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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 503
CCOHS Chemical Name: 1,4-Dioxane

Synonyms:
1,4-Diethylene dioxide
Diethylene dioxide
Diethylene ether
Diethylene oxide
1,4-Dioxacyclohexane
Dioxan
p-Dioxane
Dioxane (non-specific name)
Dioxanne
Dioxyethylene ether
Tetrahydro-1,4-dioxin
Tetrahydro-p-dioxin

Chemical Name French: Dioxane
Chemical Name Spanish: 1,4-Dioxano
CAS Registry Number: 123-91-1
UN/NA Number(s): 1165
RTECS Number(s): JG8225000
EU EINECS/ELINCS Number: 204-661-8
Chemical Family: Saturated cyclic aliphatic ether / cyclic diether / dioxane
Molecular Formula: C4-H8-O2
Structural Formula: -CH2-CH2-O-CH2-CH2-O-(6-membered ring)

SECTION 2. DESCRIPTION

Appearance and Odour:
Clear, colourless liquid with an ether-like odour; hygroscopic (absorbs moisture from the air).(18,38,39)

Odour Threshold:
Values vary widely. 0.8 ppm-172 ppm (detection) (geometric mean odour threshold: 12 ppm); 1.8-278 ppm (recognition) (geometric mean odour threshold: 22 ppm) (40)

Warning Properties:
POOR - odour threshold values vary widely and TLV exceeds many of the reported odour threshold values. In addition, olfactory fatigue may occur.

Composition/Purity:
May contain small amounts of water (up to 0.1%), acetic acid (up to 0.01%) and related ethers such as 2-methyl-1,3-dioxolane and bis(2-chloroethyl) ether as impurities, depending on the grade.(1) Explosive peroxides may slowly form during storage in contact with air and light. Stabilizers can be added to prevent the formation of peroxides.(41)

Uses and Occurrences:
1,4-Dioxane is used mainly as a stabilizer for chlorinated solvents, particularly 1,1,1-trichloroethane. It is also used as a solvent; as a chemical intermediate; as a stable reaction medium for diverse reactions; as a dyeing, staining and printing adjuvant; in cleaning and detergent preparations; and as a scintillation counter fluid.(38,39)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Clear, colourless liquid with an ether-like odour. Hygroscopic. FLAMMABLE LIQUID AND VAPOUR. May accumulate static charge by flow or agitation. Vapour is heavier than air and may spread long distances. Distant ignition and flashback are possible. Slowly forms explosive peroxides in the presence of air and light, and in the absence of inhibitors. Highly volatile. May be irritating to the respiratory tract. Central nervous system depressant. Moderate to high vapour concentrations may cause headache, nausea, dizziness, drowsiness, confusion, unconsciousness and death. EYE IRRITANT. Causes eye irritation. POSSIBLE CANCER HAZARD - may cause cancer, based on animal information. May be an aspiration hazard. Swallowing or vomiting of the liquid may result in aspiration into the lungs.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
1,4-Dioxane readily evaporates and can quickly form high vapour concentrations. Low concentrations (approximately 50-200 ppm) are irritating to the eyes, nose and throat. It is possible to become used to these effects and they may not provide adequate warning of exposure. Higher concentrations can cause central nervous system depression with symptoms such as nausea, headache, vomiting, a feeling of drunkenness, incoordination and unconsciousness. There have been a few deaths reported following exposure to 1,4-dioxane. In one case, the estimated exposure ranged from 200-650 ppm (average 470 ppm). Liver and kidney injury have been observed.
Exposure of volunteers to 160 ppm for 10 minutes caused slight nose irritation. Exposure to 550 ppm for 1 minute cause more severe irritation, but was not considered intolerable.(1) In another study, nose and throat irritation was reported by the majority of 12 volunteers exposed to 300 ppm for 15 minutes.(2) The sensation of irritation may soon subside (olfactory fatigue).(1,3) Brief exposures to high concentrations (approximately 1600 ppm) may cause tearing (lachrymation) and a burning sensation in the nose and throat.(1) In five fatal cases, the initial symptoms were irritation, coughing, nausea, vomiting, headache, drowsiness, poor sense of balance, stomach pains and loss of appetite. Eventually, kidney failure, coma and death ensued. Severe damage to lungs, brain, liver and kidney were noted at autopsy.(4) In another case, death occurred after 1 week exposure to 200-650 ppm (average 470 ppm), with significant skin contact. Liver and kidney injury were noted at autopsy. Alcohol abuse may have increased susceptibility of this individual to the effects of 1,4-dioxane.(5)

Skin Contact:
1,4-Dioxane can probably cause mild irritation to the skin, based on limited animal and human information.
Application of 0.5 mL of pure or technical grade 1,4-dioxane 3 times daily dried the skin of a volunteer, but did not produce irritation.(6)
1,4-Dioxane may be absorbed through the skin to a slight extent, based on limited animal information. Any 1,4-dioxane which contacts the skin will rapidly evaporate and inhalation effects should also be considered.

