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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 243
CCOHS Chemical Name: Toluene

Synonyms:
Methylbenzene
Methylbenzol
Phenylmethane
Toluol

Chemical Name French: Toluène
Chemical Name Spanish: Tolueno

Trade Name(s):
Methacide

CAS Registry Number: 108-88-3
UN/NA Number(s): 1294
RTECS Number(s): XS5250000
EU EINECS/ELINCS Number: 203-625-9
Chemical Family: Aromatic hydrocarbon / alkylbenzene / monoalkylbenzene
Molecular Formula: C7-H8
Structural Formula: C6H5-CH3

SECTION 2. DESCRIPTION

Appearance and Odour:
Clear, colourless liquid with a benzene-like odour.(2,16)

Odour Threshold:
There is a wide variation in values reported: 0.16-37 ppm (detection); 1.9-69 ppm (recognition).(18)

Warning Properties:
NOT RELIABLE: Wide variation in odour threshold values. Smell may not be noticed after short exposure. Very short exposure (3-5 minutes) to the vapour has caused slight eye irritation at 300 ppm.(3)

Composition/Purity:
Toluene is marketed mainly as nitration and industrial grades, the purity being dependent on the the specific gravity and boiling range of the product. Reagent grade with a purity greater than 99% is available.(16) Some grades of toluene contain as impurities small amounts of ethylbenzene, xylene isomers and/or benzene (level reported to vary between about 0.025 and 1% depending on grade of toluene).(3) Consult your manufacturer/supplier or Material Safety Data Sheet for the exact composition of the toluene in the product you are using. See the CHEMINFO reviews of benzene, ethylbenzene and mixed xylenes for additional information, if applicable.

Uses and Occurrences:
Toluene is used mainly for the manufacture of benzene. It is also used for the manufacture of toluene diisocyanates, benzoic acid, benzyl chloride, benzoyl chloride, phenol, xylene (mixed isomers), plasticizers (e.g. butyl benzoate), sodium benzoate, benzaldehyde, styrene, para-methylstyrene, terephthalic acid, caprolactam, explosives (e.g. trinitrotoluene), vinyltoluene, benzyl salicylate, benzotrichloride, toluenesulfonic acid and toluenesulfonyl chloride. A significant proportion of toluene is not isolated in pure form, but is added to motor fuels as a mixture with other aromatics (reformate or pyrolysis gasoline) to improve octane ratings. Toluene is also an important solvent and is used for paints and coatings; in inks, gums, and resins; in the leather industry; most oils; rubber; vinyl organosols; pharmaceuticals; and other formulated products using a solvent carrier; as an adhesive solvent in plastic toys and model airplanes; as a paint thinner; and as a diluent and thinner in nitrocellulose lacquers.(19,20,84,85)
Toluene occurs in nature in crude oil, natural gas deposits and the volatile emissions from volcanoes and forest fires.(16)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Clear, colourless liquid with a benzene-like odour. FLAMMABLE LIQUID AND VAPOUR. Liquid can accumulate static charge by flow or agitation. Vapour is heavier than air and may spread long distances. Distant ignition and flashback are possible. Liquid can float on water and may travel to distant locations and/or spread fire. Can decompose at high temperatures forming toxic gases. Closed containers may rupture and explode in heat of fire. Mild central nervous system depressant. Vapour may cause headache, nausea, dizziness, drowsiness, confusion and incoordination. SKIN IRRITANT. Causes moderate skin irritation. Aspiration hazard. Swallowing or vomiting of the liquid may result in aspiration into the lungs. REPRODUCTIVE HAZARD - may cause developmental toxicity, based on animal information. Confined space hazard. Can accumulate in confined spaces, producing a fire and toxicity hazard.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Inhalation of toluene vapour can affect the central nervous system (CNS). At approximately 50 ppm, slight drowsiness and headache have been reported. Irritation of the nose, throat and respiratory tract has occurred between 50 and 100 ppm. About 100 ppm has caused fatigue and dizziness; over 200 ppm has caused symptoms similar to drunkenness, numbness, and mild nausea; and over 500 ppm has caused mental confusion and incoordination. Higher concentrations (estimated at higher than 10000 ppm) can result in unconsciousness and death.(3,64) Most serious incidences of exposure have occurred when the vapour has accumulated in confined spaces.

In some studies, relatively high exposures (well above exposure limits) have affected performance on neurobehavioural tasks. In a study of 1290 workers (1178 men, 112 women) exposed to toluene in 12 rotogravure factories and 194 non-exposed workers, there was no significant relationship between toluene blood levels before and after the work shift and results obtained from neurological tests and assessment of subjective complaints (headache, other discomfort). The highest blood level found was 1000 microg/L, which was estimated to be the equivalent to exposure to 70-80 ppm.(65) Six healthy volunteers were exposed 3 times at 14-day intervals to 0 or 100 ppm toluene for 6 hours and monitored for effects on physical and neuropsychological performance. The exposure significantly decreased performance on complex tasks and increased the response time in simple brief tests. The differences in performance were greatest after exercise.(66) Male volunteers exposed for 6 hours to 100 ppm experienced headaches, dizziness and a feeling of intoxication. There were no significant decreases in performance in a battery of manual and mental tasks. However, the volunteers reported that the tests were more difficult.(67) In another test with volunteers, exposure to 150 ppm for 7 hours caused a decrease in performance of some neurobehavioural tasks.(68)

A review of studies on the effects of toluene exposure and colour vision concludes that short-term exposure to toluene does not have an effect on colour discrimination, even when exposures are relatively high (50-150 ppm for 8 hours or 290-360 ppm for 30 minutes, time weighted averages).(69)

In two cases of acute occupational exposure, there were no blood disorders or liver or kidney damage observed.(10) Historical reports of blood effects reported to be caused by toluene are more than likely due to benzene contamination. Benzene is well known to be toxic to the blood. Liver and kidney effects, as well as heart disturbances, have been reported in cases of solvent abuse (glue-sniffing).(2) Reversible kidney failure was reported in a worker following a severe occupational exposure in a paint factory.(3)

Skin Contact:
Toluene is a moderate skin irritant, based on animal information. Prolonged contact can cause dermatitis (dry, red skin). Absorption of toluene through the skin may contribute significantly to the overall exposure.(60,70) Although no reports of harmful effects following skin absorption were located.
Application of undiluted toluene in a chamber for 3 minutes to 6 volunteers resulted in irritation and rapid skin absorption.(70)

Eye Contact:
Toluene is a very mild eye irritant, based on animal evidence.
In people, very short exposure (3-5 minutes) to the vapour has caused slight eye irritation at 300 ppm.(3) Longer exposures (6-7 hours) to 100 or 150 ppm also caused slight irritation.(67,68)

Ingestion:
There are case reports of accidental ingestion of toluene causing severe central nervous system (CNS) depression and death. Toluene is readily absorbed following ingestion producing symptoms similar to those described for inhalation above.(2,51) Toluene may be aspirated, which is the inhalation of a chemical into the lungs, during ingestion or vomiting. Severe lung irritation, damage to the lung tissues and death may result. Ingestion of approximately 60 mL (2 oz) toluene was fatal to an adult within 30 minutes in one reported case. The authors state that the probable cause of death was depression of the central nervous system.(2,51) However, it is possible that the toluene was aspirated and death was caused by aspiration. Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

Repeated or prolonged exposure to toluene may cause dry, red, itchy, cracked skin (dermatitis).

