1981).

1) Corneal corrosion in one worker and partial loss of the corneal and conjunctival epithelia of another worker following ocular contact with xylene-containing paint was reported (Ansari, 1997). These effects were rated as grade II chemical burns, similar to that produced by alkaline materials. The paint pH was 8.5 to 8.9. Other potentially harmful chemicals were also present in the paint.

a) The chemical burns were treated with topical steroids, cyclopentolate, vitamin C, and antibiotic drops. Healing occurred within 5 to 8 days of paint exposure in these 2 workers.

b) RABBITS: Discomfort, blepharospasm, conjunctivitis and mild reversible corneal injury has been produced in rabbits (Grant & Schuman, 1993). In rabbit eyes in the Standard Draize Test, results were reported as mild in one study and severe in another (RTECS , 2000).
c) RABBITS: Application of 2 drops of xylene into rabbit eyes produced slight conjunctival irritation and very slight transient corneal injury (Wolf et al, 1956).

B) KERATOPATHY

1) All-day exposure to high vapor concentrations caused vacuolar epithelial keratopathy in several workers, with symptoms of foggy vision and photophobia. The lesions resolved within 2 to 4 weeks (Grant & Schuman, 1993; Riihimaki & Hanninen, 1987).
2) Furniture polishers exposed to mixed solvents containing xylene who had complaints of eye irritation and photophobia clinically had corneal epithelial vacuoles (Riihimaki & Hanninen, 1987).
3) CASE REPORT: A 24-year-old man developed decreased visual acuity, irritation, increased corneal thickness, and vacuolar epithelial and stromal keratopathy after being splashed in the eye with an insecticide that was 84% xylene. Vision and symptoms improved over 4 weeks after treatment with ocular prednisolone 1% drops (Trujillo et al, 2003).
4) EXPERIMENTAL ANIMALS: Vacuolar keratopathy has been produced experimentally in cats exposed to sublethal vapor concentrations. This could not be reproduced in rabbits (Grant & Schuman, 1993).

3.4.5)

A) IRRITATION

1) Nasal irritation has been reported after exposure to vapor concentrations of 110 to 460 ppm (Cavender, 1994).
2) Very mild barely detectable nasal irritation was reported in 1 of 6 volunteers during a 15 minute exposure to vapor concentrations of 230 ppm or 460 ppm (Carpenter et al, 1975). Irritation quickly resolved with discontinuation of exposure.
3) The irritant effect of xylene vapors is a good warning property which generally causes workers to discontinue exposure (Finkel, 1983), although such effects should be used as the sole means of environmental control.
4) Dryness of the nasal mucosa may occur with chronic exposure (Cavender, 1994).

B) ODOR THRESHOLD

1) CASE SERIES: Based on a study with 6 individuals, the odor threshold for xylene vapors was calculated as 1.0 ppm, with some individuals able to detect the odor of xylene at 0.14 ppm. Olfactory fatigue occurred in about one-half of the subjects (Carpenter et al, 1975).

3.4.6)

A) DISCOMFORT

1) INGESTION: Local throat irritation and a sensation of burning can occur.
2) INHALATION: Sore and dry throats have been reported after acute or chronic exposure to xylene vapors (Finkel, 1983; Cavender, 1994). Vapor concentrations greater than 200 ppm are more likely to cause sore throat (Ellenhorn & Barceloux, 1988).
3) CASE STUDY: Fifteen minutes of exposure to vapor concentrations ranging from 110 to 690 ppm produced mild throat irritation in 1 or 2 of 6 volunteers (Carpenter et al, 1975). Irritation resolved with discontinuation of exposure.
4) CASE STUDY: Six workers involved in the destruction and removal of xylene-containing epoxy resin concrete developed sore throat, nonproductive hacking cough, and slight to moderate mucous membrane erythema. Proposed causative agents included xylene, amine salts, or resin decomposition products (Joyner & Pegues, 1961).

Cardiovascular

3.5.2)

A) VENTRICULAR FIBRILLATION

1) WITH POISONING/EXPOSURE

a) Information concerning cardiac effects of xylene in humans is limited. A MEDLINE search from 1966 through mid-1995 for literature concerning xylene and cardiac dysrhythmias identified only 2 human case reports (in Polish) (Sikora & Gala, 1967) (Tomaszewdki et al, 1978). Hypoxia could not be ruled out as a contributing factor in these cases (Riihimaki & Hanninen, 1987).
b) ABSENCE OF EFFECTS: Studies of humans exposed to xylene vapor concentrations up to 1,300 mg/m(3) for 30 minutes to over an hour, with and without exercise, did not report significant heart rate or ECG changes (Astrand et al, 1978; Gamberale et al, 1978).
c) Unexplained sudden deaths among deliberate inhalational solvent abusers have been assumed to be due to a decrease in the myocardial threshold to the arrhythmogenic effects of endogenous epinephrine and subsequent development of non-perfusing ventricular dysrhythmias (Reinhardt et al, 1973).
d) Benzene, toluene, and chlorinated hydrocarbon solvents have been associated with cardiac dysrhythmias and occasionally cardiac arrest in humans, presumably due to a decrease in the myocardial threshold to the arrhythmogenic effects of endogenous epinephrine and subsequent development of non-perfusing ventricular dysrhythmias (Hanig & Herman, 1991) (Gosselin et al, 1984).

B) VASODILATATION

1) WITH POISONING/EXPOSURE

a) Inhalation of high concentrations causes vasodilation of peripheral vessels with facial flushing/redness and feeling of warmth (Sandmeyer, 1981).

C) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 17-year-old worker acutely poisoned by xylene developed evidence of myocardial damage on the ninth day of treatment (Sikora & Gala, 1957).

3.5.3)

A) ANIMAL STUDIES

1) DYSRHYTHMIA

a) RATS: Defective repolarization and dysrhythmias have been produced in rats exposed to xylene (Morvai et al, 1976).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Xylene is a central nervous system depressant (Ellenhorn, 1997). Respiratory depression and respiratory arrest may occur with significant exposure (Gosselin et al, 1984).
b) CASE STUDY: Inhalation of xylene-containing paint fumes for approximately 18.5 hours by 3 workers in a confined space resulted in loss of consciousness in all 3 individuals and death in 1 case. Estimated xylene vapor concentration was 10,000 ppm. Toluene exposure may also have occurred (Morley et al, 1970).

