1,4Dioxane [factsheet]

1,4-DIOXANE

Please Note: The main source of information for this fact sheet is EPA's Integrated Risk Information System (IRIS), which contains information on the carcinogenic effects of 1,4-dioxane including the unit cancer risk for oral exposure. Other secondary sources include the Hazardous Substances Data Bank (HSDB), a database of summaries of peer-reviewed literature, and the Registry of Toxic Effects of Chemical Substances (RTECS), a database of toxic effects that are not peer reviewed.

Environmental/Occupational Exposure

* Occupational exposure to 1,4-dioxane is the most likely route of exposure. (1)

* Dioxane has been detected in both surface water and groundwater. (2)

Assessing Personal Exposure

* No information was located regarding the measurement of personal exposure to 1,4-dioxane.

Health Hazard Information

Acute Effects:

* In a fatal case of acute (short-term) 1,4-dioxane poisoning by inhalation, hepatic and renal lesions, and demyelination and edema of the brain were observed in the individual. (2)

* Acute inhalation exposure to high levels of 1,4-dioxane has caused vertigo and irritation of the eyes, nose, throat, and lungs in humans. It may also irritate the skin. (3,4)

* Some symptoms of poisoning include the irritation of the upper respiratory passages, coughing, irritation of eyes, drowsiness, vertigo, headache, anorexia, stomach pains, nausea, vomiting, coma, and death; these symptoms were observed in workers, but length of exposure was unknown. (5)

* Convulsions, collapse, and effects to the kidneys and liver were observed in rabbits injected with 1,4-dioxane. (2)

* Acute animal tests, such as the LC₅₀ and LD₅₀ tests in rats, mice, rabbits, and guinea pigs, have demonstrated 1,4-dioxane to have moderate acute toxicity by inhalation or dermal exposure, and low to moderate acute toxicity by ingestion. (6)

Chronic Effects (Noncancer):

* Damage to the liver and kidneys has been observed in rats chronically (long-term) exposed in their drinking water. (2)

* EPA has not established an RfC or an RfD for 1,4-dioxane. (7)

Reproductive/Developmental Effects:

* No information is available on the reproductive and developmental effects of 1,4-dioxane in humans. (2)

* No evidence of gross, skeletal, or visceral malformations was found in the offspring of rats exposed via gavage (experimentally placing the chemical in the stomach). Embryotoxicity was observed only at the highest dose. (3)

Cancer Risk:

* In three epidemiologic studies on workers exposed to 1,4-dioxane, the observed number of cancer cases did not differ from the expected cancer deaths. (7)

* Several studies of rats and mice exposed to 1,4-dioxane in their drinking water have reported increased incidences of liver carcinomas and adenomas and nasal cavity squamous cell carcinomas. (2,7-9)

* No treatment-related lesions resulted from exposure to vapor in rats. (7)

* EPA has classified 1,4-dioxane as a Group B2, probable human carcinogen. (7)

* EPA uses mathematical models, based on human and animal studies, to estimate the probability of a person developing cancer from drinking water containing a specified concentration of a chemical. EPA calculated an oral unit risk estimate of 3.1 H 10^-7 (Fg/L)^-1. EPA estimates that, if an individual were to drink water containing 1,4-dioxane at 3.0 Fg/L* over his or her entire lifetime, that person would theoretically have no more than a one-in-a-million increased chance of developing cancer as a direct result of drinking water containing this chemical. Similarly, EPA estimates that drinking water containing 30.0 m g/L would result in not greater than a one-in-a-hundred thousand increased chance of developing cancer, and water containing 300.0 m g/L would result in not greater than a one-in-ten thousand increased chance of developing cancer. (7)

* EPA's Office of Air Quality Planning and Standards, for a hazard ranking under Section 112(g) of the Clean Air Act Amendments, has ranked 1,4-dioxane in the nonthreshold category. The 1/ED₁₀ value is 0.034 per (mg/kg)/d and this would place it in the low category under Superfund's ranking for carcinogenic hazard. (10)