It is not possible to conclude that long-term occupational exposure to toluene causes effects on the nervous system, vision, or the immune system based on the available information. Liver and kidney effects are only expected to occur if exposure concentrations are very high. Hearing loss has been observed in workers in some studies following long-term exposure to toluene and noise and in animals exposed to very high concentrations of toluene. Solvent abuse (glue-sniffing) has caused severe impairment of the central nervous system and kidney damage. The extreme exposures experienced during solvent abuse are not considered relevant to occupational exposure to toluene.

Nervous System:
Numerous studies of rotogravure printers, painters and rubberized-matting workers with long-term exposure to toluene are inconclusive about the potential of toluene to cause central nervous system (CNS) damage. Most studies do not have good exposure data, several indicate alcohol consumption as a confounder and few have used the neurobehavioural tests recommended by the World Health Organization.(3,52) Some studies report changes such as memory loss, sleep disturbances, incoordination or loss of ability to concentrate, while others report no effects.(3,64) Recent studies using sensitive neurobehavioural tests have shown altered scores for exposed workers but whether or not these results actually indicate CNS damage is not clear.(12,13,71,72) Other studies have shown no change in neurobehavioural measurements for workers with long-term exposure to toluene.(73,74,75)
In a study of 1226 workers exposed to toluene in 12 rotogravure factories and 109 non-exposed workers, no significant relationships were found between the duration of toluene exposure and the results of neurological tests or subjective complaints (headache, other discomfort).(76) Severe impairment of the CNS has been reported in cases of long-term solvent abuse (glue-sniffing).(64,77) These extreme exposures to toluene are not relevant to occupational situations.

Respiratory Sensitization:
Toluene is not a respiratory sensitizer. Despite widespread use, no reports of respiratory sensitization were located.

Skin:
Prolonged contact to toluene is expected to cause dermatitis (dry, red skin) because of its defatting action.

Skin Sensitization:
Toluene is not a skin sensitizer. Despite widespread use, no reports of skin sensitization in humans were located. A negative result was obtained in a well-conducted but unconfirmed animal test.

Kidneys/Urinary System:
Kidney effects are not expected to occur unless exposures are very high.
In population studies of workers exposed long-term to levels up to 200 ppm, there was no clear evidence of kidney damage. There are reports of kidney damage in people exposed long-term to high concentrations of toluene as a result of solvent abuse (glue-sniffing). These extreme exposures are not relevant to occupational situations.(2,3,51)
In a recent study, 50 workers from shoe factories who were exposed to toluene for at least 5 years were compared with 25 unexposed controls in an analysis of kidney dysfunction. The exposed workers had a significantly higher level of an enzyme (N-acetyl-B-D-glucosaminidase), which is used as an early sign of tubular lesions. Smoking was taken into account, however there was no discussion of concurrent exposures to other chemicals.(78) Therefore, no firm conclusions about toluene can be drawn from this study.
Kidney effects have only been seen in animal studies involving long-term inhalation or ingestion exposure to relatively high concentrations.

Liver:
Liver effects are not expected to occur unless exposures are very high.
There is little evidence of liver damage in workers exposed to up to 500 ppm toluene or in people with long-term solvent abuse (glue-sniffing). Some studies indicate that long-term exposure to 30-350 ppm may result in increased levels of liver enzymes, an early indicator of liver injury.(2,3)
Liver effects have only been seen in animal studies involving long-term inhalation and ingestion exposure to relatively high concentrations.

Eyes/Vision:
A review of several studies on toluene and its effects on colour vision concluded that the evidence is inconclusive as to whether long-term exposure to toluene results in a persistent impairment of colour vision.(69)
In a meta-analysis of 11 studies, no consistent effects on colour vision were seen following toluene exposure.(79) In addition, no effects on colour vision were seen in workers who were exposed to less than 50 ppm toluene in 14 rotogravure plants and monitored for colour perception over 5 years.(80)
Alterations in vision, for example, reduced sharpness of vision (acuity) and suppressed colour vision have been documented following exposure to mixed solvents.(3) It is not possible to attribute these effects to toluene directly.

Hearing:
Firm conclusions cannot be drawn based on the limited information available. Hearing loss has been observed in workers in some studies following long-term exposure to toluene and noise and in animals exposed to very high concentrations of toluene.
A study of 58 workers exposed to toluene and noise for at least 10 years showed a greater hearing loss in workers exposed to both toluene and noise than in workers exposed to noise only. Average toluene exposures ranged from 33.0-164.6 ppm.(102) In another study, 333 male workers exposed to less than 50 ppm toluene in a rotogravure printing plant were followed for 5 years. There was no relationship between hearing loss and toluene exposure.(81) In a study of 49 workers in a printing plant who were exposed for an average of 20.3 years, there were significant decreases in the brainstem auditory evoked potentials (brain wave activity that occurs in response to clicks or certain tones) in comparison to 59 unexposed controls.(82) These results could suggest hearing loss, but possible other exposures, including noise exposure, were not considered. A study of 96 workers exposed to n-hexane and toluene showed greater hearing loss in exposed workers compared to controls. Hearing loss was greater in workers exposed to n-hexane and toluene and noise.(101) Exposure concentrations were not reported. In a study, which is not available in English, workers exposed to an average of 295 ppm for 2-20 years had an increase in hearing impairment. However, the effects from noise exposure were not considered.(3, unconfirmed)

Blood/Blood Forming System:
Recent studies do not show consistent effects on the blood from long-term toluene exposure. Effects noted in workers before the 1950s are attributed to exposure to benzene, a contaminant of toluene at that time.(2,3,5)

Immune System:
There is some information indicating that workers exposed to toluene may have slight effects on the immune system, but these studies are limited by concurrent exposure to other solvents.(2) A recent review of the evidence of immune effects for various chemicals concluded that there is weak evidence that toluene causes immunotoxicity.(104)
Short-term studies in mice provide conflicting evidence. A decrease in white blood cells was seen in female rats exposed to 1250 ppm for 15 weeks but not in male rats exposed to up to 2500 ppm.