B) IRRITATION SYMPTOM

1) WITH POISONING/EXPOSURE

a) High vapor concentrations irritate the mucous membranes and respiratory tract (Hathaway et al, 1996). There are limited reports of resulting effects, possibly because the highly irritating vapors discourage continuing exposure (Finkel, 1983).
b) High concentrations of aromatic hydrocarbons, in general, can cause laryngeal and bronchial irritation, pneumonitis, severe breathing difficulties, and other effects relating to respiratory tract irritation (Gosselin et al, 1984).
c) CASE SERIES: Joyner et al (1961) reported upper respiratory tract effects in 6 workers involved in the destruction and removal of xylene-containing epoxy resin concrete. The principal symptoms included sore throat, nonproductive, hacking cough, and slight to moderate mucous membrane erythema. Three workers had slightly elevated temperatures. Analytical studies were unable to definitively isolate the causative agent, but xylene, amine salts, or resin decomposition products were implicated (Joyner & Pegues, 1961).
d) CASE SERIES: Thirteen of 38 workers overexposed to xylene vapors complained of respiratory tract irritant effects including cough, breathlessness, and chest tightness (Bakinson & Jones, 1985).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) The effects of exposure to high xylene vapor concentrations have not been well documented in humans. Concentrated vapors or aerosols of aromatic hydrocarbons, in general, can cause intense respiratory tract irritation and noncardiogenic pulmonary edema which may be delayed in onset (Gosselin et al, 1984; Sandmeyer, 1981). Intravenous injection or pulmonary aspiration of xylene can result in chemical pneumonitis, hemorrhage, and noncardiogenic pulmonary edema (Sandmeyer, 1981) (Sevejk et al, 1992).
b) CASE SERIES: Three workers who inhaled paint fumes in a confined space for approximately 18.5 hours lost consciousness and one died. Postmortem examination revealed acute pulmonary edema. The effects were attributed to xylene vapors at an estimated concentration of 10,000 ppm. Toluene exposure may also have occurred (Morley et al, 1970).
c) CASE REPORT: Intravenous injection of 8 mL (0.1 mg/kg) resulted in noncardiogenic pulmonary edema, cyanosis, and coma. Respiratory failure developed within a few minutes of injection (Sevejk et al, 1992).

D) PNEUMONITIS

1) WITH POISONING/EXPOSURE

a) Chemical pneumonitis, hemorrhage, and noncardiogenic pulmonary edema may result from aspiration of xylene or xylene-containing vomitus (Gosselin et al, 1984).

E) BRONCHITIS

1) WITH POISONING/EXPOSURE

a) Chronic bronchitis occurs more frequently in workers exposed to solvents such as xylene. Volume of expired air was lower than in control subjects (HSDB , 2000).

Neurologic

3.7.2)

A) COMA

1) WITH POISONING/EXPOSURE

a) High vapor concentrations (greater than 3000 ppm) cause CNS depression with confusion and coma (Riihimaki & Hanninen, 1987; Budavari, 1996; Bakinson & Jones, 1985).
b) CASE REPORT: Three painters exposed to 10,000 ppm of xylene in the tank of a ship developed prolonged coma and one died (Morley et al, 1970). Toluene exposure may also have occurred.

B) CENTRAL STIMULANT ADVERSE REACTION

1) Chronic exposure may cause CNS excitation followed by depression. Tremors, apprehension, irritability, and insomnia may occur (Cavender, 1994; ILO, 1983).

C) CENTRAL NERVOUS SYSTEM DEFICIT

1) Low vapor concentrations (100 to 690 ppm) produce mild dizziness, drowsiness, giddiness, and lightheadedness; tolerance develops after several days of exposure (Carpenter et al, 1975; Glass, 1961; Riihimaki & Hanninen, 1987). Headache has been reported (Carpenter et al, 1975; Gamberale et al, 1978; Bakinson & Jones, 1985; Klaucke et al, 1982).
2) CHRONIC EXPOSURE: CNS excitation followed by depression, with symptoms of paresthesias, impaired memory, dizziness, weakness, and fatigue can occur (Cavender, 1994; ILO, 1983).

D) COORDINATION PROBLEM

1) WITH POISONING/EXPOSURE

a) Equilibrium disturbances have been correlated with blood concentrations of 318 mcg/100 mL (HSDB , 2000). Complaints of equilibrium disturbances were reported by workers exposed to paints containing greater than 50% (by weight) xylene, lesser amounts of trimethylbenzene and butanol, and minor amounts of white spirit (Ruijten et al, 1994).

E) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) EEG studies revealed minor changes (increased alpha frequencies) in 9 subjects exposed to an airborne concentration of 200 ppm for 4 hours or to brief peak concentrations of 400 ppm or less (Seppalainen et al, 1991).

F) AMNESIA

1) WITH POISONING/EXPOSURE

a) ACUTE EXPOSURE: Inhalation of 435 to 1300 mg/m(3) for 15 minutes to 6 hours/day for 4 days resulted in changes in numerative ability, reaction time, short-term memory, and EEG changes (HSDB , 2000).
b) CHRONIC EXPOSURE: Memory, mood, equilibrium, and sleep disturbances were more common in female histology laboratory workers exposed daily to formaldehyde, xylene, and toluene compared to controls (hospital clerical workers); associated symptoms included headache and indigestion (HSDB , 2000).

G) NEUROPATHY

1) WITH POISONING/EXPOSURE

a) In paint manufacturing plant workers, electroneuromyography (ENMG) recordings revealed a tendency to lower amplitudes of action potentials in the median nerve (Riihimaki & Hanninen, 1987).
b) Motor conduction velocity of the median nerve was significantly decreased in painters exposed to paints containing xylene (50% by weight), trimethylbenzene, butanol, and white spirit (minor amounts) (Ruijten et al, 1994).

H) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Generalized seizures repeatedly occurred in an adolescent with a preexisting seizure disorder after use of a xylene-based model airplane glue (Arthur & Curnock, 1982). Using a glue which did not contain xylene did not result in seizures.
b) One case of precipitation of latent epilepsy was attributed to heavy exposure to xylene (80%) and methylglycolacetate (20%) vapors (Goldie, 1960).