Eye Contact:
Liquid 1,4-dioxane can cause moderate to severe eye irritation, based on animal information. The vapour can cause eye irritation and tearing.
Exposure to 300 ppm for 15 minutes produced eye irritation in the majority of 12 volunteers.(2) Eye irritation was also noted by volunteers exposed to 50 ppm.(3)

Ingestion:
There is no human information available. Short-term oral toxicity to animals following ingestion is low. Symptoms may include nausea, vomiting and other effects described for "Inhalation" above.
1,4-Dioxane may be inhaled (aspirated) into the lungs during ingestion or vomiting, based on its physical properties. If aspirated, severe lung injury with potentially fatal accumulation of fluid (pulmonary edema) may result. No cases of 1,4-dioxane aspiration have been reported.
Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

1,4-Dioxane is considered a possible human carcinogen, based on animal evidence.

Very few studies have examined the long-term effects of 1,4-dioxane exposure in humans.(6) It is not possible to draw a conclusion from these studies because of significant design limitations (e.g. small study population, unknown exposures, multiple exposures).

Skin:
Repeated or prolonged skin contact may result in dry, red, itchy skin.

Skin Sensitization:
It is not possible conclude that 1,4-dioxane causes allergic skin reactions, based on the available information.
One report describes a woman who developed dermatitis developed several weeks after exposure to 1,4-dioxane. Skin sensitivity tests showed pronounced hypersensitivity. The woman may have had increased susceptibility because the same area of skin had been burned several months earlier.(6) Additional information is not available in English.
One case of allergic contact dermatitis has been reported.(9, unconfirmed) The original paper cannot be located and there are no further details are available for evaluation.

Kidneys/Urinary System:
There is no human information available.
An animal study suggests that 1,4-dioxane may cause kidney toxicity following ingestion of doses considerably lower than those known to cause liver cancer. However, statistical analysis of the data was not reported and is not possible to draw conclusions based on study. Kidney effects have been observed in animal studies using much higher, carcinogenic doses.

Liver:
A study of 74 employees with an average exposure duration of 25 years to up to approximately 13 ppm 1,4-dioxane showed evidence of liver toxicity in 6/24 current workers. The authors noted that all 6 workers were habitual drinkers.(6,8) There are no further details available in English.
An animal study suggests that 1,4-dioxane may cause liver toxicity following ingestion of doses considerably lower than those known to cause liver cancer. However, statistical analysis of the data was not reported. Therefore, it is not possible to draw conclusions from this study. Liver effects have been observed in animal studies using much higher, carcinogenic doses.

Carcinogenicity:

1,4-Dioxane is possibly carcinogenic to humans.(10,11) 1,4-Dioxane is carcinogenic to animals. Tumour sites associated with 1,4-dioxane exposure in animal studies are the liver (rat, mouse and guinea pig), nose (rat and mouse) and gall bladder (guinea pig).(56) A small number of long-term human studies have not shown increased rates of cancer.(7,10,11,12,13)

The International Agency for Research on Cancer (IARC) has concluded that this chemical is possibly carcinogenic to humans (Group 2B).

The American Conference of Governmental Industrial Hygienists (ACGIH) has designated this chemical as an animal carcinogen (A3).

The US National Toxicology Program (NTP) has listed this chemical as reasonably anticipated to be a human carcinogen.

Teratogenicity and Embryotoxicity:
There is no human information available. 1,4-Dioxane has produced slight developmental effects, in the presence of slight maternal toxicity, in an animal study. 1,4-Dioxane has been observed in human breast milk, in one small study.(15)

Reproductive Toxicity:
There is no human or animal information available.

Mutagenicity:
The available human and animal information does not suggest that 1,4-dioxane is mutagenic. One study reports no chromosomal changes in 6 workers exposed to 1,4-dioxane in a manufacturing plant.(8,12) There are no further details available in English and no firm conclusions can be drawn from this limited study. Most studies using live animals have produced negative results and/or used inappropriate routes of exposure (injection).(8,32,35,36,37) Three studies (32,33,34) showed mutagenic effects in live animals, but these studies are considered weak and inconclusive. In two studies (33,34), the mutagenic effects were observed at doses capable of producing significant other toxicity. The other study (32) used a non-standard study design.