In a study of 1226 workers exposed to toluene in 12 rotogravure factories compared with 119 non-exposed workers, no significant relationships were found between the duration of toluene exposure and the results of physical examinations, blood and neurological tests or subjective complaints (headache, other discomfort).(76)

Carcinogenicity:

Toluene is not considered carcinogenic.
There have been several human population studies that have examined the possible relationship between toluene exposure and cancer. Most types of cancer were not significantly associated with toluene exposure in any study. Stomach cancer mortality, lung cancer rates and colorectal cancers were elevated in some studies, but not others. Because most of the studies involved multiple exposures and there are inconsistencies in the findings, it is not possible to conclude that toluene exposure is associated with cancer in humans. The International Agency for Research on Cancer (IARC) has concluded there is inadequate evidence for the carcinogenicity of toluene in humans.(30) Toluene did not cause tumours in rats and mice exposed by inhalation in a well-conducted study.

The International Agency for Research on Cancer (IARC) has concluded that this chemical is not classifiable as to its carcinogenicity to humans (Group 3).

The American Conference of Governmental Industrial Hygienists (ACGIH) has designated this chemical as not classifiable as a human carcinogen (A4).

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:
Toluene is a developmental toxicity hazard, based on information obtained from animal studies. Fetotoxicity (reduced fetal weight), behavioural effects (effects on learning and memory) and hearing loss (in males) have been observed in the offspring of rats exposed by inhalation to 1200 or 1800 ppm toluene. These effects were observed in the absence of maternal toxicity.
A detailed review of toluene and its potential to cause teratogenicity/embryotoxicity in occupational situations has been published.(38) This review concludes that although many occupational studies have evaluated general solvent exposure and pregnancy outcomes, few studies have specifically investigated toluene exposure. Most of these studies have involved exposure to solvents in general or to certain solvent classes, with toluene exposure addressed as a co-exposure or identified as a common exposure in a sub-group. Outcomes of concern included miscarriages and teratogenicity (congenital malformations).
Six studies examined the association of toluene exposure with miscarriages. Four of the six studies were performed on similar groups of Finnish workers, by the same group of researchers, which can reduce overall confidence in the conclusions. Despite this and other limitations (e.g. recall bias, multiple chemical exposures), these studies do provide evidence suggesting there may be an association between occupational toluene exposure and the occurrence of miscarriages. Nevertheless, further research is required before it will be possible to conclude that there is a causal relationship between toluene exposure and an increased incidence of miscarriages.
One study reported an increased incidence of malformations (renal-urinary and gastrointestinal) in children born to women with a history of exposure to aromatic solvents, particularly toluene. However, it is not possible to draw specific conclusions regarding toluene from this study, because the toluene-specific results were based on a very small number of workers who were exposed to multiple chemicals.
Concerns about the potential teratogenicity of toluene in humans have also arisen due to effects (facial aberrations, reduced growth, neurobehavioural delay, renal/urinary problems) seen in solvent abuse cases (glue-sniffing).(2,39,83) These extreme exposures to toluene, as well as other confounding factors such as tobacco and alcohol abuse, are not relevant to occupational situations.

Reproductive Toxicity:
Toluene is not considered a reproductive hazard. No conclusions can be drawn based on the available human information. Reproductive effects have not been observed in animal studies.
A review of toluene and its potential to cause reproductive toxicity in workers has been published.(38) Three cross-sectional studies evaluated fertility in women exposed to toluene or in the wives of exposed men. No conclusions can be drawn based on these studies due to limitations such as selection bias, recall bias, and the fact that the workers were exposed to other potentially harmful chemicals. Another study suggests that menstrual function is not affected by exposure to toluene.(15)
A case report describes testicular atrophy and reduced spermatogenesis in one man who abused toluene for 10 years.(8) This extreme exposure situation is not relevant to occupational exposures.

Mutagenicity:
There is insufficient information available to conclude that toluene is mutagenic. Results from human studies are inconclusive. Both positive and negative results have been obtained in studies for various mutagenic effects in peripheral blood lymphocytes of workers exposed to toluene. In some studies, the workers were exposed to many organic solvents. However, most of the studies were conducted with rotogravure printing plant workers who were exposed primarily to toluene, but also have concurrent exposure to printing ink.(2,3,30,39,60) In one study of 42 printing workers exposed for an average of 18.9 years, there was a significant increase in sister chromatid exchanges (SCEs) in peripheral lymphocytes in the exposed workers compared to 45 unexposed controls after accounting for the influence of alcohol and smoking. The workers were concurrently exposed to ink.(109) Positive results have also been obtained in studies where there was concurrent exposure to benzene (a mutagen) and/or where smoking could not be eliminated as a causative factor.(59) A negative result (SCEs in peripheral blood lymphocytes) was obtained in 5 male volunteers exposed to 50 ppm of toluene over 3 consecutive days (7 hr/d), repeated 3 times at 2-week intervals.(62)
In animal studies, negative results were obtained in rats and mice exposed orally or by inhalation. Toluene has caused mutagenicity in animal studies using routes of exposure that are not relevant to occupational situations. Negative results were obtained at non-toxic doses in cultured mammalian cells, in several tests using bacteria and in a test using yeast. Negative and positive results were obtained in fruit flies (Drosophila).

Toxicologically Synergistic Materials:
Combined exposure to toluene and noise, toluene and n-hexane, toluene and aspirin or toluene, ethylbenzene and noise has caused a synergistic loss of hearing in animal studies. Increased hearing loss has also been observed in workers in some studies following long-term exposure to toluene and noise.

Potential for Accumulation:
Toluene is readily absorbed by inhalation, ingestion and through the skin. Inhaled toluene appears quickly in the brain fat (lipid) where it is rapidly eliminated. The half-life in human adipose tissue is 0.5-2.7 days. Toluene is removed rapidly from the blood. It is metabolized in the liver where it is converted via several steps primarily to hippuric acid, which is excreted in the urine. A small amount of toluene is also exhaled unchanged.(30,51,64)
Toluene has been identified in human milk.(39,51)


SECTION 4. FIRST AID MEASURES

Inhalation:
This is chemical is flammable. Take proper precautions (e.g. remove any sources of ignition). Remove source of contamination or move victim to fresh air. Obtain medical advice.