Gastrointestinal

3.8.2)

A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH POISONING/EXPOSURE

a) Severe gastrointestinal distress occurs after ingestion (Cavender, 1994).
b) CASE REPORTS: Anorexia and vomiting occurred in a worker exposed to a solvent containing 75% xylene at airborne concentrations of 60 to 350 ppm (Hathaway et al, 1996). Anorexia was reported in another patient exposed to a mixture of 75% xylene and 25% various benzene compounds (Glass, 1961).
c) Chronic vapor inhalation may cause anorexia and nausea (Sandmeyer, 1981).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Hepatotoxicity has been reported after ingestion, deliberate inhalational abuse, and workplace exposure, but many of these studies have been limited by lack of control groups, lack of exposure data, and exposure to other chemicals (e.g., halogenated hydrocarbons) which are hepatotoxic. Studies of exposed workers compared with unexposed controls have found no differences in serum liver enzyme levels (HSDB , 2000; Riihimaki & Hanninen, 1987).
b) CASE REPORTS: Two survivors of exposure to estimated xylene vapors concentrations of 10,000 ppm in the tank of a ship developed increased liver transaminases, peaking at 48 hours (Morley et al, 1970). Hypoxia and concomitant exposure to toluene may have contributed to these effects.
c) No significant increases in hepatic enzymes were reported in workers with long-term exposure to vapors of 12 solvents (primarily xylene) at concentrations within 50 percent of the 1981 Swedish Threshold Limit Values, or in 5 workers exposed to concentrations 5 times the TLV (Lundberg & Hakansson, 1985).

3.9.3)

A) ANIMAL STUDIES

1) HEPATOCELLULAR DAMAGE

a) Chronic xylene exposure (gavage) in rats resulted in increased liver weight in both males and females (Condie et al, 1988).
b) Rats exposed to an airborne concentration of 1600 ppm of p-xylene 6 hours/day for 1 or 3 days developed increased liver weight and hepatic cytochrome P-450 concentrations, without overt hepatotoxicity (Simmons et al, 1991).

2) ENZYME ABNORMALITY

a) Ethanol and xylene had additive stimulatory effects on hepatic microsomal monooxygenases. This may enhance the liver's metabolic capacity and modify biological/toxic effects of occupational solvent exposure in alcohol abusers (Wisniewska-Knypl et al, 1989).
b) Xylene increases hepatic and renal chemical metabolizing enzyme activities in rats. Ethanol plus xylene enhances these effects (Elovaara et al, 1980).

1) Daily inhalation of xylene by rats for 6 hours/day, for up to 18 weeks resulted in increased 7-ethoxycoumarin O-deethylase, 2,5-diphenyloxazole hydroxylase and UDP-glucuronyltransferase activities in rat liver microsomes.
2) Combined exposure to xylene (inhalation) and 15 to 20 percent ethanol (PO) produced greater increases in cytochrome P-450 concentrations and isozyme activities than treatment with xylene alone.
3) Renal ethoxycoumarin deethylase activity was increased by exposure to xylene or ethanol, with additive effects resulting from combined exposure.

Genitourinary

3.10.2)

A) ALBUMINURIA

1) WITH POISONING/EXPOSURE

a) Workers exposed to xylene and toluene have had albuminuria, microhematuria, and pyuria (Cavender, 1994) (HSDB, 1992).
b) CONTROLLED STUDY: Paint manufacturing workers exposed primarily to xylene and toluene excreted more albumin than controls (Askergren et al, 1981). Urinary erythrocytes and leukocytes were also increased (Askergren, 1981). Beta-2-microglobulin excretion was not significantly different between exposed workers and controls (Askergren et al, 1981).

B) URINE FINDING

1) WITH POISONING/EXPOSURE

a) CONTROLLED STUDY: Painters exposed to toluene and xylenes at relatively low concentrations had a greater excretion of beta-glucuronidase and lysozyme in the urine that did unexposed controls (Franchini et al, 1983).

C) ABNORMAL URINE

1) After several days of painting a water tank with an agent containing 65% xylene/35% benzene, half of the workforce experienced nausea and excreted red to coffee-brown urine (Sandmeyer, 1981).

D) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Pronounced but reversible kidney damage occurred in one survivor of an 18.5 hour exposure to xylene vapors estimated at 10,000 ppm. Hypoxic injury and exposure to toluene may have also occurred (Morley et al, 1970).
b) CASE REPORT: An adult developed renal failure following sniffing paint which contained xylol (Martinez et al, 1989), a commercial grade of xylene and benzene derivatives (Sax & Lewis, 1987).

1) Dehydration and acid-base disturbances were present. Prior to admission the patient had a 1 week episode of anorexia, vomiting, and coma. The patient also had a history of chronic ethanol use and a 14 year history of paint sniffing.

3.10.3)

A) ANIMAL STUDIES

1) RENAL FUNCTION ABNORMAL

a) Moderate nephrotoxicity (increased gamma-glutamyl transpeptidase and alkaline phosphatase activities and increased glucose excretion) was produced in rats exposed to o-xylene vapor concentrations of 3000 ppm for 4 hours (Morel et al, 1998).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Renal tubular acidosis, hyperchloremic high anion gap metabolic acidosis, hypokalemia, hypobicarbonatemia, and hypophosphatemia occurred in an adult following repeated sniffing of paint which contained xylol (Martinez et al, 1989), a mixture of xylenes and benzene derivatives (Sax & Lewis, 1987).

B) OSMOLALITY DISTURBANCE

1) WITH POISONING/EXPOSURE

a) An elevated osmol gap (15 mmol/kg to 31 mmol/kg over an 8-hour period) was reported in a patient who ingested approximately 250 mL of lacquer thinner containing methyl ethyl ketone, toluene, and xylene (Brubacher et al, 1999). It is believed that ongoing absorption and hepatic metabolism inhibition contributed to the increase in the osmol gap.