Toxicologically Synergistic Materials:
Increased toxicity has been observed in rats when 1,4-dioxane was orally administered with acetonitrile or tetrachloroethylene. It is not known if alcohol increased the toxicity of 1,4-dioxane in employees who have become ill or died after exposure to 1,4-dioxane.(6)

Potential for Accumulation:
1,4-Dioxane probably does not accumulate. Small doses of 1,4-dioxane are rapidly broken down in the body.(17) Human volunteers exposed by inhalation to 50 ppm for 6 hours cleared 1,4-dioxane with an estimated half-life of 1 hour. Greater than 99% of the absorbed 1,4-dioxane was eliminated as urinary beta- hydroxyethoxyacetic acid, with only trace amounts (0.7%) of 1,4-dioxane detected.(3) In rodents, there is a limited ability to metabolize 1,4-dioxane to beta-hydroxyethoxyacetic acid.(12) Exposure to high concentrations can saturate the body's ability to metabolize 1,4-dioxane.(18)


SECTION 4. FIRST AID MEASURES

Inhalation:
This product is flammable and a possible cancer hazard. Take proper precautions to ensure your own safety before attempting rescue (e.g. remove any sources of ignition, wear appropriate protective equipment, use the "buddy" system). Remove source of contamination or move victim to fresh air. If breathing has stopped, trained personnel should begin artificial respiration (AR) or, if the heart has stopped, cardiopulmonary resuscitation (CPR) immediately. Avoid mouth-to-mouth contact by using mouth guards or shields. Immediately transport victim to an emergency care facility.

Skin Contact:
Avoid direct contact. Wear chemical protective clothing, if necessary. As quickly as possible, flush contaminated area with lukewarm, gently running water for at least 5 minutes, or until the chemical is removed. Under running water, remove contaminated clothing, shoes, and leather goods (e.g. watchbands, belts). If irritation persists, repeat flushing. Obtain medical advice immediately. Discard contaminated clothing, shoes and leather goods.

Eye Contact:
Avoid direct contact. Wear chemical protective gloves, if necessary. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for at least 20 minutes, or until the chemical is removed, while holding the eyelid(s) open. Take care not to rinse contaminated water into the unaffected eye or onto the face. Obtain medical attention immediately.

Ingestion:
NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 240 to 300 mL (8 to 10 oz) of water. If vomiting occurs naturally, have victim lean forward to reduce risk of aspiration. Rinse mouth and repeat administration of water. Obtain medical attention immediately.

First Aid Comments:
Provide general supportive measures (comfort, warmth, rest).
Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.



SECTION 5. FIRE FIGHTING MEASURES

Flash Point:
12 deg C (54 deg F) closed cup (42)

Lower Flammable (Explosive) Limit (LFL/LEL):
2.0% (42)

Upper Flammable (Explosive) Limit (UFL/UEL):
22.0% (42)

Autoignition (Ignition) Temperature:
180 deg C (356 deg F) (42)

Sensitivity to Mechanical Impact:
Pure 1,4-dioxane is not sensitive to impact. 1,4-Dioxane slowly forms explosive peroxides in the presence of air and light and in the absence of inhibitors. 1,4-Dioxane contaminated with high concentrations of peroxides may explode on impact.(38,42)

Sensitivity to Static Charge:
1,4-Dioxane may accumulate static electricity by flow or agitation due its very low conductivity (0.5 pS/m at 25 deg C).(43) Vapour in the flammable range can be ignited readily by static discharge of sufficient energy.

Minimum Ignition Energy:
Less than 0.3 millijoules.(43)

Combustion and Thermal Decomposition Products:
Carbon monoxide, toxic, irritating chemicals.

Fire Hazard Summary:
Flammable liquid. Can release vapours that form explosive mixtures with air at, or above, 12 deg C. Vapour is heavier than air and may travel a considerable distance to a source of ignition and flash back to a leak or open container. Can accumulate in confined spaces, resulting in a toxicity and flammability hazard. Closed containers may rupture violently and suddenly release large amounts of product when exposed to fire or excessive heat for a sufficient period of time. Slowly forms explosive peroxides upon standing in the presence of air and light and in the absence of inhibitors. Peroxides can be detonated by friction, impact or heating. Closed containers containing peroxides may rupture violently in the heat of fire.

Extinguishing Media:
Use water spray, carbon dioxide, dry chemical powder, "alcohol resistant" foam or polymer foam. Water may be ineffective, because it may not cool 1,4-dioxane below its flash point. Fire fighting foams, such as "alcohol resistant" foams are the extinguishing agent of choice for most flammable liquid fires.

Fire Fighting Instructions:
Evacuate area and fight fire from a safe distance or protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products.
Stop leak before attempting to stop the fire. If the leak cannot be stopped, and if there is no risk to the surrounding area, let the fire burn itself out. If the flames are extinguished without stopping the leak, vapours could form explosive mixtures with air and reignite. Water can extinguish the fire if used under favourable conditions and when hose streams are applied by experienced firefighters trained in fighting all types of flammable liquid fires. If possible, isolate materials not yet involved in the fire, and move containers from fire area if this can be done without risk, and protect personnel. Otherwise, fire-exposed containers or tanks should be cooled by application of hose streams and this should begin as soon as possible and should concentrate on any unwetted portions of the container. If this is not possible, use unmanned monitor nozzles and immediately evacuate the area.
If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours and to protect personnel attempting to stop a leak. Water spray can be used to dilute spills to non-flammable mixtures and flush spills away from ignition sources. Solid streams of water may be ineffective and spread material. For a massive fire in a large area, use unmanned hose holder or monitor nozzles; if this is not possible withdraw from fire area and allow fire to burn. Stay away from ends of tanks, but be aware that flying material from ruptured tanks may travel in any direction. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire.