Skin Contact:
As quickly as possible, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Quickly and gently blot or brush away excess chemical. Immediately wash gently and thoroughly with lukewarm, gently flowing water and non-abrasive soap for 15-20 minutes. If irritation persists, obtain medical attention. Completely decontaminate clothing, shoes and leather goods before re-use or discard.

Eye Contact:
Quickly and gently blot or brush chemical off the face. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for 5 minutes, while holding the eyelid(s) open. Obtain medical advice.

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. If vomiting occurs naturally, have victim lean forward to reduce risk of aspiration. Have victim rinse mouth with water again. Immediately obtain medical attention.

First Aid Comments:
Provide general supportive measures (comfort, warmth, rest).
Consult a doctor and/or the nearest Poison Control Centre for all exposures except under 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:
4 deg C (39.2 deg F) (closed cup) (20,86,87); 4.4 deg C (40 deg F) (closed cup) (23,84)

Lower Flammable (Explosive) Limit (LFL/LEL):
1.2% (19,23)

Upper Flammable (Explosive) Limit (UFL/UEL):
7.1% (19,23,87)

Autoignition (Ignition) Temperature:
480 deg C (896 deg F) (23,87); 552 deg C (1025.6 deg F) (3,20)

Electrical Conductivity:
Less than 1 pS/m (87,88)

Minimum Ignition Energy:
0.24 millijoules at 4.1% (88)

Flammable Properties:

Specific Hazards Arising from the Chemical:
During a fire, irritating/toxic gases, such as carbon monoxide, carbon dioxide, reactive hydrocarbons, and aldehydes may be generated. Vapour can accumulate in confined spaces resulting in a flammability and toxicity 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.

Extinguishing Media:
Carbon dioxide, dry chemical powder, appropriate foam, water spray or fog. Water may be effective for cooling, but may not be effective for extinguishing a fire because it will not cool toluene below its flash point.(23) Fire fighting foams, such as multipurpose alcohol-resistant foams, are recommended for most flammable liquid fires.(23) Foam manufacturers should be consulted for recommendations regarding types of foams and application rates.

Fire Fighting Instructions:
Evacuate area and fight fire from a safe distance or a protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products. Wear full protective suit if exposure is possible. See Protection of Firefighters.
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.
Closed containers may rupture violently when exposed to the heat of the fire and suddenly release large amounts of products. Always stay away from ends of tanks, but be aware that flying material (shrapnel) from ruptured tanks may travel in any direction. If possible, isolate materials not yet involved in the fire and move containers from fire area if this can be done without risk. Protect personnel. Otherwise, cool fire-exposed containers, tanks or equipment by applying hose streams. Cooling should begin as soon as possible (within several minutes) and should concentrate on any unwetted portions of the container. Apply water from the side and a safe distance. Cooling should continue until well after the fire is out. 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 the leak. Water spray can be used to flush spills away from ignition sources. Dike fire control water for appropriate disposal. Solid streams of water may be ineffective and spread material.
For an advanced or massive fire in a large area, use unmanned hose holders or monitor nozzles; if this is not possible withdraw from fire area and allow fire to burn. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank.
After the fire has been extinguished, toxic atmospheres may remain. Before entering such an area, especially confined areas, check the atmosphere with an appropriate monitoring device while wearing a full protective suit.

Protection of Fire Fighters:
Toluene is a health hazard (and a skin contact hazard). Do not enter without wearing specialized equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. Chemical protective clothing (e.g. chemical splash suit) and positive pressure self-contained breathing apparatus (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: 0 - Normally stable, even under fire conditions, and not reactive with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 92.14

Conversion Factor:
1 ppm = 3.76 mg/m3; 1 mg/m3 = 0.27 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: -95 deg C (-139 deg F) (20,86)
Boiling Point: 110.6 deg C (231.1 deg F) (86,87)
Decomposition Temperature: Not available.
Relative Density (Specific Gravity): 0.867 at 20 deg C (86,90); 0.862 at 25 deg C (86) (water = 1)
Solubility in Water: Sparingly soluble (53 mg/100 mL at 25 deg C (91,92))
Solubility in Other Liquids: Soluble in all proportions in most organic solvents such as ethanol, acetone, diethyl ether, ethyl alcohol, benzene, chloroform and glacial acetic acid.(84,87)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = 2.73 (experimental) (93)
pH Value: Not applicable
Viscosity-Dynamic: 0.586 mPa.s (0.586 centipoises) at 20 deg C; 0.552 mPa.s (0.552 centipoises) at 25 deg C (86)
Viscosity-Kinematic: 0.676 mm2/s (0.676 centistokes) at 20 deg C; 0.64 mm2/s (0.64 centistokes) at 25 deg C (calculated)
Saybolt Universal Viscosity: 27.8 Saybolt Universal Seconds at 37.8 deg C (100 deg F) (calculated)
Surface Tension: 28.52 mN/m (28.52 dynes/cm) at 20 deg C; 27.92 mN/m (27.92 dynes/cm) at 25 deg C (86,94)
Vapour Density: 3.18 (air = 1) (calculated)
Vapour Pressure: 2.93 kPa (22 mm Hg) at 20 deg C (2,3); 3.79 kPa (28.4 mm Hg) at 25 deg C (91,92)
Saturation Vapour Concentration: Approximately 29000 ppm (2.9%) at 20 deg C; 37400 ppm (3.74%) at 25 deg C (calculated)
Evaporation Rate: 2.0 (n-butyl acetate = 1) (95,96); 6.1 (diethyl ether = 1) (95)
Henry's Law Constant: 6.73 x 10(2) Pa.m3/mol (cited as 6.64 x 10(-3) atm.m3/mol) at 25 deg C (91,92); log H = -0.57 (dimensionless constant; calculated)

SECTION 10. STABILITY AND REACTIVITY

Stability:
Normally stable.

Possibility of Hazardous Reactions:
None known.

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.