Hematologic

3.13.2)

A) MYELOSUPPRESSION

1) WITH POISONING/EXPOSURE

a) As with toluene, early studies of occupational xylene exposure reported aplastic anemia and other bone marrow effects (De Oliveira, 1936) (Lob, 1952), (Hirsch, 1932). These reports involved xylene heavily contaminated with benzene. Xylene itself is not myelotoxic (Hathaway, 1996), as confirmed by more recent experimental animal studies (Carpenter et al, 1975; Cavender, 1994; NTP, 1986).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH POISONING/EXPOSURE

a) Brief hand immersion results in erythema and a burning/prickling sensation (onset a in few minutes; duration 30 to 60 minutes), followed by some scaling the next day (Riihimaki & Hanninen, 1987).
b) CASE STUDY: Fifteen minutes of occluded exposure to xylene on the forearms of 4 individuals resulted in slight transient erythema. Severe erythema developed in a person who had a history of episodic acute urticaria, erythema, and desquamation, possibly associated with airborne xylene (Palmer & Rycroft, 1993).

B) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) Prolonged skin contact causes defatting, with dry skin, blistering, eczema, or dermatitis (ILO, 1983; Sandmeyer, 1981; Harbison, 1998; Riihimaki & Hanninen, 1987).
b) CASE STUDY: Repeated episodes of widespread urticaria with erythema and desquamation of the facial skin were reported in a woman exposed to xylene airborne concentrations which were estimated to exceed an 8 hour exposure limit of 100 ppm. A 15 minute occluded patch test with xylene on the forearm resulted in severe erythema, heat, and wheal development which persisted for more than 1 hour (Palmer & Rycroft, 1993).
c) Prolonged exposure to highly concentrated liquid solvents with occlusion of the exposed area of skin increases the likelihood of dermal effects (Rosenberg, 1990).

3.14.3)

A) ANIMAL STUDIES

1) RASH

a) m-Xylene has produced both moderate and severe reactions in rabbits in the Standard Draize Test (RTECS , 2000).
b) A severe reaction was reported in an open draize test involving 10 mcg of m-xylene (RTECS , 2000). The original foreign report was not available for review.

2) SKIN NECROSIS

a) Ten to 20 applications of xylene to the skin of rabbits for 2 to 4 weeks under an occlusive wrap resulted in moderate to marked irritation (based on rating of erythema), and moderate necrosis, defined as edema and superficial necrosis with a chapped appearance of the skin with patchy exfoliation (Wolf et al, 1956). There was no evidence of systemic effects from skin absorption of xylene in this study.

3) BULLOUS ERUPTION

a) Prolonged, occluded exposure to undiluted xylene produced blisters in rabbits (Riihimaki & Hanninen, 1987).

Endocrine

3.16.2)

A) DISORDER OF MENSTRUATION

1) WITH POISONING/EXPOSURE

a) In 2 studies, menorrhagia and dysmenorrhea were reported amongst women exposed to xylene in addition to toluene, benzene, white spirit, or other chemicals (Barlow & Sullivan, 1982). The specific cause of these menstrual disorders could not be determined in either study.

Immunologic

3.19.2)

A) DISORDER OF IMMUNE FUNCTION

1) WITH POISONING/EXPOSURE

a) Prolonged exposure to xylene may reduce immunologic resistance, increasing susceptibility to pathogens (ILO, 1983). Absence of immunological effects has also been reported.
b) Workers chronically exposed to benzene, toluene, and xylene had reduced numbers of T-lymphocytes but did not have decreased T-lymphocyte function and did not have an increased incidence of respiratory or urinary tract infections as compared to controls (Moszcyzynsky & Lisiewicz, 1984).

Reproductive

3.20.1)

3.20.2)

A) HUMANS

1) There are few well-conducted studies concerning the reproductive effects of xylene in humans. Available information is limited by combined exposures, previous history of abnormal pregnancies, lack of exposure characterization, and lack of control groups. Most reports are anecdotal.
2) Among all offspring malformations recorded in Czechoslovakia from 1959 to 1966, skeletal malformations were reported in 1 stillborn male whose mother reported being exposed to 3,000 mL of xylene, daily during the 3rd to 16th week of pregnancy (Kucera, 1968). A cause and effect relationship cannot be made from this report.

a) Reported exposure to other solvents (not xylene) during pregnancy in 4 other cases was possibly associated with sacral agenesis. Sacral agenesis was also produced in offspring of chickens exposed to xylene (Kucera, 1968).

3) No increased incidence of birth defects was reported in a study of laboratory workers exposed to xylene during early pregnancy (Taskinen et al, 1994). Exposure to other solvents and chemicals also occurred. An increased incidence of spontaneous abortions was reported.
4) In a Finnish matched-pair registry of congenital malformations, xylene was one of many solvents linked with birth defects. The registry consists of 1047 case mothers and their referents who were interviewed about their exposure to organic solvents. The authors concluded that more pairs must be gathered before reasonable judgment is made regarding the teratogenicity of xylene and the other organic solvents (Kurppa et al, 1983).
5) One case of hydrocephaly was reported in the child of a woman with xylene exposure, but who had also experienced one previous abnormal pregnancy (Holmberg, 1979).
6) Stillbirth with caudal regression has been associated with exposure to xylene vapors during pregnancy (Bingham et al, 2001). Sacral agenesis was associated with close contact during pregnancy with fat solvents, including xylene (Schardein, 2000).
7) In a Czechoslovakian study, five of nine cases of 'caudal regression syndrome' between 1959 and 1966 involved mixed maternal exposure to xylene and other solvents; in a follow-up study the association was less strong (Kucera, 1968; Barlow & Sullivan, 1982). A similar birth defect was produced by xylene in chickens (Kucera, 1968).

B) ANIMAL STUDIES

1) Reviews of animal experiments have concluded that xylene is not clearly teratogenic but is embryotoxic and fetotoxic, particularly at doses which produce maternal toxicity (Barlow & Sullivan, 1982; Council on Scientific Affairs, 1985; Hood & Ottley, 1985; NTP, 1986).
2) Teratogenic effects have been reported in some, but not all, studies (IRIS , 1995) Shepphard, 1995; (Schardein, 1993). Maternal toxicity was not always addressed.

a) The use of the term "teratogenicity" varies. Minor malformations are often considered embryotoxic effects, rather than frank teratogenicity. Defects which naturally occur in the species under study are generally disregarded (if similar to controls), but in some studies may have been included as evidence of teratogenic effects.
b) A chemical may not be considered a direct-acting teratogen if maternal toxicity is present. Well-conducted studies address the issue of maternal toxicity.

