1,4-Dioxane

SECTION 2: Hazards identification

CANADIAN WHMIS SYMBOLS EMERGENCY OVERVIEW RISK May form explosive peroxides. Limited evidence of a carcinogenic effect. 1 of 16 Irritating to eyes and respiratory system. Highly flammable. Repeated exposure may cause skin dryness and cracking.

Potential Acute Health Effects

SWALLOWED • Accidental ingestion of the material may be damaging to the health of the individual. • Ingestion of certain dioxanes has produced liver hypertrophy and enlargement (hepatomegaly). An aspiration hazard may exist. EYE • There is evidence that material may produce eye irritation in some persons and produce eye damage 24 hours or more after instillation. Severe inflammation may be expected with pain. There may be damage to the cornea. Unless treatment is prompt and adequate there may be permanent loss of vision. Conjunctivitis can occur following repeated exposure. SKIN • Repeated exposure may cause skin cracking, flaking or drying following normal handling and use. • Skin contact with the material may damage the health of the individual; systemic effects may result following absorption. • There is some evidence to suggest that the material may cause mild but significant inflammation of the skin either following direct contact or after a delay of some time. Repeated exposure can cause contact dermatitis which is characterized by redness, swelling and blistering. • Absorption of some dioxanes through the skin has resulted in damageto the liver, kidney and brain. • Open cuts, abraded or irritated skin should not be exposed to this material. • Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected. INHALED • The material can cause respiratory irritation in some persons. The body's response to such irritation can cause further lung damage. • Inhalation of vapors or aerosols (mists, fumes), generated by the material during the course of normal handling, may be damaging to the health of the individual. • Dioxane was widely used as an epoxy resin solvent in 1950-1960's but toxicity concerns has caused replacement by less hazardous substitutes. Symptoms of sub-acute exposures include gastric distress, drowsiness, vertigo, dyspnea and tenderness in the lumbar and abdominal regions. Dioxane is metabolically converted to beta-hydroxyethoxyacetic acid (HEAA) in man and rats. If man oxidises dioxane as rapidly as the rat, sub-lethal doses may induce severe metabolic acidosis. Since the odour of dioxane is not irritating, atmospheric concentrations high enough to produce anaesthesia and organ damage may not provoke alarm. Inhalation of concentrated vapours has caused anaesthesia, renal and hepatic damage and death due to acute renal failure in five humans. Pathological findings included haemorrhagic nephritis and central necrosis of the liver. Several cases of death in humans have been documented after exposure to high concentrations of 1,4-dioxane. Five deaths that occurred within a period of 2 weeks among factory workers engaged in a process that involved primarily exposure to 1,4-dioxane vapors, although minimal dermal exposure could have not been avoided. Three of the subjects suffered from abdominal pain and vomiting before death occurred. Post-mortem examination of the subjects showed extensive gross and microscopic lesions to the liver and kidneys. Based on observations, it was suggested that the effects on the kidneys may have been responsible for the fatal outcome and that liver necrosis, although widespread, was compatible with recovery. No exposure levels were available in these case reports. An additional fatal case of a worker exposed to 1,4-dioxane for only 1 week has been described; whose post-mortem examination showed kidney and liver alterations. The room in which the patient had worked had no exhaust ventilation and the worker was not provided a respirator. The minimum concentration of 1,4-dioxane in the room was 208 ppm and the maximum was in excess of 650 ppm; the average concentration was 470 ppm. In addition, dermal exposure may have been considerable in this case. In a group of six individuals exposed to 2,000 ppm 1,4-dioxane vapors for 3 minutes in a 10 m3 chamber, there were no complaints of nasal discomfort, but one out of four subjects exposed to 1,000 ppm for 5 minutes complained of constriction of the throat ; however, the exposure concentrations were not verified. Exposure of five subjects to about 278 ppm for a few minutes (unspecified) produced slight mucous membrane irritation, and 1,390 ppm caused a slight prickling in the nose, and scratchiness and dryness in the throat . Exposure to 300 ppm 1,4-dioxane for 15 minutes produced nose and throat irritation among a group of 12 volunteers . At 200 ppm, the report does not indicate the presence or absence of symptoms, but considers the exposure acceptable. A 10-minute exposure to 1,600 ppm 1,4-dioxane produced slight nose and throat irritation that persisted throughout the test in a group of five individuals. In another experiment by the same investigators, exposure of the same five persons to 5,500 ppm 1,4-dioxane for 1 minute resulted in a burning sensation to the nose and throat . Exposure of four men to 50 ppm for 6 hours reportedly caused no adverse respiratory signs or alterations in respiratory function, assessed 24 hours and 2 weeks after exposure; however, no data were provided in the study. Exposure of 12 volunteers (6 males and 6 females) to 20 ppm 1,4-dioxane for 2 hours caused no significant respiratory effects during exposure or up to 3 hours after exposure. Short-term exposure of humans to concentrations that eventually caused death produced serious liver damage. Five lethal cases, in which postmortem examination of the patients was undertaken, revealed an enlarged liver and centrilobular necrosis of the liver cells. Swollen kidneys with hemorrhage was seen in subjects who died following exposure to unknown amounts of 1,4-dioxane in the air. These subjects showed oliguria and/or anuria and in one case there was bloody urine. Microscopic examination showed hemorrhage around the glomeruli with some necrosis. No evidence of kidney damage was found in a cross-sectional study of 74 workers exposed to concentrations of 1,4-dioxane between 0.006 and 14.3 ppm for an average length of exposure of almost 25 years. Studies in animals, mostly early studies, provide information on lethality of relatively high concentrations of 1,4-dioxane in several species and also indicate that the kidneys and liver, and in some cases, the lungs, are the main targets of high airborne concentrations of 1,4-dioxane. Short-term exposure to 5,000 ppm 1,4-dioxane was lethal to rats, mice, and rabbits, whereas 10,000 ppm was lethal to guinea pigs). A 4-hour LC50 of 14,261 ppm was calculated for rats. An additional study in guinea pigs reported that the minimum period of exposure that caused the death of the majority of a group of six animals was 180 minutes to 30,000 ppm; no deaths occurred in groups exposed to up to 10,000 ppm for up to 480 minutes. One out of four rabbits exposed to 2,000 ppm 1,4-dioxane 3 hours/day, 5 days/week died on week 4 of exposure, and the cause of death was attributed to renal and hepatic lesions. Data in volunteers acutely exposed to vapors of 1,4-dioxane suggest that the chemical is readily and almost completely absorbed through the lungs. Studies in animals also show that 1,4-dioxane is readily absorbed after inhalation and oral exposure, but much less 1,4-dioxane is absorbed through the skin. 2 of 16 In animals injected with radiolabelled 1,4-dioxane, 1,4-dioxane-derived radioactivity distributed widely throughout the body, and no organ seemed to preferentially accumulate radiolabel. In humans and animals, 1,4-dioxane is metabolized to ß-hydroxyethoxyacetic acid (HEAA) by mixed-function oxidase enzymes; HEAA can be converted to 1,4-dioxane-2-one under acidic conditions. Both of these products are rapidly and extensively eliminated in the urine. Unchanged 1,4-dioxane can also be excreted in the urine and in exhaled air, but mainly after high-dose exposure. Studies have shown that the metabolism of 1,4-dioxane in rats is saturable at high doses. There is virtually no information regarding the toxicokinetics of 1,4-dioxane in humans following oral or dermal exposure. There is no indication that 1,4-dioxane or HEAA accumulates in the body.

Potential chronic health

There has been concern that this material can cause cancer or mutations, but there is not enough data to make an assessment. Long-term exposure to respiratory irritants may result in disease of the airways involving difficult breathing and related systemic problems. Prolonged or repeated skin contact may cause drying with cracking,irritation and possible dermatitis following. Limited evidence suggests that repeated or long-term occupational exposure may produce cumulative health effects involving organs or biochemical systems. Chronic exposure to dioxanes may produce injury to the liver, kidney and brain. Repeated or prolonged exposures may result in the formation of tumors, typically of the liver and gall-bladder. Cyclic ethers can cause cancers, especially of the liver.