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Ethylene Glycol and Propylene Glycol Toxicity
What is Propylene Glycol?

Course: WB 1103
CE Original Date: October 3, 2007
CE Renewal Date: October 3, 2010
CE Expiration Date: October 3, 2012
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Learning Objectives

Upon completion of this section, you should be able to

  • describe the properties and uses of propylene glycol

Introduction

In contrast to ethylene glycol, a potent cause of acute toxicity in humans, propylene glycol is a “generally recognized as safe” (GRAS) additive for foods and medications. Propylene glycol rarely causes toxic effects, and then only under very unusual circumstances.

Uses

Propylene glycol is a Generally Recognized as Safe (GRAS) food additive that is widely used in

  • food and tobacco products,
  • pharmaceuticals, and
  • cosmetics.

In certain medicines, cosmetics, and food products, propylene glycol acts as

  • an emulsifying agent,
  • industrial drying agent,
  • surfactant, and
  • solvent.

Concentrations in Food

Concentrations in foods range from <0.001% in eggs and soups to about 15% in some seasonings and flavorings. Propylene glycol is an FDA-approved additive for military dietary rations (Agency for Toxic Substances and Disease Registry 1997).

Use in Textiles

The largest amounts of propylene glycol are used in the textile industry, where it is an intermediate in polyester fiber production.

Synonyms

Synonyms for propylene glycol include

  • 1,2-propanediol,
  • 1,2-dihydroxypropane,
  • methyl glycol, and
  • trimethyl glycol (Agency for Toxic Substances and Disease Registry 1997).

Special Uses

Aerosolized propylene glycol can provide dense “smoke” without flames. It is used

  • by the military as a smoke screen to conceal the movement of troops on the battlefield and
  • as a smoke simulator in various types of fire-training procedures and theatrical productions

De-Icing

  • Propylene glycol is sometimes used as a de-icing agent; however, ethylene glycol is used more often because it costs less.

Sources of Exposure

In the general population, propylene glycol exposure occurs primarily through ingestion of food and medications and through dermal contact with cosmetics or topical medications. Propylene glycol is used as a solvent in cosmetics and pharmaceuticals, in various formats

  • oral
  • injectable
  • topical

For example, it makes up 40% of intravenous phenytoin (Dilantin) and other injectable medications (Meditext 2004).

No adverse health effects are likely to occur from normal use of these products. However, heavy use of injectable medications with propylene glycol (Louis, Kutt et al. 1967; Seay, Graves et al. 1997; Yorgin, Theodorou et al. 1997; Wilson, Reardon et al. 2000), or prolonged and extensive topical application on compromised skin, such as burns (Peleg, Bar-Oz et al. 1998), has caused excess levels of propylene glycol in the body.

Who is at Risk?

Propylene glycol toxicity has been reported only rarely and in unusual circumstances. For example, toxicity may result from

  • excessively large or rapidly infused intravenous injections of propylene glycol-containing medications, excessively large or rapidly infused intravenous injections of propylene glycol-containing medications (Louis, Kutt et al. 1967; Seay, Graves et al. 1997; Yorgin, Theodorou et al. 1997; Wilson, Reardon et al. 2000)
  • prolonged dermal contact during treatment of burns

Those at special risk include

  • neonates
  • infants
  • the elderly (Martin and Finberg 1970; MacDonald, Getson et al. 1987; Glover and Reed 1996; Peleg, Bar-Oz et al. 1998).

Increased sensitivity (Reprotext 2004) may be seen in people with pre-existing

  • skin conditions
  • eye conditions
  • (possibly) allergic conditions

Biological Fate

Absorption of propylene glycol from the gastrointestinal tract is rapid: maximal plasma concentrations in humans occur within 1 hour after ingestion.

Metabolites

Propylene glycol is metabolized in the liver by alcohol dehydrogenase to

  • lactic acid, and then
  • pyruvic acid

Both of these metabolites are normal constituents of the citric acid cycle and are further metabolized to

  • carbon dioxide and
  • water

About 45% of an absorbed propylene glycol dose is excreted by the kidneys unchanged or as the glucuronide conjugate.

Half-Life

The elimination half-life of propylene glycol is about 4 hours.

Physiological Effects

Topical application to injured skin (as a component of burn creams) or intravenous administration (as an excipient in certain anticonvulsant, antianginal, antibiotic, or other medications) has sometimes been associated with

  • Hyperosmolality,
  • lactic acidosis,
  • intravascular hemolysis,
  • complications of CNS depression,
  • seizures,
  • coma,
  • hypoglycemia, and
  • renal failure

Central Nervous System Effects

CNS depression is the primary manifestation of acute propylene glycol poisoning.

Metabolic Effects

Metabolic acidosis

Metabolic conversion of propylene glycol to lactic and pyruvic acids can contribute to metabolic acidosis and an abnormal anion gap.

Hyperosmolality

Unchanged propylene glycol circulating in the body causes hyperosmolality.

Examples of Propylene Glycol Poisoning

Although propylene glycol is nontoxic under normal conditions, it can cause poisoning in rare and unusual circumstances.

In one case, an 8-month-old infant with large surface area second-degree and third-degree burns was treated for many days with topical silver sulfadiazine containing a large amount of propylene glycol. The infant developed acute metabolic acidosis and cardiorespiratory arrest. The daily dose of propylene glycol was 9,000 mg/kg. Serum propylene glycol levels were highest on day 14 (1,059 mg/dL) when the osmolal gap was 75 mOsm/L (normal: <10 mOsm/L) (Fligner, Jack et al. 1985).