3) Inhalation exposure to xylene in various experimental animal species during critical gestational periods resulted in a variety of congenital abnormalities ranging from external deformities and internal anomalies to increased fetal deaths (Kucera, 1968) Mirkova, 1983).
4) One study in rats failed to demonstrate teratogenicity (Tatrai, 1980).
5) Near lethal oral doses of mixed xylenes produced maternal toxicity and a greater incidence of malformations (cleft palate in the absence of reduced weight, wavy ribs) in mice (Marks & Ledoux, 1982).
6) Sacral agenesis was produced in offspring of chickens exposed to xylene (Kucera, 1968).
7) AMA COUNCIL REVIEW - There is ample evidence that xylene produces embryotoxicity (reduced body weight, retarded ossification, retarded kidney development, increased extra rib) and fetotoxicity in mice and rats, but xylene is not considered teratogenic (Council on Scientific Affairs, 1985).
8) Xylene was found to be teratogenic in mice but not rats by inhalation in some studies; oral exposure produced cleft palate, wavy ribs and other developmental toxicity in the rat (Schardein, 2000). Musculoskeletal developmental abnormalities, postimplantation mortality and fetotoxicity were reported in mice and rats after inhalation exposure; fetotoxity and abortion were reported in rabbits after inhalation exposure (RTECS, 2002).
9) Delayed formation of bone and extra ribs have been reported, but these are considered normal variants in mice and rats. Of the isomers, p-xylene caused effects at doses not toxic to the mother (Barlow & Sullivan, 1982). The three isomers were reported to be teratogenic in the mouse in a single study (Nawrot & Staples, 1980).
10) Neurobehavioral effects, including learning and memory were seen in offspring of female rats exposed to 500 ppm technical xylene (Hass et al, 1995; Hass et al, 1997).

3.20.3)

A) HUMANS

1) ABORTION

a) The odds ratio for spontaneous abortions was 3.1 for exposure to xylene at least 3 times per week during the first trimester in female laboratory workers (Taskinen et al, 1994). No increase in birth defects were identified. Exposure to other solvents and chemicals also occurred.
b) Exposure to concentrations of xylene and toluene which periodically exceeded allowable exposure limits was associated with toxicosis, increased risk of miscarriage, hemorrhage during childbirth, and infertility (ILO, 1983).

2) PLACENTAL BARRIER

a) Xylene crosses the placenta in humans and mice, and is found in human breast milk (Barlow & Sullivan, 1982; Bingham et al, 2001) HSDB, 2002).

3.20.4)

A) HUMANS

1) BREAST MILK

a) Xylene is found in human breast milk (Barlow & Sullivan, 1982; Bingham et al, 2001) HSDB, 2002).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1330-20-7 (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) IARC Classification

a) Listed as: Xylenes
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

3.21.2)

3.21.3)

A) LACK OF INFORMATION

1) Adequate epidemiological studies in humans exposed only to xylene are not available (NTP, 1986). Xylene is not classified as a human carcinogen (IRIS , 1995).

B) LYMPHOMA-LIKE DISORDER

1) In one epidemiological study, 11 of 61 males with non-Hodgkins lymphoma reported exposure to xylene (Olsson & Brandt, 1981). There was a possible relationship between organic solvent exposure and supradiaphragmatic presentation of non-Hodgkin's lymphoma (HSDB , 2000).

C) CARCINOMA

1) Occupational exposure to xylene was associated with limited evidence of increased risk of colorectal cancer in one case-control study on Canadian workers (Gerin et al, 1998; Goldberg et al, 2001). Interviews, including job histories were translated into a risk of occupational exposure in 3730 cancer patients and 533 population controls. The researchers concluded that although there was an occupational association between colon cancer and xylene exposure, further investigation was warranted. (2001).
2) Case-control studies linking xylene exposure with an increased risk for hematopoietic malignancies are considered inadequate. The technical grade of xylene used in early studies contained unknown amounts of benzene, a probable carcinogen (ACGIH, 2001).

3.21.4)

A) LACK OF EFFECT

1) Xylene was not carcinogenic in rats or mice in a study by the US National Toxicology Program (NTP, 1986).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status. Laboratory studies on patients should be directed mostly towards symptoms.
B) In patients with respiratory symptoms, chest x-rays and arterial blood gases may be needed, and pulse oximetry monitoring is indicated.
C) In symptomatic patients, monitor CBC, serum electrolytes, renal function tests, liver enzymes, and urinalysis.
D) Xylene or methylhippuric acid (major metabolite) concentrations (breath or blood) are used for occupational monitoring, but are not useful to guide therapy for acute exposure.

4.1.2)

A) HEMATOLOGIC

1) Obtain a baseline CBC in all symptomatic patients.

B) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes in symptomatic patients.
2) Monitor renal and liver function tests.

4.1.3)

A) URINARY LEVELS

1) The concentration of methyl hippuric acid excreted in the urine has been shown to be linearly correlated with the extent of xylene exposure (HSDB , 2000).

B) URINALYSIS

1) Obtain baseline urinalysis in symptomatic patients.
2) Monitor renal function tests. In patients with prolonged exposure, urinalysis may reveal protein, red blood cells, urobilin, and urobilinogen in the urine (ILO, 1983).

Methods

1) Xylene can be measured directly in breath or blood or as a conjugate in urine. Gas chromatography is most commonly used to measure xylene in blood (Riihimaki & Hanninen, 1987) and urinary metabolites of xylene (Morin et al, 1981).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who remain symptomatic should be admitted until they are clearly improving or asymptomatic. Patients with significant CNS depression, dysrhythmias, or pulmonary toxicity should be admitted to an ICU.
B) If a patient is symptomatic, admission is indicated. Asymptomatic patients can be observed for 6 hours and discharged if they remain asymptomatic. In a series of 184 cases of accidental hydrocarbon ingestions, none of the 120 patients with no initial symptoms developed later complications (Machado et al, 1988).

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with inadvertent ingestions of small quantities of hydrocarbons can remain at home. Eye and skin exposures with only minor irritation can be managed at home after washing or irrigation.
B) Accidental ingestions of small quantities can be managed at home provided the patient is asymptomatic, there is access to follow-up and there are no indications of child abuse or attempted suicide (Machado et al, 1988).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for patients with significant symptoms. Consult a pulmonologist or intensivist for patients with significant pulmonary toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with symptoms greater than minor irritation, and any deliberate exposure should be sent to a healthcare facility for evaluation and treatment.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) GI decontamination is not indicated due to the potential for aspiration.