Protection of Fire Fighters:
1,4-Dioxane is a possible human carcinogen. Do not enter any fire area without wearing specialized protective equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. A full-body encapsulating chemical protective suit with positive pressure self-contained breathing apparatus (MSHA/NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Health: 2 - Intense or continued (but not chronic) exposure could cause temporary incapacitation or possible residual injury.
NFPA - Flammability: 3 - Liquids and solids that can be ignited under almost all ambient temperature conditions.
NFPA - Instability: 1 - Normally stable, but can become unstable at elevated temperatures and pressures, or may react vigorously, but non-violently with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 88.12

Conversion Factor:
1 ppm = 3.597 mg/m3; 1 mg/m3 = 0.278 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: 11.8 deg C (53.2 deg F) (39,44)
Boiling Point: 101.3 deg C (214.3 deg F) (18,39)
Relative Density (Specific Gravity): 1.034 at 20 deg C (water = 1) (38,44,45)
Solubility in Water: Soluble in all proportions (18,38,46)
Solubility in Other Liquids: Soluble in all proportions in most organic solvents, for example, aliphatic and aromatic hydrocarbons, ethers, alcohols, ketones and chlorinated hydrocarbons.(18,38,39)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = -0.27 (measured) (47)
pH Value: Neutral
Viscosity-Dynamic: 1.23 mPa.s (1.23 centipoise) at 20 deg C (44); 1.19 mPa.s (1.19 centipoise) at 25 deg C (49)
Viscosity-Kinematic: 1.190 mm2/s (1.190 centistokes) at 20 deg C (calculated)
Saybolt Universal Viscosity: 29.7 Saybolt Universal Seconds at 37.8 deg C (100 deg F) (calculated)
Surface Tension: 36.9 mN/m (36.9 dynes/cm) at 20 deg C (38,39)
Vapour Density: 3.03 (air = 1) (38,49)
Vapour Pressure: 4 kPa (30 mm Hg) at 20 deg C (11,44,46); 5.08 kPa (38.09 mm Hg) at 25 deg C (48)
Saturation Vapour Concentration: 39500 ppm (3.95%) at 20 deg C; 50250 ppm (5.03%) at 25 deg C (calculated)
Evaporation Rate: 2.17 (n-butyl acetate = 1) (44); 7.3 (diethyl ether = 1) (44)
Henry's Law Constant: 0.4864 Pa.m3/mole (4.80 X 10(-6) atm.m3/mole) at 25 deg C (50)
Critical Temperature: 312 deg C (593.6 deg F) (39)
Critical Pressure: 5140 kPa (50.72 atm) (39)

Other Physical Properties:
DIELECTRIC CONSTANT: 2.23 at 20 deg C (39)


SECTION 10. STABILITY AND REACTIVITY

Stability:
1,4-Dioxane is stable indefinitely when perfectly dry. However, since it is hygroscopic, it forms peroxides when standing in the presence of air or oxygen.(18) These peroxides may explode when concentrated by evaporation or distillation.(38,44) Stable in closed containers under nitrogen at room temperature.(18)

Hazardous Polymerization:
Does not occur.

Incompatibility - Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.


STRONG OXIDIZING AGENTS (e.g. nitric acid, perchloric acid, silver perchlorate) - can react violently with risk of fire and explosion.(42,51)
CATALYTIC HYDROGEN and NICKEL (RANEY) - reacts explosively with hydrogen and Raney nickel catalyst above 210 deg C.(42,51)
SULFUR TRIOXIDE - forms an explosive mixture at room temperature.(51)
DECABORANE - forms impact-sensitive mixtures.(51)
TRIETHYNYLALUMINUM - the complex with 1,4-dioxane may explode upon sublimation or decompose violently upon heating.(51)
SILVER and BARIUM TETRAFLUOROBROMATES - ignite in contact with 1,4-dioxane.(51)

Hazardous Decomposition Products:
1,4-Dioxane can form peroxides upon prolonged exposure to air and light, in the absence of inhibitors.

Conditions to Avoid:
Heat, open flames, static discharge, sparks and other ignition sources, moisture, air, light, and absence or depletion of inhibitor.