NITRIC ACID and SULFURIC ACID - reaction with nitric acid is extremely violent, especially in the presence of sulfuric acid. Inadequate control may lead to a runaway or explosive reaction.(23,24)
POTASSIUM CHLORATE - mixtures of powdered chlorate and toluene explode as violently as nitro compound explosives.(24)
STRONG OXIDIZING AGENTS (e.g. nitric acid and bromine trifluoride) - increased risk of fire and explosion.(24)
NITROGEN TETROXIDE - mixture exploded.(23,24)
TETRANITROMETHANE - forms sensitive, highly explosive mixtures.(24)
SILVER PERCHLORATE - forms explosive complexes.(23,24)
SULFUR DICHLORIDE - violent reaction, greatly accelerated in the presence of iron or ferric chloride.(24)
SULFURIC ACID - reaction generates a great amount of heat (exothermic).
URANIUM HEXAFLUORIDE - very vigorous reaction.(24)

Hazardous Decomposition Products:
During a fire, carbon monoxide, carbon dioxide, reactive hydrocarbons and aldehydes may be generated.

Conditions to Avoid:
Electrostatic discharge, sparks, open flames, heat and other ignition sources.

Corrosivity to Metals:
Not corrosive to metals, such as stainless steels (330 and 400 series), aluminum alloys (e.g. type 3003), carbon steel (e.g. types 1010 and 1020); cast iron, nickel and nickel-base alloys (Monel, Hastelloy, Inconel and Incoloy), copper and its alloys, brass and bronze, copper-nickel, tantalum, titanium and zirconium.(97,98)

Corrosivity to Non-Metals:
Attacks plastics, such as polyvinyl chloride (PVC), chlorinated polyvinyl chloride (CPVC), polypropylene, acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile (SAN), polyethersulfone, polyurethane (rigid), polybutylene terephthalate, polysulfone, high-density polyethylene (HDPE), ultra high molecular weight polyethylene (UHMWPE), crosslinked polyethylene (XLPE), polyphenylene oxide (Noryl), thermoset polyester, polystyrene and ethylene vinyl acetate (EVA) (98,99); elastomers, such as nitrile rubber (Nitrile Buna N; NBR), ethylene propylene (EP), ethylene propylene diene (EPDM), ethylene propylene terpolymer (EPT), chloroprene, styrene-butadiene (SBR), polyurethane, butyl rubber (isobutylene isoprene), natural rubber, isoprene, neoprene, flexible polyvinyl chloride (PVC), chlorosulfonyl polyethylene (Hypalon), low density polyethylene (LDPE), silicone, ethylene vinyl acetate (EVA) and Fluoraz (98,100); and coatings, such as coal tar epoxy and epoxy chemical resistant.(98) Does not attack plastics, such as Teflon and other fluorocarbons, like ethylene tetrafluoroethylene (EFTE; Tefzel), ethylene chlorotrifluoroethylene (ECTFE; Halar) and polyvinylidene fluoride (PVDF; Kynar), polyvinylidene chloride, nylon, polyetherether ketone (Peek), polyethylene terephthalate and thermoset epoxy (98,99); elastomers, such as Viton A and other fluorocarbons, like Teflon, Chemraz and Kalrez (98,100); and coatings, such as phenolic, urethanes and vinyls.(98)

Stability and Reactivity Comments:
See reference 24 for additional information on some of the reactions of toluene.


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (rat): 7585 ppm (4-hour exposure); cited as 28.1 mg/L (4-hour exposure); conducted according to European Union guidelines (39, unconfirmed)
LC50 (rat): 8000 ppm (4-hour exposure) (11)
LC50 (mouse): 7100 ppm (4-hour exposure); cited as 5300 ppm (7-hour exposure) (11)

LD50 (oral, male rat): 5580 mg/kg (cited as 5.58 g/kg) (27)
LD50 (oral, 14-day old rat): 3000 mg/kg (cited as 3.0 g/kg) (14)
LD50 (oral, young adult rat): 6400 mg/kg (cited as 6.4 g/kg) (14)
LD50 (oral, older adult rat): 7400 mg/kg (cited as 7.4 g/kg) (14)

LD50 (dermal, rabbit): 12125 mg/kg (cited as 14.1 mL/kg) (1)

Eye Irritation:

Toluene is a very mild eye irritant.

In an OECD compliant test, application of 0.1 mL undiluted toluene produced very mild irritation in rabbits (average scores at 24, 48 and 72 hours: corneal opacity: 0/4; iris injury: 0/2; conjunctival irritation: 1.5/3; chemosis: 1.5/4; modified maximum average score 9/110; all scores were 0 by day 10).(31) In another OECD compliant test, application of 0.1 mL of undiluted toluene produced slight irritation in rabbits (scored 22.67/110).(32) In an unpublished study, carried out according to OECD guidelines, application of 0.1 mL of toluene caused very mild irritation in rabbits (average scores at 24, 48 and 72 hours: corneal opacity: 0/4; iris injury: 0/2; conjunctival irritation: 1.47/3; chemosis: 0.39/4; all scores were 0 by day 7).(39, unconfirmed) Other tests have shown mild, moderate, severe or corrosive injury. However, the test protocols do not meet current standards or insufficient information is provided to interpret the results.(1,28,29)

Skin Irritation:

Toluene is a moderate skin irritant.

In an unpublished study, conducted according to OECD guidelines, administration of 0.5 mL of undiluted toluene to intact skin, under a semi-occlusive cover for 4 hours, produced moderate irritation in rabbits. The maximum mean scores were: erythema: 2.43 at 72 hours and 7 days; edema: 1.43 at 72 hours. The average scores at 24, 48 and 72 hours were: erythema: 1.81/4; edema: 1.10/4.(39) Another OECD compliant test showed slight irritation in rabbits following the application of 0.5 mL of undiluted toluene to intact skin for 4 hours (average score at 24, 48 and 72 hours: 2.94/8). In the same study, application of 0.5 mL of undiluted toluene for 4 hours to intact or abraded skin produced moderate irritation in rabbits (average score at 1, 24 and 48 hours: 3.42/8).(33) Application of 0.01 mL of undiluted toluene produced moderate irritation in rabbits (graded 4/10).(1) In a repeated application test, 10-20 applications over 2-4 weeks produced slight to moderate irritation, with slight tissue death (necrosis) in rabbits.(28) Other tests, which do not meet OECD guidelines, have shown mild or moderate irritation to intact and abraded skin, with prolonged exposure (23 or 24 hours).(17,33,37,40)

Effects of Short-Term (Acute) Exposure:

Inhalation and oral exposure studies using several species show that the major effect of toluene is on the central nervous system (CNS). Persistent hearing loss has been seen in rats exposed by inhalation to 1000 ppm and higher for 3 days or longer. Hearing loss has also been shown in guinea pigs at 250 ppm and higher, and in rats given 620 mg/kg/day orally for 4 weeks, but persistence was not assessed in these studies. An increase in liver weight and mild liver changes were seen in rats, mice and rabbits exposed by inhalation to 810 ppm for 7 days.