6.5.2)

A) SUMMARY

1) Emesis, gastric lavage and activated charcoal are generally NOT indicated following ingestion of xylene because of the possibility of aspiration of gastric contents. Activated charcoal may be considered in rare instances when there is a very toxic coingestant.

B) ACTIVATED CHARCOAL

1) 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.

2) 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) PULMONARY ASPIRATION

1) In patients with initial symptoms of aspiration (coughing, choking), observe respiratory status for 6 hours. If symptoms continue or progress obtain a chest x-ray and monitor arterial blood gases or pulse oximetry.
2) MONITOR PATIENT for RESPIRATORY DISTRESS. Monitoring for at least 6 hours has been recommended for possible aspiration pneumonitis (Weiss, 1994)
3) Supplemental oxygen with PEEP, CPAP, or ECMO may be necessary. Aerosolized albuterol (eg, 2.5 mg via nebulizer) or other bronchodilators may be required (Kearney, 1994). Avoid excessive fluids and prophylactic antibiotics. The use of steroids is controversial and is not generally advised (Weiss, 1994).
4) ACUTE LUNG INJURY

a) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
b) 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).

1) 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)

c) 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).
d) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
e) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
f) 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).
g) 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).

5) If CNS depression occurs, endotracheal intubation, assisted ventilation, and supplemental oxygen may be required.

B) CONDUCTION DISORDER OF THE HEART

1) PRECAUTIONS

a) Monitor cardiac function. Epinephrine and other sympathomimetic amines should be used with caution because xylene may decrease the myocardial threshold to the arrhythmogenic effects of such drug and arrhythmias might result.

2) LIDOCAINE/INDICATIONS

a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

3) LIDOCAINE/DOSE

a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

4) LIDOCAINE/MAJOR ADVERSE REACTIONS

a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

5) LIDOCAINE/MONITORING PARAMETERS

a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

6) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) Monitor fluid and electrolyte status. Correct hypokalemia and acidosis with potassium and bicarbonate. CAUTION: Hypocalcemia may ensue following fluid and electrolyte replenishment. Avoid excessive administration of fluids if pulmonary edema is present.

D) EXTRACORPOREAL MEMBRANE OXYGENATION

1) Extracorporeal membrane oxygenation (ECMO) has been reported to be successful therapy in children with hydrocarbon pulmonary aspiration (Jaeger et al, 1987; Hart et al, 1991).

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) Monitor for respiratory distress. Delayed pulmonary edema may not develop for 24 to 72 hours. If symptomatic, obtain chest x-ray; if severe, monitor arterial blood gases or pulse oximetry. PEEP or CPAP may be necessary. If CNS depression, noncardiogenic pulmonary edema, or ARDS develop, endotracheal intubation, assisted ventilation, and supplemental oxygen may be required. Monitor cardiac function and avoid epinephrine and other sympathomimetic drugs whenever possible.

B) 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).

C) CONDUCTION DISORDER OF THE HEART

1) Monitor cardiac function. Epinephrine and other sympathomimetics should be used with caution. Xylene may decrease the myocardial threshold to the arrhythmogenic effects of such drugs, increasing the risk of arrhythmias.
2) Hemodynamically significant tachycardia may be treated with propranolol. Esmolol, 25 to 100 micrograms per kilogram per min IV, has also been recommended (Weiss, 1994).
3) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

4) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

D) FLUID/ELECTROLYTE BALANCE REGULATION

1) Monitor fluid and electrolyte status. Correct hypokalemia and acidemia with intravenous potassium and sodium bicarbonate.

a) PRECAUTIONS: Hypocalcemia may ensue following fluid and electrolyte replenishment. This should be corrected with intravenous calcium.

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) BURN

1) In rare instances, burns similar to those seen with alkaline products have been reported after ocular exposure to xylene containing products. In cases in which such injury is evident, treatment similar to that used after caustic eye injury should be considered. The following information is derived from treatment of caustic chemical eye burns.
2) ASSESSMENT CAUSTIC EYE BURNS: It may take 48 to 72 hours after the burn to assess correctly the degree of ocular damage (Brodovsky et al, 2000).
3) The 1965 Roper-Hall classification uses the size of the corneal epithelial defect, the degree of corneal opacification and extent of limbal ischemia to evaluate the extent of the chemical ocular injury (Brodovsky et al, 2000; Singh et al, 2013):

a) GRADE 1 (prognosis good): Corneal epithelial damage; no limbal ischemia.
b) GRADE 2 (prognosis good): Cornea hazy; iris details visible, ischemia less than one-third of limbus.
c) GRADE 3 (prognosis guarded): Total loss of corneal epithelium; stromal haze obscures iris details; ischemia of one-third to one-half of limbus.
d) GRADE 4 (prognosis poor): Cornea opaque; iris and pupil obscured, ischemia affects more than one-half of limbus.

4) A newer classification (Dua) is based on clock hour limbal involvement as well as a percentage of bulbar conjunctival involvement (Singh et al, 2013):

a) GRADE 1 (prognosis very good): 0 clock hour of limbal involvement and 0% conjunctival involvement.
b) GRADE 2 (prognosis good): Less than 3 clock hour of limbal involvement and less than 30% conjunctival involvement.
c) GRADE 3 (prognosis good): Greater than 3 and up to 6 clock hour of limbal involvement and greater than 30% to 50% conjunctival involvement.
d) GRADE 4 (prognosis good to guarded): Greater than 6 and up to 9 clock hour of limbal involvement and greater than 50% to 75% conjunctival involvement.
e) GRADE 5 (prognosis guarded to poor): Greater than 9 and less than 12 clock hour of limbal involvement and greater than 75% and less than 100% conjunctival involvement.
f) GRADE 6 (very poor): Total limbus (12 clock hour) involved and 100% conjunctival involvement.

5) SUMMARY

a) If ocular damage is minor, artificial tears/lubricants, topical cycloplegics, and antibiotics may be all that are needed.

6) ARTIFICIAL TEARS

a) To promote re-epithelization, preservative-free artificial tears/lubricants (eg, hyaluronic acid hourly) may be used (Fish & Davidson, 2010; Tuft & Shortt, 2009).