Corrosivity to Metals:
1,4-Dioxane is not corrosive to the common metals. Carbon steel, stainless steels, iron, dry aluminum, copper, brass, bronze, aluminum and silicon bronze, nickel, tantalum and titanium have good resistance (less than 20 mils (505 um)/year).(52)

Corrosivity to Non-Metals:
1,4-Dioxane can attack many plastics (e.g. polyesters, high molecular weight polyethylene and PVC) and elastomers (e.g. Viton A, isoprene, natural rubber, neoprene, Nitrile Buna-N, and silicone rubbers).(52)

Stability and Reactivity Comments:
See references 49 for a description of methods used to destroy any explosive peroxides formed in 1,4-dioxane. In addition to these methods, peroxides can also be destroyed by reducing agents, such as iron (II) or tin (II) chlorides or sodium bisulfite, activated carbon or activated basic alumina.(39)


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (mouse): 7270 ppm (4-hour exposure); cited as 37000 mg/m3 (10300 ppm) (2-hour exposure) (16,19, unconfirmed)
LC50 (female rat): 14250 ppm (4-hour exposure); cited as 51.3 mg/L (4-hour exposure) (20)

LD50 (oral, rat): 5340 mg/kg; cited as 5.17 cc/kg (21)
LD50 (oral, rabbit): 2060 mg/kg; cited as 2 cc/kg (21)

LD50 (dermal, rabbit): 7600 mg/kg (cited as 7600 microL/kg) (16, unconfirmed)

Eye Irritation:

1,4-Dioxane is a moderate to severe irritant.

Application of 0.1 mL of undiluted 1,4-dioxane produced severe irritation in rabbits (graded 4/10; scored over 5, where 5 is severe injury).(22) Application of 100 mg caused moderate irritation in rabbits a standard Draize test.(16, unconfirmed)

Skin Irritation:

Limited evidence suggests that 1,4-dioxane may be a mild irritant.

Mild irritation was observed in rabbits an open irritation test.(16, unconfirmed)

Effects of Short-Term (Acute) Exposure:

Inhalation and oral exposure to high concentrations has produced central nervous system effects (weakness, nausea, vomiting, incoordination, unconsciousness and death), as well as kidney and liver injury. There is some evidence that skin absorption can occur.

Inhalation:
Studies, with several species exposed to varying concentrations of vapour or aerosol (1000-31000 ppm), have shown symptoms such as marked irritation, central nervous system effects (loss of balance and unconsciousness), accumulation of fluid in the lungs, pneumonia, liver and kidney injury and deaths.(1,18,23)

Skin Contact:
A small amount applied to the uncovered skin of monkeys for 24 hours was absorbed.(24) Application to the skin of rabbits for up to 5 hours resulted in rapid absorption, with symptoms such as incoordination, unconsciousness and death.(25) It is not clear that precautions were taken to avoid inhalation exposure in these experiments.

Ingestion:
Dogs orally exposed to a total of approximately 3000 mg/kg over 9 days died of liver and kidney failure. Signs and symptoms included quietness, loss of appetite, vomiting, weakness, inability to stand, laboured respiration and unconsciousness.(1) Several limited studies have shown central nervous system effects (vomiting, signs of drunkenness, muscular incoordination) and kidney and liver injury in animals given oral doses. Similar effects have been observed in lethal dose studies.(6,21)

Effects of Long-Term (Chronic) Exposure:

A limited study, which did not statistically analyze the data, describes liver and kidney injury in rats exposed to oral doses as low as 94 mg/kg/day for 2 years. Irritation of the respiratory tract, nervous system effects and/or liver and kidney injury have been observed in animals exposed by inhalation and ingestion to higher doses.

Inhalation:
Rats, rabbits, dogs and guinea pigs exposed by inhalation to 50-111 ppm for up to two years experienced no adverse effects.(26) In a limited study, cats, rabbits and guinea pigs exposed to 1350 ppm for 45 days showed evidence of slight kidney and liver toxicity. When cats, mice, rabbits and guinea pigs inhaled 2700 ppm for up to 34 days, most animals (7/10) died. Respiratory tract irritation, nervous system effects and severe liver and kidney toxicity were observed.(27) Rabbits exposed to 800 ppm for 30 days died of kidney failure.(28)

Skin Contact:
In a limited study, repeated dermal application of an unspecified amount of 1,4-dioxane over approximately 14 weeks produced kidney and liver damage in rabbits and guinea pigs.(23) It is not clear if precautions were taken to avoid inhalation exposure.

Ingestion:
Rats (60/sex/group) were maintained on drinking water containing 0, 0.01, 0.1 or 1.0% 1,4-dioxane for 2 years. Reported doses were 9.6, 94 or 1015 mg/kg/day for males and 19, 148 or 1599 mg/kg/day for females (calculated by the authors on days 114-198). Analysis of the 1,4-dioxane showed the presence of common impurities of the commercial product (e.g. 10-340 ppm hydrogen peroxide, 220-1340 ppm crotonaldehyde and 6-108 ppm 1-methyl-1,3-dioxolane). At 1.0%, significantly higher mortality was observed during the first 4 months of the study, but then mortality rates became comparable to the controls. At 1.0%, body weights were reduced throughout the study. Autopsy showed significantly increased liver weights in animals exposed to 1%. Variable degrees of kidney and liver damage (renal tubular epithelial and hepatocellular degeneration and necrosis) were observed in animals exposed to 1.0 and 0.1%. Evidence of hepatic and renal tubular regeneration was also observed at these doses. Statistical analysis of the data was not reported. None of these changes were observed in rats exposed to 0.01%. A significant increase in the number of hepatic tumours was observed in animals exposed to 1%. Rats that received 0.1 or 0.01% showed no tumour formation considered related to treatment.(29) Rats (50/sex/group) were exposed to 0, 200, 1000 or 5000 ppm 1,4-dioxane in drinking water for 2 years. Approximate doses are 20, 100 or 500 mg/kg/day for males and females. Body weights were decreased for both sexes exposed to 5000 ppm. Dose-related spongiosis hepatitis was observed in males at all doses, with statistical significance at 1000 ppm (100 mg/kg), and in females exposed to 5000 ppm (500 mg/kg).(57) Other ingestion studies have shown liver and kidney effects in rats and mice exposed to higher doses.(8)