Physical Properties

* The chemical formula of 1,4-dioxane is C₄H₈O₂, and its molecular weight is 88.10 g/mol. (4)

* 1,4-Dioxane occurs as a colorless flammable liquid that is miscible in water. (2,4)

* 1,4-Dioxane has a faint pleasant odor, with an odor threshold of 24 ppm. (4,11)

* The vapor pressure for 1,4-dioxane is 30 mm Hg at 20 EC. (2)

Uses

* 1,4-Dioxane is used as a solvent for cellulose acetate, ethyl cellulose, benzyl cellulose, resins, oils, waxes, some dyes, and other organic and inorganic compounds. (2,4)

Health Data from Inhalation Exposure

Concentration (mg/m³)	Health numbers^a	Regulatory, advisory numbers^b	Reference
1,000,000.0
_ _ _ _ 100,000.0
_ _ _ _ 10,000.0	* LC₅₀ (rats) (46,000 mg/m³) * LC₅₀ (mice) (37,000 mg/m³)		6 6
_ _ _ _ 1,000.0
_ _ _ _ 100.0		* MSHA standard (360 mg/m³)	6
_ _ _ _ 10.0		* ACGIH TLV and OSHA PEL (90 mg/m³)	6

ACGIH TLVCAmerican Conference of Governmental and Industrial Hygienists' threshold limit value expressed as a time-weighted average; the concentration of a substance to which most workers can be exposed without adverse effects.

LC₅₀ (Lethal Concentration₅₀)CA calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population.

MSHACMine Safety and Health Administration.

OSHA PELCOccupational Safety and Health Administration's permissible exposure limit expressed as a time-weighted average; the concentration of a substance to which most workers can be exposed without adverse effect averaged over a normal 8-h workday or a 40-h workweek.

^a Health numbers are toxicological numbers from animal testing or risk assessment values developed by EPA.

^b Regulatory numbers are values that have been incorporated in Government regulations, while advisory numbers are nonregulatory values provided by the Government or other groups as advice.

References

1. M. Sittig. Handbook of Toxic and Hazardous Chemicals and Carcinogens. 2nd ed. Noyes Publications, Park Ridge, NJ. 1985.

2. U.S. Environmental Protection Agency. p-Dioxane Health Advisory. Office of Drinking Water, Washington, DC. 1987.

3. E.J. Calabrese and E.M. Kenyon. Air Toxics and Risk Assessment. Lewis Publishers, Chelsea, MI. 1991.

4. The Merck Index. An Encyclopedia of Chemicals, Drugs, and Biologicals. 11th ed. Ed. S. Budavari. Merck and Co. Inc., Rahway, NJ. 1989.

5. U.S. Department of Health and Human Services. Hazardous Substances Data Bank (HSDB, online database). National Toxicology Information Program, National Library of Medicine, Bethesda, MD. 1993.

6. U.S. Department of Health and Human Services. Registry of Toxic Effects of Chemical Substances (RTECS, online database). National Toxicology Information Program, National Library of Medicine, Bethesda, MD. 1993.

7. U.S. Environmental Protection Agency. Integrated Risk Information System (IRIS) on 1,4-Dioxane. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Cincinnati, OH. 1993.

8. International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Cadmium, Nickel, Some Epoxides, Miscellaneous Industrial Chemicals and General Considerations on Volatile Anaesthetics. Volume 11. World Health Organization, Lyon. 1976.

9. National Cancer Institute (NCI). Bioassay of 1,4-Dioxane for Possible Carcinogenicity. CAS No. 123-91-1. NCI Carcinogenesis Technical Report Series No. 80. NCI-CG-TR80. National Institutes of Health, Bethesda, MD. 1978.

10. U.S. Environmental Protection Agency. Technical Background Document to Support Rulemaking Pursuant to the Clean Air ActCSection 112(g). Ranking of Pollutants with Respect to Hazard to Human Health. EPAB450/3-92-010. Emissions Standards Division, Office of Air Quality Planning and Standards, Research Triangle Park, NC. 1994.

11. J.E. Amoore and E. Hautala. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. Journal of Applied Toxicology, 3(6):272-290. 1983.