Phenytoin and Propylene Glycol

Propylene glycol is a common diluent for injectable medications. It constitutes 40% of the intravenous form of phenytoin. This high concentration is necessary to

  • maintain the phenytoin crystals in a stable preparation and
  • prevent their precipitation

In some patients given intravenous phenytoin, propylene glycol was reported to cause

  • hypotension,
  • cardiac conduction disturbances, and
  • cardiac dysrhythmias

Fatal cardiac and respiratory arrests have also been reported, but these effects may have been due to the cardioactive phenytoin. (Donovan and Cline 1991).

Lack of Renal Effects

Propylene glycol has not been associated with nephrotoxicity caused by calcium oxalate in humans. Unlike ethylene glycol, propylene glycol is not metabolized to oxalic acid, so calcium oxalate is not deposited in the kidneys (Agency for Toxic Substances and Disease Registry 1997).

Contact Dermatitis

Propylene glycol can be a skin sensitizer, resulting in allergic contact dermatitis in some individuals (Reprotext 2004).

Comparison with Ethylene Glycol

In comparing the toxicity of ethylene glycol with that of propylene glycol, LaKind et al. (1999) stated that “From the standpoint of lethality, acute effects, and reproductive, developmental, and kidney toxicity, the toxicity of ethylene glycol exceeds that of propylene glycol (LaKind, McKenna et al. 1999). Further, localized dermal effects from ethylene glycol and propylene glycol are both mild, with data suggesting that propylene glycol may have a skin contact sensitization potential. Finally, propylene glycol exposure in laboratory animals has been associated with reversible hematological changes; no data were located for ethylene glycol from which to draw a toxicological comparison.”

Clinical Presentation

Although the toxicity of propylene glycol is low, if excessively large amounts are absorbed, the following health effects may be seen

  • an elevated osmolal gap,
  • severe metabolic acidosis (caused by the metabolism of propylene glycol to lactic acid), and
  • coma, seizures, and hypoglycemia (rarely, among patients who ingested large amounts of propylene glycol over several days).

Treatment

Metabolic acidosis caused by large amounts of propylene glycol in injected medications should be treated with sodium bicarbonate. In severe cases, hemodialysis is effective in correcting hyperosmolality by removing propylene glycol from the blood (Demey, Daelemans et al. 1988; Parker, Fraser et al. 2002). Ethanol therapy, as described for ethylene glycol-poisoned patients, is unnecessary for patients having propylene glycol poisoning.

Standards and Regulations

There is no workplace or environmental standard for propylene glycol. FDA considers an average daily dietary intake of 23 mg/kg of body weight to be safe for persons 2-65 years of age (Agency for Toxic Substances and Disease Registry 1997).

Key Points

  • Propylene glycol is used in various foods, cosmetics, and pharmaceutical products.
  • Propylene glycol toxicity is not expected in normal environmental or occupational exposures.
  • Propylene glycol toxicity is metabolized to compounds that are normal constituents of the citric acid cycle.
  • Large doses and unusual circumstances are necessary for the development of propylene glycol toxicity.
  • Propylene glycol poisoning is marked initially by CNS depression and an elevated osmolal gap and, later, by an increased anion gap.
  • Unlike ethylene glycol, propylene glycol does not produce nephrotoxicity in humans.
  • Treatment for propylene glycol poisoning is supportive. It may involve correction of metabolic acidosis using sodium bicarbonate therapy and, for severe cases, hemodialysis.

   

Progress Check

19. Propylene glycol is used as which of the following in food products, cosmetics, and pharmaceutical products?

A. an emulsifying agent
B. an industrial drying agent
C. a surfactant or solvent
D. all of the above

Answer:

To review relevant content, see Uses in this section.

20. In contrast to ethylene glycol, propylene glycol rarely causes toxic effects. This is mainly because

A. Absorption of propylene glycol from the gastrointestinal tract is slow.
B. Propylene glycol is metabolized to more toxic compounds.
C. Ethylene glycol is metabolized in the liver to less toxic metabolites.
D. Propylene glycol is metabolized to compounds that are normal constituents of the citric acid cycle.

Answer:

To review relevant content, see Biological Fate in this section.

21. Unlike ethylene glycol, propylene glycol has not been associated with renal toxicity. For what reason?

A. Propylene glycol is not metabolized in kidneys.
B. Propylene glycol is not metabolized to more toxic metabolites to the kidneys.
C. Propylene glycol is not metabolized to oxalic acid, so calcium oxalate is not deposited in the kidneys.
D. None of the above.

Answer:

To review relevant content, see Biological Fate in this section.

22. Ethanol therapy is unnecessary for patients having propylene glycol poisoning for which of the following reasons?

A. Ethanol is used to saturate the alcohol dehydrogenase enzyme (ADH) so that propylene glycol will be excreted unchanged in the urine.
B. Ethanol is used to saturate the alcohol dehydrogenase enzyme (ADH) so that propylene glycol will cause less toxic effects since the metabolism in the liver is competitively inhibited.
C. Propylene glycol is metabolized in the liver by alcohol dehydrogenase (ADH) to the normal constitutes of the citric acid cycle. It is unnecessary to use ethanol to exhaust ADH which in fact detoxifies propylene glycol to nontoxic constitutes.
D. Ethanol therapy does not help.

Answer:

To review relevant content, see Biological Fate in this section.

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