Carcinogenicity:
The International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of 1,4- dioxane to experimental animals.(10,11)
Following oral administration in mice, rats and guinea pigs, 1,4-dioxane produced an increased incidence of liver cancer in mice, tumours of the nasal cavity, liver, mammary gland and lining of the abdomen in rats and liver and gall bladder tumours in guinea pigs.(11) Negative results were obtained in one study where rats were exposed by inhalation.(26) Mouse skin painting studies have reported no significant carcinogenic effects.(13,18,30)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Slight developmental effects have been observed in the presence of slight maternal toxicity.
1,4-Dioxane was fed to rats at 258, 516 or 1033 mg/kg (cited as 0.25, 0.5 or 1.0 mL/kg) on days 6-15 of pregnancy. Mothers in the high dose group had slightly lower weight gains. Fetuses in this group had reduced average weight gains and slowed development of the sternum.(31) No conclusions can be drawn from other studies in which 1,4-dioxane was administered with 1,1,1-trichloroethane.(12,18)

Reproductive Toxicity:
The potential reproductive toxicity of 1,4-dioxane has not been evaluated. No conclusions can be drawn from one study in which 1,4- dioxane was administered with 1,1,1-trichloroethane.(12,18)

Mutagenicity:
The available information does not suggest that 1,4-dioxane is mutagenic. Most in vivo studies have produced negative results and/or used inappropriate routes of exposure (injection).(8,32,35,36,37) Three studies (32,33,34) have shown mutagenic effects in live animals, but these studies are considered weak and inconclusive. In two studies (33,34), the mutagenic effects were observed at doses capable of producing significant other toxicity. The other study (32) used a non-standard study design.
Female rats were given 0, 168, 840, 2550 or 4200 mg/kg of 1,4-dioxane 21 and 4 hours prior to sacrifice. Small, but statistically significant, increases in DNA damage (DNA strand breaks) were observed in the liver cells of animals exposed to 2550 and 4200 mg/kg. Biochemical changes in liver function were observed at 840 mg/kg and above. Microscopic examination showed minimal to mild vacuolar degeneration in the cytoplasm in the liver samples from 3/5 rats exposed to 2550 mg/kg. No liver lesions were seen in any other treatment group, including animals exposed to 4200 mg/kg.(33) Reproducible, dose-related, positive results were obtained in the mouse bone marrow micronucleus test in male mice (strain C57BL6) exposed orally to 900-3600 mg/kg and in females treated orally with 5000 mg/kg (only 1 dose tested). Negative results were obtained in male C57BL6 mice exposed to 450 mg/kg. Negative results were obtained for another strain of male mice (BALB/c) exposed to 5000 mg/kg orally in a single experiment.(34) This study suggests that the mutagenicity observed may have been strain-specific. Male mice were given a single oral dose of 1000, 2000 or 3000 mg/kg. No treated animals died or showed overt signs of toxicity. Statistically significant, dose-dependent increases in micronucleated hepatocyte frequency were observed at 2000 and 3000 mg/kg.(32) This study is of questionable significance because liver cells don't normally divide and the animals were partially hepatactomized to induce cell division.
Positive and negative results have been obtained in tests using cultured mammalian cells. Positive results (DNA inhibition) have been reported in cultured human cells.(16, unconfirmed) Negative results have been obtained in bacteria, in the presence and absence of metabolic activation, in yeast, and in insects.(3,8,10,12,13,18)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Schrenk, H.H., et al. Toxicity of dioxane. Journal of Industrial Hygiene and Toxicology. Vol. 18, no. 7 (1936). p. 448-460
(2) Silverman, L., et al. Further studies on sensory response to certain industrial solvent vapors. Journal of Industrial Hygiene and Toxicology. Vol. 28 (1946). p. 262-266
(3) Young, J.D., et al. Pharmacokinetics of 1,4-dioxane in humans. Journal of Toxicology and Environmental Health. Vol. 3 (1977). p. 507-520
(4) Barber, H. Haemorrhagic nephritis and necrosis of the liver from dioxane poisoning. Guy's Hospital Reports. Vol. 84 (1934). p. 267-280
(5) Johnstone, R.T. Death due to dioxane? A.M.A. Archives of Industrial Health. Vol. 20 (Dec. 1959). p. 445-447