Inhalation:
Studies with rats have shown that up to approximately 1000 ppm causes excitation and increased activity. At approximately 2000 ppm, there is CNS depression with drowsiness, incoordination and unconsciousness. Death at higher concentrations is from respiratory failure.(2,3,5) Mice exposed to 2000-6000 ppm for 20 minutes had signs of CNS depression including decreased arousal, disturbances of gait, mobility, righting reflex and coordination.(41) Mice exposed to 1000-6000 ppm for 30 minutes had a dose-related decrease in anxiety-like behaviour, which was significant at all concentrations.(42) Female macaque monkeys were exposed head-only to 500-4500 ppm for 50 minutes. At 2000 ppm and higher, there was a decreased cognitive function (attention deficit), as evidenced by increased response time and decreased accuracy in a conditioned response task.(43) Studies in rats have shown persistent hearing loss at high frequencies following inhalation of concentrations above 1000 ppm for 3 days or longer.(2,39,44) Guinea pigs were exposed to 0, 250, 500 or 1000 ppm for 5 days (8 hr/d) or to 0 or 500 ppm for 4 weeks (8 hr/d, 5 d/wk). Hearing loss was seen for all toluene exposures and was dose-related.(45) Hearing loss has also been observed in a mouse strain that had a genetic predisposition to hearing loss.(6) Female mice exposed to 1000 ppm for 4 weeks (5 hr/d, 5 d/wk) had decreasing olfactory sensitivity throughout the exposure, continued for 2 weeks post-exposure, then returned to normal.(46) Mice, rats, and rabbits exposed to 810 ppm (cited as 3000 mg/m3) for 7 days (8 hr/d) had a significant increase in relative liver weight and subcellular changes in the liver, which could be seen with electron microscopy.(47) Rats exposed to 30 or 300 ppm for 4 weeks (6 hr/d, 5 d/wk) had mild changes in the thyroid gland (females only) and mild changes in the upper respiratory tract epithelium.(48)

Ingestion:
Rats were given a single dose of 0, 2580, 3870 or 5100 mg/kg(cited as 0, 3.0, 4.5 and 6.0 mL/kg) undiluted toluene and monitored for neurotoxic effects using a battery of functional tests on days 1, 7 and 14. Within 1 hour of dosing, the animals became hyperactive for more than 8 hours. Significantly increased horizontal activity occurred in males at 3870 and 5100 mg/kg, and in females at 5100 mg/kg. Significantly decreased vertical activity occurred in both sexes at all doses. By day 14 vertical activity scores were still depressed in the 2580 and 3870 mg/kg groups.(49) Male rats given oral doses of 0, 400, 800 or 1200 mg/kg toluene in corn oil (cited as 0.4, 0.8 or 1.2 g/kg) showed significant elevations in heart rate at the two highest doses.(105) Male mice were given 0, 5, 22 or 105 mg/kg/day in their drinking water for 4 weeks. No mortality, clinical signs or changes in body weight gain were observed. A significant increase in brain neurotransmitters (serotonin, norepinephrine) was observed at all doses. The maximum effect on neurotransmitters and their metabolites was at 22 mg/kg/day.(50) These changes were not correlated with behavioural or anatomical changes. Studies in mice orally exposed for 14 or 28 days have shown conflicting evidence as to the immune system toxicity of toluene.(51) Hearing loss was reported in rats given 620 mg/kg/day for 4 weeks.(5)

Effects of Long-Term (Chronic) Exposure:

Reduced performance on some neurobehavioural tests has been noted mainly at 500 ppm and higher in rats and mice. However, in general, these effects are reversible. Persistent effects in rats include a decrease in hippocampus weight following exposure to 1500 ppm for 6 months and changes in brain neurotransmitter levels following exposure to 500 and 1500 ppm for 6 months. Changes in brain neurotransmitter levels have also been noted in rats exposed to 40 ppm for 16 weeks. However, reversibility was not assessed. Inhalation of 625 ppm and higher for 15 weeks resulted in increased liver weight in mice. Inhalation of 1250 ppm and higher for 15 weeks or ingestion of 625 mg/kg/day for 13 weeks led to an increase in the weights of several organs (kidney, liver, brain, heart) in rats and mice. In rats exposed to 600 or 1200 ppm for 2 years, there was a dose-dependent increase in severity of kidney effects. A significant increase in white blood cells was seen in female rats exposed by inhalation to 1250 ppm for 15 weeks. Tissue death (necrosis) was seen in the brains of rats exposed orally to 1250 mg/kg/day (females only) and 2500 mg/kg/day for 13 weeks.

Inhalation:
Numerous studies using rats and mice have shown reduced performance on some neurobehavioural tests but not others, both during and after inhalation exposures mainly of 500 ppm and higher. In general, these effects were reversible.(3,52) In a study where rats were exposed to 0, 500 or 1500 ppm for 6 months (6 hr/d, 5 d/wk) and tested in a battery of neurobehavioural tests 2 months post-exposure, most results were the same for treated animals as for controls. There was a dose-related decrease in the weight of the hippocampus, which was significant at 1500 ppm and changes (mostly increases) in brain neurotransmitter (serotonin, norepinephrine) levels at 500 and 1500 ppm.(7) In rats exposed to 40 ppm toluene for 16 weeks (104 hr/wk - the pattern of exposure was a 48-hr exposure, 24-hr with no exposure, 56-hr exposure, 52-hr no exposure), there was a significant change in the rate of production of brain neurochemicals (dopamine, serotonin). The effect was greater in females than in males.(53) These changes were not correlated with behavioural or anatomical changes and reversibility was not measured. Rats were exposed to 0, 100, 625, 1250, 2500 or 3000 ppm for 15 weeks (6.5 hr/d, 5 d/wk). At 3000 ppm, 8/10 males died during week 2. No other deaths occurred during the study. Both sexes exposed to 2500 ppm and higher had significantly decreased body weight. Significant increases in relative organ weights were: liver weight in males at 1250 ppm and higher and in females at 2500 ppm; kidney weight in both sexes at 1250 ppm and higher; brain, heart and lung weights in both sexes at 2500 ppm. At 1250 ppm and higher, there was a significant decrease in white blood cell count in females. Mice were similarly exposed to toluene. At 3000 ppm, 6/10 males and 10/10 females died during week 2 and at 2500 ppm, 7/10 females died before the end of the study. Significant increases in relative organ weights were: lung weight in females at 100 ppm and higher (non-dose-related); liver weight in females at 625 ppm and higher and in males at 1250 ppm and higher; kidney weights in females at 1250 ppm and higher. An increase in cell size (hypertrophy) was seen in the central lobe of the liver in male mice at 2500 ppm and higher.(5) Rats were exposed to 0, 600 or 1200 ppm for 15 months or 2 years (6.5 hr/d, 5 d/wk). Mice were exposed to 0, 120, 600 or 1200 ppm on the same schedule. No significant decrease in body weights or survival was observed for either species. No significant effects were observed in mice. In rats exposed for 2 years, there was a dose-dependent increase in severity of effects on the kidneys, which did not involve hyaline droplet formation (an effect specific to male rats). Mild to moderate degeneration of the olfactory and respiratory epithelium was seen in both sexes at all doses after 15 months or 2 years of exposure.(5,54) Rats exposed to 0, 30.1, 99.7 or 299 ppm (6 hr/d, 5 d/wk) for 2 years had no observable effects from the toluene exposure.(55)