7) TOPICAL CYCLOPLEGIC

a) Use to guard against development of posterior synechiae and ciliary spasm (Brodovsky et al, 2000a; Grant & Schuman, 1993a). Cyclopentolate 0.5% or 1% eye drops may be administered 4 times daily to control pain (Tuft & Shortt, 2009; Spector & Fernandez, 2008).

8) TOPICAL ANTIBIOTICS

9) PAIN CONTROL

a) If pain control is required, oral or parenteral NSAIDs or narcotics are preferred to topical ocular anesthetics, which may cause local corneal epithelial damage if used repeatedly (Spector & Fernandez, 2008; Grant & Schuman, 1993a). However, topical 0.5% proparacaine has been recommended (Spector & Fernandez, 2008).

10) SUMMARY

a) If the damage is minor, the above may be all that is needed. For grade 3 or 4 injuries, one or more of the following may be used, only with ophthalmologic consultation: acetazolamide, topical timolol, topical steroids, citrate, ascorbate, EDTA, cysteine, NAC, penicillamine, tetracycline, or soft contact lenses.

11) ARTIFICIAL TEARS

a) To promote re-epithelization, preservative-free artificial tears/lubricants (eg, hyaluronic acid hourly) may be used (Fish & Davidson, 2010; Tuft & Shortt, 2009).

12) PAIN CONTROL

13) CARBONIC ANHYDRASE INHIBITOR

a) Acetazolamide (250 mg orally 4 times daily) may be given to control increased intraocular pressure (Singh et al, 2013; Tuft & Shortt, 2009; Spector & Fernandez, 2008).

14) TOPICAL STEROIDS

a) DOSE: Dexamethasone 0.1% ointment 4 times daily to reduce inflammation. If persistent epithelial defect is present, discontinue dexamethasone by day 14 to reduce the risk of stromal melt (Tuft & Shortt, 2009). Other sources suggest that corticosteroids should be stopped if the epithelium has not covered surface defects by 5 to 7 days (Grant & Schuman, 1993b).
b) Topical prednisolone 0.5% has also been used. A further increase in corneoscleral melt may occur if topical steroids are used alone. In one study, topical prednisolone 0.5% was used in combination with topical ascorbate 10%; no increase in corneoscleral melt was observed when topical steroids were used until re-epithelization (Singh et al, 2013; Fish & Davidson, 2010).
c) In one retrospective study, fluorometholone 1% drops were administered every 2 hours initially, then decreased to four times daily when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete (Brodovsky et al, 2000b).

1) STUDY: The combination of intensive topical corticosteroids, topical citrate and ascorbate, and oral citrate and ascorbate was associated with improved best corrected visual acuity and a trend towards more rapid corneal reepithelialization in Grade 3 alkali burns in one retrospective study (Brodovsky et al, 2000b).

15) ASCORBATE

a) Oral or topical ascorbate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
b) DOSE: Ascorbate 10% 4 times daily topically or 1 g orally (2 g/day) (Singh et al, 2013; Tuft & Shortt, 2009).
c) Ascorbate is needed for the formation of collagen and the concentration of ascorbate in the anterior chamber is decreased when the ciliary body is damaged by alkali burns (Tuft & Shortt, 2009; Grant & Schuman, 1993b). In one retrospective study, ascorbate drops (10%) were administered every 2 hours, then decreased to 4 times a day when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete. These patients also received 500 mg of oral ascorbate 4 times daily, until discharge from the hospital (Brodovsky et al, 2000b).

16) CITRATE

a) Topical citrate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
b) DOSE: Potassium citrate 10% 4 times daily topically (Tuft & Shortt, 2009).
c) Citrate chelates calcium, and thereby interferes with the harmful effects of neutrophil accumulation, such as release of proteolytic enzymes and superoxide free radicals, phagocytosis and ulceration (Grant & Schuman, 1993b). In one retrospective study, 10% citrate drops were administered every 2 hours, then decreased to 4 times a day when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete. These patients also received a urinary alkalinizer containing 720 mg of citric acid anhydrous and 630 mg of sodium citrate anhydrous 3 times daily, until discharge from the hospital (Brodovsky et al, 2000b).

17) COLLAGENASE INHIBITORS

a) Inhibitors of collagenase can inhibit collagenolytic activity, prevent stromal ulceration, and promote wound healing. Several effective agents, such as cysteine, n-acetylcysteine, sodium ethylenediamine tetra acetic acid (EDTA), calcium EDTA, penicillamine, and citrate, have been recommended (Singh et al, 2013; Tuft & Shortt, 2009; Perry et al, 1993; Seedor et al, 1987).
b) TETRACYCLINE: Has been found to have an anticollagenolytic effect. Systemic tetracycline 50 mg/kg/day reduced the incidence of alkali-induced corneal ulcerations in rabbits (Seedor et al, 1987).
c) DOXYCYCLINE: Decreased epithelial defects and collagenase activity in a rabbit model of alkali burns to the eye (Perry et al, 1993). DOSE: 100 mg twice daily (Tuft & Shortt, 2009).

18) ANTIBIOTICS

a) An antibiotic ophthalmic ointment or drops should be used for as long as epithelial defects persist (Brodovsky et al, 2000a; Grant & Schuman, 1993a). Topical erythromycin or tetracycline ointment may be used (Spector & Fernandez, 2008). In patients with severe burns, a topical fluoroquinolone antibiotic drop 4 times daily may also be used (Tuft & Shortt, 2009). A topical fourth generation fluoroquinolone has been recommended as an antimicrobial prophylaxis in patients with large epithelial defect (Fish & Davidson, 2010).

19) TOPICAL CYCLOPLEGIC

a) Cyclopentolate 0.5% or 1% eye drops may be administered 4 times daily to control pain (Tuft & Shortt, 2009; Spector & Fernandez, 2008).

20) SOFT CONTACT LENSES

a) A bandage contact lens (eg, silicone hydrogel) may make the patient more comfortable and protect the surface (Fish & Davidson, 2010; Tuft & Shortt, 2009). Hydrophilic high oxygen permeability lenses are preferred (Singh et al, 2013). Soft lenses with intermediate water content and inherent rigidity may facilitate reepithelialization. The use of 0.5 normal sodium chloride drops hourly and artificial tears or lubricant eyedrops instilled 4 times a day may help maintain adequate hydration and lens mobility.

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

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) 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).