(6) NIOSH criteria for a recommended standard: occupational exposure to dioxane. US Department of Health, Education and Welfare, 1977
(7) Buffler, P.A., et al. Mortality follow-up of workers exposed to 1,4- dioxane. Journal of Occupational Medicine. Vol. 20, no. 4 (Apr. 1978). p. 255-259
(8) DeRosa, C.T., et al. Health evaluation of 1,4-dioxane. Toxicology and Industrial Health. Vol. 12, no. 1 (1996). p. 1-43
(9) Scientific basis for Swedish occupational standards IV. Arbete Och Halsa. Vol. 36 (1983). p. 35-42
(10) 1,4-Dioxane (group 2B). In: International Agency for Research on Cancer (IARC). IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Suppl. 7. Overall evaluations of carcinogenicity: an updating of IARC monographs volume 1 to 42. World Health Organization, 1987. p. 201
(11) 1,4-Dioxane. In: International Agency for Research on Cancer (IARC). IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. Vol. 71, Part 2. World Health Organization, 1999. p. 589-602
(12) Dioxane. In: Documentation of the threshold limit values and biological exposure indices. 6th ed. Suppl. American Conference of Governmental Industrial Hygienists, 1997
(13) IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol. 11. World Health Organization, 1976. p. 247-256
(14) Report on Carcinogens. 11th ed. US Department of Health and Human Services, Public Health Service, National Toxicology Program
(15) Fisher, J., et al. Lactational transfer of volatile chemicals in breast milk. American Industrial Hygiene Association Journal. Vol. 58 (1997). p. 425-431
(16) RTECS record for p-dioxane. Last updated: 1998-09
(17) Andersen, M.E. Saturable metabolism and its relationship to toxicity. CRC Critical Reviews in Toxicology. Vol. 9, no. 2 (May 1981). p. 105, 130-132
(18) Gingell, R., et al. Glycol ethers and other selected glycol derivatives. In: Patty's industrial hygiene and toxicology. 4th ed. Edited by G.D. Clayton, et al. Vol. II. Toxicology. Part D. John Wiley and Sons, 1994. p. 37, 2821-2830
(19) Izmerov., N.F., et al. Toxicometric parameters of industrial toxic chemicals under single exposure. Centre of International Projects, 1982. p. 63
(20) Pozzani, U.C., et al. The toxicological basis of threshold limit values: 5. The experimental inhalation of vapor mixtures by rats with notes upon the relationship between single dose inhalation and single dose oral data. American Industrial Hygiene Association Journal. Vol. 20 (1959). p. 364-369
(21) Laug, E.P., et al. The toxicology of some glycols and derivatives. Journal of Industrial Hygiene and Toxicology. Vol. 21 (1939). p. 173-201
(22) Carpenter, C.P., et al. Chemical burns of the rabbit. American Journal of Ophthalmology. Vol. 29 (1946). p. 1363-1372
(23) Fairley, A., et al. The toxicity to animals of 1:4-dioxan. Journal of Hygiene. Vol. 34 (Dec. 1934). p. 486-501
(24) Marzulli, F.N., et al. In vivo skin penetration studies of 2,4- toluenediamine, 2,4-diaminoanisole, 2-nitro-p-phenylenediamine, p-dioxane and n- nitrosodiethanolamine in cosmetics. Food & Cosmetics Toxicology. Vol. 19, no. 6 (1981). p. 743-747
(25) Nelson, N. Solvent toxicity with particular reference to certain octyl alcohols and dioxanes. Medical Bulletin. Vol. 11 (1951). p. 226-501
(26) Torkelson, T.R., et al. 1,4-Dioxane. II. Results of a 2-year inhalation study in rats. Toxicology and Applied Pharmacology. Vol. 30 (1974). p. 287-298
(27) Gross, E. The individual solvents: dioxane (diethylene dioxide). In: Toxicology and hygiene of industrial solvents. Edited by K.B. Lehmann, et al. Springer, 1938. p. 263-307
(28) Smyth, Jr., H.F. Improved communication - Hygienic standards for daily inhalation. American Industrial Hygiene Association Quarterly. Vol. 17 (1956). p. 129-185
(29) Kociba, R.J., et al. 1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicology and Applied Pharmacology. Vol. 30 (1974). p. 275-286
(30) Tobin, P.S., et al. An evaluation of skin painting studies as determinants of tumorigenesis potential following skin contact with carcinogens. Regulatory Toxicology and Pharmacology. Vol. 2, no. 1 (1982). p. 22-37
(31) Giavini, E., et al. Teratogenesis study of dioxane in rats. Toxicology Letters. Vol. 26, no. 1 (1985). p. 85-88
(32) Morita, T, et al. 1,4-Dioxane is not mutagenic in five in vitro assays and mouse peripheral blood micronucleus assay, but is in mouse liver micronucleus assay. Environmental and Molecular Mutagenesis. Vol. 32 (1998). p. 269-280