Ingestion:
Rats and mice were given 0, 312, 625, 1250, 2500 or 5000 mg/kg/day in corn oil for 13 weeks (5 d/wk). All mice and rats given 5000 mg/kg/day died within the first week. At 2500 mg/kg, 8/10 male rats, 1/10 female rats, 4/10 male mice and 4/10 female mice died before the end of the study. At 2500 and 5000 mg/kg/day, there were clinical signs of CNS depression, tearing (lachrymation) and excessive salivation. Male rats had a significantly decreased body weight at 2500 mg/kg/day and liver and kidney weights were significantly increased at 625 mg/kg/day and higher. In female rats, liver, kidney and heart weights were significantly increased at 1250 mg/kg/day. An increase in cell size (hypertrophy) was seen in the central lobe of the liver in rats exposed to 2500 mg/kg/day. Tissue death (necrosis) was seen in the brain at 1250 mg/kg/day in male rats and at 2500 mg/kg/day in female rats. Liver weights were significantly increased in female mice exposed to 312 mg/kg/day and higher and in male mice exposed to 1250 mg/kg/day and higher.(5) Female rats given 0, 118, 354 or 590 mg/kg/day of toluene in olive oil for up to 6 months showed no signs of toxicity.(28)

Skin Sensitization:
Toluene is not a skin sensitizer.
In an unpublished study, carried out according to OECD guidelines, a negative result was obtained in a Guinea Pig Maximization Test. Guinea pigs were given an intradermal injection of 10% toluene in corn oil and exposed epidermally to undiluted toluene. After two weeks animals were challenged with 50% and 25% toluene. A single guinea pig showed discrete or patchy redness from the 50% solution.(39, unconfirmed)

Carcinogenicity:
The International Agency for Research on Cancer (IARC) has concluded there is inadequate evidence for the carcinogenicity of toluene in experimental animals.(16,30)
Toluene was not considered carcinogenic in a National Toxicology Program study where mice and rats (60/sex/group) were exposed by inhalation to 0, 120, 600 or 1200 ppm for 24 months (6.5 hr/d, 5 d/wk).(5,16,30) However, in this study, all of the toluene-exposed female mice and the 1200 ppm group of male mice had a single adenoma in the pituitary gland (in the pars intermedia). This is a very rare tumour and this observation may indicate a possible marginal tumorigenic effect.(39) Rats exposed by inhalation to 0, 30.1, 99.7 or 299 ppm for 2 years (6 hr/d, 5 d/wk) showed no increase in tumours.(55) Toluene has been used as a solvent control in a number of skin painting studies in mice where it did not cause an increased incidence of skin tumours.(16,30) In a recent skin-painting study in mice, which was carried out according to US EPA guidelines, toluene caused skin irritation and an increase in malignant tumour incidence, which was just below statistical significance.(39) Rats were exposed orally to 0, 500 or 800 mg/kg/day in olive oil for 2 years (4 d/wk). There was a non-dose-related increase in the total tumours at both doses and in specific tumours at different doses.(56) Rats exposed orally to 500 mg/kg/day for 2 years (4-5 d/wk) had significant increases in hemolymphoreticular neoplasias and malignant tumours. This study is not considered adequate for evaluation of carcinogenicity because of the use of a single dose.(30,39)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Toluene does cause developmental effects in animals, based on fetotoxicity (reduced fetal weight), behavioural effects (effects on learning and memory) and hearing loss (in males) observed in the offspring of rats exposed by inhalation to 1200 or 1800 ppm. These effects were observed in the absence of maternal toxicity.
Rats (16/group) were exposed to 1800 ppm toluene or clean air on days 7-20 of pregnancy. The dose was targeted so as not to induce marked toxicity in the mothers and no toxicity was seen. Fetotoxicity, as evidenced by reduced birth weight, was observed in the offspring. Differences in performance on a behavioural test designed to measure learning and memory (the Morris water maze test) were observed, especially in the female offspring. There was a slight tendency toward hearing loss in exposed male offspring. This effect was statistically significant at 8 kHz.(35) In a related study, rats (18 exposed/14 controls) were exposed to 1200 ppm on day 7 of pregnancy to postnatal day 18 (35 days). Again, the dose was targeted so as not to induce marked toxicity in the mothers and no toxicity was seen. A statistically significant reduction in birth weight was seen in offspring born to exposed mothers. Delayed reflex development, increased short-term motor activity and significant reductions in learning and memory (as measured by performance on Morris maze test (especially in females)) were observed. Effects on learning and memory persisted after exposure terminated (3.5 months). Decreased hearing function was also observed and this effect was statistically significant in males at 16 mHz.(34) In a 2-generation study, male and female rats were exposed by inhalation to 0, 100, 500 and 2000 ppm for 80 days (6 hr/d, 5 d/wk) before mating, through lactation. Males and females of the same dose group were mated. In addition, males and females exposed to 2000 ppm were mated to untreated partners. Reduced fetal weight was observed in the offspring of females exposed to 2000 ppm. A significant increase in skeletal variations (rudimentary ribs, unossified sternebrae) was also observed and was likely related to the reduced fetal weights. There was no decrease in survival and no increase in fetal malformations from the toluene exposure. Signs of slight maternal toxicity were evidenced by decreased maternal body weight noted only at lactation day 21 in the first generation 2000 ppm females (females treated only) and both groups of second generation 2000 ppm females.(57) Numerous other studies have evaluated the potential effects of toluene on the offspring of rats, mice or rabbits, primarily following inhalation exposure. In one well-conducted study, no effects in the offspring were observed in rabbits exposed to 30, 100 or 300 ppm or to 100 or 500 ppm during days 6-18 of pregnancy. Maternal toxicity was not observed.(9) In other studies where maternal toxicity was observed, reduced fetal weight and/or increased mortality in the offspring have been reported.(36,37,106) Other studies have had significant design limitations including continuous exposure regimes, lack of statistical evaluation of the data and incomplete or no evaluation of maternal toxicity.(3,8,39)