6.9.2)

A) SUPPORT

1) Dermatitis has been treated with topical steroids, followed by soaks or moisturizers. Barrier creams or protective gloves may be required in workers with dermatitis.

B) DERMATITIS

1) Preclude further direct dermal exposure in workers who develop dermatitis. Use of barrier creams or protective gloves may be required.
2) Short courses of topical steroids followed by soaks or use of moisturizing creams may be beneficial.

C) GENERAL TREATMENT

1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

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

Abstracts

Case Reports

1) Three workers were exposed to a 90 percent xylene-containing solvent while painting. One worker who had extreme cyanosis of the face and extremities died. The second worker was severely hypothermic and the breath smelled of solvent fumes. The third worker regained consciousness in the emergency department. Speech was slurred and ataxia was present. Neither of the 2 survivors could remember the events of the day on which they were overcome (Morley et al, 1970).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) The estimated oral lethal dose is 15 to 30 mL (Gosselin et al, 1984).

1) INHALATION

a) CASE REPORT (ADULT, LETHAL): 10,000 ppm for a 6 hour exposure (RTECS , 2001).
b) CASE REPORT (ADULT, LETHAL): 10,000 ppm for an exposure of up to 18.5 hours; 2 similarly-exposed coworkers survived (Morley et al, 1970).

Maximum Tolerated Exposure

1) INHALATION

a) ADULT: 200 ppm; conjunctivitis, respiratory effects (RTECS , 2001).
b) 100 ppm for 8 hours (Hathaway et al, 1996).
c) INTRAVENOUS

1) Intravenous injection of 8 mL (0.1 mL/kg) resulted in life-threatening respiratory failure. The patient survived with aggressive supportive care (Sevcik et al, 1992).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) EQUILIBRIUM - Equilibrium disturbances have been correlated with blood concentrations of 318 micrograms/100 milliliters (HSDB , 2000).
b) Reported concentrations of xylene in human serum or plasma in fatal cases ranged from 3 to 40 micrograms per milliliter (HSDB , 2000).

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) Xylene (o, m, and p isomers)

a) TLV:

1) TLV-TWA: 100 ppm
2) TLV-STEL: 150 ppm
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: BEI
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) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.

c) TLV Basis - Critical Effect(s): URT and eye irr; CNS impair
d) Molecular Weight: 106.16

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) Adopted Value

1) Xylene (o, m, and p isomers)

a) TLV:

1) TLV-TWA: 100 ppm
2) TLV-STEL: 150 ppm
3) TLV-Ceiling:

b) Notations and Endnotes:

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

c) TLV Basis - Critical Effect(s): URT and eye irr; CNS impair
d) Molecular Weight: 106.16

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 CAS1330-20-7 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

C) Carcinogenicity Ratings for CAS1330-20-7 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Xylene (o, m, and p isomers)

2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Xylene (o, m, and p isomers)

3) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Xylenes

a) D : Not classifiable as to human carcinogenicity.

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): 3 ; Listed as: Xylenes

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

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

D) OSHA PEL Values for CAS1330-20-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Xylenes (o-, m-, p-isomers)
2) Table Z-1 for Xylenes (o-, m-, p-isomers):

a) 8-hour TWA:

1) ppm: 100

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

2) mg/m3: 435

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) Reference: ACGIH, 1991; ATSDR, 1995; Clayton & Clayton, 1981; Hathaway (et al, 1996; Hayes & Laws, 1991 HSDB, 2001 IRIS, 2001 Lewis, 2000 RTECS, 2001

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 1548 mg/kg

2) LD50- (ORAL)MOUSE:

a) 2119 mg/kg
b) 1590 mg/kg (Hayes & Laws, 1991)
c) Female, 5251 mg/kg (ACGIH, 1991)
d) Male, 5627 mg/kg (ACGIH, 1991)

3) LD50- (INTRAPERITONEAL)RAT:

a) 2459 mg/kg

4) LD50- (ORAL)RAT:

a) 4300 mg/kg -- changes in liver and respiratory system
b) 10 mL/kg (Hayes & Laws, 1991)
c) 1590 mg/kg (Hayes & Laws, 1991)
d) 3523-8600 mg/kg (ACGIH, 1991)

5) LD50- (SUBCUTANEOUS)RAT:

a) 1700 mg/kg

6) TCLo- (INHALATION)HUMAN:

a) 200 ppm -- conjunctive irritation and other changes in sense organs and in respiratory system

7) TCLo- (INHALATION)MOUSE:

a) Female, 1 g/m(3) for 12H at 6-15D of pregnancy -- Fetotoxicity; Developmental abnormalities in musculoskeletal system
b) Female, 2000 ppm for 6H at 6-12D of pregnancy -- Fetotoxicity
c) Female, 4000 ppm for 6H at 6-12D of pregnancy -- Altered growth statistics in newborn; Physical effects on newborn
d) 1250 mg/m(3) for 2H/60D - intermittent -- Effects on phosphatases; Changes in testicular weight

8) TCLo- (INHALATION)RAT:

a) Female, 50 mg/m(3) for 6H at 1-21D after birth -- reproductive changes (Lewis, 2000)
b) Female, 50 mg/m(3) for 6H at 1-21D after birth -- teratogenic changes (Lewis, 2000)
c) Female, 250 mg/m(3) for 24H at 7-15D of pregnancy -- Developmental abnormalities in musculoskeletal system
d) Female, 50 mg/m(3) for 6H at 1-21D of pregnancy -- Altered post-implantation mortality; Fetotoxicity; Developmental cranio- facial abnormalities
e) Female, 50 mg/m(3) for 6H at 1-21D of pregnancy -- Developmental abnormalities in musculoskeletal system and other developmental abnormalities; Altered growth statistics in newborn
f) 1600 ppm for 20H/7D - intermittent -- General anesthetic; Changes in erythrocyte (RBC) count; Death
g) 15 mg/m(3) for 24H/85D - continuous -- Changes in recordings from specific areas of CNS; Changes in leukocyte (WBC) count
h) 800 ppm for 14H/6W - intermittent -- Change in acuity
i) 300 ppm for 6H/18W - intermittent -- Changes in liver and urinary system; Effects on hepatic microsomal mixed oxidase

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Other

1) Most people begin to taste xylene in water at 0.53-1.8 ppm (ATSDR, 1995)

Animal Toxicology

References

General Bibliography

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XYLENE

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

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

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