(33) Kitchin, K. T., et al. Is 1,4-dioxane a genotoxic carcinogen? Cancer Letters. Vol. 53, no. 1 (1990). p. 67-71
(34) Mirkova, E. Activity of the rodent carcinogen 1,4-dioxane in the mouse bone marrow micronucleus assay. Mutation Research. Vol. 322 (1994). p. 142- 144
(35) McFee, A.F., et al. Results of mouse bone marrow micronucleus studies on 1,4-dioxane. Mutation Research. Vol. 322 (1994). p. 145-148
(36) Stott, W. T., et al. Differentiation of the mechanisms of oncogenicity of 1,4-dioxane and 1,3-hexachlorobutadiene in the rat. Toxicology and Applied Pharmacology. Vol. 60, no. 2 (1981). p. 287-300
(37) Tinwell, H., et al. Activity of 1,4-dioxane in mouse bone marrow micronucleus assays. Mutation Research. Vol. 322 (1994). p. 148-150
(38) HSDB record for 1,4-dioxane. Last revised: 1999-01-20
(39) Surprenant, K.S. Dioxane. In: Ullmann's encyclopedia of industrial chemistry. 5th completely revised ed. Vol. A 8. VCH Verlagsgesellschaft, 1987. p. 545-550
(40) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 17,56
(41) 1,4-Dioxane CAS: 123-91-1. Joint assessment of commodity chemicals no. 2. European Chemical Industry Ecology and Toxicology Centre (ECETOC), Feb. 1983
(42) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 325; NFPA 49; NFPA 491
(43) Chemical safety sheets: working safely with hazardous chemicals. Kluwer Academic Publishers, 1991
(44) Stoye, D. Solvents. In: Ullmann's encyclopedia of industrial chemistry. 5th completely revised ed. Vol. A 24. VCH Verlagsgesellschaft, 1993. p. 482, 485, 496
(45) Karas, L., et al. Ethers. In: Kirk-Othmer encyclopedia of chemical technology. 4th ed. Vol. 9. John Wiley and Sons, 1994. p. 860-868
(46) Verschueren, K. Handbook of environmental data on organic chemicals. 3rd ed. Van Nostrand Reinhold Company, 1996. p. 873-875
(47) On-line LogP (octanol/water partition coefficient) database, including experimental data (Interactive LogKow (KowWin)) (URL: http://esc- plaza.syrres.com/interkow/kowdemo.htm)
(48) Daubert, T.E., et al. Data compilation tables of properties of pure compounds. American Institute of Chemical Engineers, 1985
(49) Sullivan, D.A. Solvents, industrial. In: Kirk-Othmer encyclopedia of chemical technology. 4th ed. Vol. 22. John Wiley and Sons, 1997. p. 548- 549, 553, 567
(50) CHEMFATE database. (URL: http://esc- plaza.syrres.com/efdb/Chemfate.htm)
(51) Bretherick's reactive chemical hazards database. Butterworth-Heinemann Ltd., 1996
(52) Schweitzer, P.A. Corrosion resistance tables: metals, nonmetals, coatings, mortars, plastics, elastomers and linings, and fabrics. 4th ed. Part A, A-D. Marcel Dekker, Inc., 1995. p. 1093-1096
(53) Dioxane. In: NIOSH pocket guide to chemical hazards. National Institute for Occupational Safety and Health, June 1997
(54) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002
(55) European Communities (EC). Commission Directive 2001/59/EC. Aug. 6, 2001
(56) 1,4-Dioxane. Priority existing chemical no. 7. Full public report. National Industrial Chemicals Notification and Assessment Scheme, June 1998
(57) Yamazaki, K., et al. Two-year toxicological study and carcinogenesis studies of 1,4-dioxane in F344 rats and BDF1 mice. Proceedings of the Second Asia-Pacific Symposium on Environmental and Occupational Health, 1993. p. 193-198
(58) Occupational Safety and Health Administration (OSHA). Organic Vapors. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc.html>
(59) National Institute for Occupational Safety and Health (NIOSH). Dioxane. In: NIOSH Manual of Analytical Methods (NMAM(R)). 4th ed. Edited by M.E. Cassinelli, et al. DHHS (NIOSH) Publication 94-113. Aug. 1994. Available at: <www.cdc.gov/niosh/nmam/nmammenu.html>

Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.


Review/Preparation Date: 2000-07-03

Revision Indicators:
EU classification 2002-02-11
EU risks 2002-02-11
EU safety 2002-02-11
EU comments 2002-02-11
Toxicological info 2003-07-07
Mutagenicity 2003-07-07
WHMIS detailed classification 2003-07-07
WHMIS health effects 2003-07-07
Emergency overview 2003-07-07
Long-term exposure 2003-07-07
First aid inhalation 2003-07-07
First aid skin 2003-07-07
Carcinogenicity 2003-07-07
Handling 2003-07-07
PEL transitional comments 2004-01-08
Resistance of materials for PPE 2004-04-06
Bibliography 2005-02-02
Bibliography 2005-04-04
Passive Sampling Devices 2005-04-04
Sampling/analysis 2005-04-04



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