Reproductive Toxicity:
The available information does not indicate that toluene is a reproductive toxin. A significant decrease in sperm was noted in rats exposed by inhalation to 2000 ppm for 90 days, an exposure that also caused mild generalized toxicity. There was no accompanying decrease in fertility. No adverse effects on reproduction were observed in other studies.
Male rats were exposed by inhalation to 0, 600 or 2000 ppm for 90 days (6 hr/d) starting 60 days before mating. Female rats were similarly exposed from 14 days before mating through to the 7th day of pregnancy. Males and females in the same dose group were paired and allowed to mate. There were no effects on mating behaviour or fertility. However, there was a significant increase in fetal mortality and in the number of mothers with dead fetuses. In males exposed to 2000 ppm, there were significant decreases in epididymis weight and in the number of sperm. The signs of toxicity observed were some signs of CNS depression during exposures, after 20 days of exposure, and mild toxic changes in the thymus and kidneys of males.(58) In a 2-generation study, male and female rats were exposed by inhalation to 0, 100, 500 and 2000 ppm for 80 days (6 hr/d, 5 d/wk) before mating, through lactation. Males and females of the same dose group were mated. In addition, males and females exposed to 2000 ppm were mated to untreated partners. There were no effects on fertility, reproductive performance or maternal behaviour during the lactation period. Signs of slight maternal toxicity were evidenced by decreased maternal body weight noted only at lactation day 21 in the first generation 2000 ppm females (females treated only) and in both groups of 2nd generation 2000 ppm females.(57) Rats and mice exposed by inhalation to 0, 100, 625, 1250 or 2500 ppm for 15 weeks (6.5 hr/d, 5 d/wk) showed no compound-related effects on sperm count, sperm motility or fertility cycle.(5)

Mutagenicity:
The available information is not sufficient to conclude that toluene is mutagenic. Positive results in live animals have only been observed in a limited, unconfirmed study and in studies using routes of exposure that are not relevant to occupational situations. Negative results have been observed in studies using rats and mice exposed orally or by inhalation. Negative results have been obtained at non-toxic doses in cultured mammalian cells, in several tests using bacteria and in a test using yeast. Negative and positive results have been obtained in fruit flies (Drosophila).
In several studies, no biologically significant increases in micronuclei or chromosome aberrations in bone marrow were induced in mice and rats exposed orally, by inhalation or by intraperitoneal injection. Negative results (DNA damage in peripheral blood, bone marrow and liver cells, and dominant lethal mutation in sperm cells) were obtained in mice exposed by inhalation.(39,59,60) In a limited study, which is not available in English, a positive result (chromosome aberrations in bone marrow) was obtained in rats exposed to 162 ppm for 1, 2.5 or 4 months (4 hr/d, 5 d/wk).(59, unconfirmed) Positive results have been obtained in other studies using routes of exposure that are not relevant to occupational situations.(39,59,60)
A positive result (DNA damage) was observed in cultured rat liver cells. However, only toxic concentrations were tested.(61) Negative results (gene mutation, sister chromatid exchanges, micronuclei, DNA damage, DNA repair) were obtained at non-toxic doses in cultured mammalian cells, with and without metabolic activation.(5,39,54,60,62) Negative results (gene mutation, DNA repair) have been obtained in several tests using bacteria, with and without metabolic activation.(5,30,39,54,60) Negative results (gene conversion, gene mutation) were also obtained in yeast.(30,39,60)
Negative results (heritable translocations, sex-linked recessive lethal mutations) and positive results (aneuploidy) were obtained in fruit flies (Drosophila).(30,39)

Toxicological Synergisms:
Combined exposure to toluene and noise, toluene and n-hexane, toluene and aspirin or toluene, ethylbenzene and noise has caused a synergistic loss of hearing in animal studies.(2,39,44,63,103)


SECTION 16. OTHER INFORMATION

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(17) Hazleton Nuclear Science Corporation. Acute oral LD50 acute dermal LD50 primary dermal irritation acute eye irritation acute inhalation LC50. Standard Oil Company of California. Date produced: 02/01/62. EPA/OTS 878220875. NTIS/OTS0215111.
(18) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 29, 77
(19) Ozokwelu, E.D. Toluene. In: Kirk-Othmer encyclopedia of chemical technology. John Wiley and Sons, 2005. Available at: <www.mrw.interscience.wiley.com/kirk/kirk_search_fs.html> {Subscription required}
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(40) MB Research Labs Inc. Report on primary dermal irritation in rabbits. Mobil Oil Corp. Date produced: 12/29/75. EPA/OTS 878210563. NTIS/OTS0206119.
(41) Tegeris, J.S., et al. A comparison of the acute behavioral effects of alkylbenzenes using a functional observational battery in mice. Fundamental and Applied Toxicology. Vol. 22 (1994). p. 240-250
(42) Paez-Martinez, N., et al. Comparative study of the effects of toluene, benzene, 1,1,1-trichloroethane, diethyl ether, and flurothyl on anxiety and nociception in mice. Toxicology and Applied Pharmacology. Vol. 193 (2003). p. 9-16
(43) Taylor, J.D., et al. Effects of toluene inhalation on behavior and expired carbon dioxide in macaque monkeys. Toxicology and Applied Pharmacology. Vol. 80 (1985). p. 487-495
(44) Morata, T.C., et al. Auditory and vestibular functions after single or combined exposure to toluene: a review. Archives of Toxicology. Vol. 69 (1995). p. 431-443
(45) McWilliams, M.L., et al. Low-level toluene disrupts auditory function in guinea pigs. Toxicology and Applied Pharmacology. Vol. 167, no. 1 (Aug. 2000). p. 18-29
(46) Jacquot, L., et al. Effects of toluene exposure on olfactory functioning: behavioural and histological assessment. Toxicology Letters. Vol. 165 (2006). p. 57-65
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Review/Preparation Date: 2007-11-14



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