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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 208
CCOHS Chemical Name: Cresol (mixed isomers)

Synonyms:
Cresol
Cresylic acid
Hydroxytoluene
Methylphenol
Oxytoluene
Cresylol
Acide cresylique
Hydroxymethylbenzene
Methylhydroxybenzene
Tricresol

Chemical Name French: Crésol (mélange d'isomères)
Chemical Name Spanish: Cresol (mezcla de isómeros)
CAS Registry Number: 1319-77-3
UN/NA Number(s): 2076 2022
RTECS Number(s): GO5950000
EU EINECS/ELINCS Number: 215-293-2
Chemical Family: Aromatic alcohol / hydroxybenzene / monohydroxybenzene / phenol / alkylphenol / methylphenol / hydroxytoluene
Molecular Formula: C7-H8-O
Structural Formula: CH3-C6H4-OH

SECTION 2. DESCRIPTION

Appearance and Odour:
Colourless, yellowish or pinkish liquid with a phenolic odour. Turns brown on exposure to air and light.(1,20,21,22)

Odour Threshold:
Probably very low. Some people can smell the individual isomers at extremely low concentrations (range: 0.01-5.4 ppb).(23) Another source states that each of the isomers has a distinct phenolic odour discernible at 5 ppm.(22)

Warning Properties:
GOOD - TLV is greater than 500 times the reported odour threshold values.

Composition/Purity:
Cresol (mixed isomers) is a mixture of o-, m- and p-isomers. Commercially available cresol, also known as cresylic acid, is a mixture of these three isomers, with small amounts of phenol and xylenols as impurities. The typical composition of cresylic acid is about 20% o-cresol, 40% m-cresol, 30% p-cresol, and 10% phenol and xylenols. The presence of phenol and xylenols could influence the overall hazards of the material. Consult your Material Safety Data Sheet (MSDS) for specific compositional information. NOTE: "Cresylic acid" is different from commercial products called "cresylic acids". Cresylic acids are mixtures of phenolic compounds, predominantly xylenols and C9-phenols, with a typical composition of 0-1% m- and p-cresol, 0-3% 2,4- and 2,6-xylenols, 10-20% 2,3- and 3,5-xylenols, 20-30% 3,4-xylenol, and 50-60% C9-phenols.(2) An arbitrary standard in use for cresylic acids is that 50% must boil above 204 deg C. If the boiling point is below 204 deg C, the material is called cresol.(24) Cresols are transported in liquid form in heatable tank cars, tank trucks, drums or tote-tanks, all made of stainless steel or phenolic resin lined carbon steel.(25,26)

Uses and Occurrences:
Cresol (mixed isomers) is used in the production of modified phenolic resins; as a solvent for synthetic resin coatings; as a metal degreasing and cutting oil, and as an agent for removing carbon deposits from combustion engines; as an ore flotation agent; in fibre treatment; as a component of agricultural chemicals; as a disinfectant, bacteriostatic agent and fumigant; in the manufacture of chemicals, dyes, and antioxidants; as an intermediate for synthetic tanning agents and for methylcyclohexanol and methylcyclohexanone; as a wood preservative; as a cleaning compound and nonionic surfactant; and as a component of photographic developers and explosives.(1,2,20,24,25)
Cresols occur naturally in various plants and in crude oil and coal tar. They are products of combustion and can be released to the atmosphere from fires associated with lightning, spontaneous combustion and volcanic activity. Low levels are present in automobile exhaust, stack emissions from municipal waste incinerators, and emissions from the incineration of vegetable matter. Cigarette smoke contains cresols and they are also found in fly ash from coal and wood combustion.(1,2)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Colourless, yellowish or pinkish liquid with a phenolic odour. Turns brown on exposure to air and light. COMBUSTIBLE LIQUID AND VAPOUR. VERY TOXIC. May be fatal if absorbed through the skin or swallowed. Can cause nervous system, kidney and blood cell damage. Vapours from heated solutions or mists may severely irritate the nose, throat and respiratory tract. CORROSIVE to the eyes and skin. May cause blindness. May cause permanent scarring.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Cresol (mixed isomers) does not readily form a vapour at room temperature. Therefore, inhalation exposure is unlikely to occur unless the cresol is heated or misted. Vapours or mists are expected to produce severe irritation of the nose and throat, based on limited human and animal information. With a severe exposure, potentially life-threatening lung injury (pulmonary edema) may occur, based on a single case report and the corrosiveness of cresols. Symptoms of pulmonary edema (shortness of breath and chest tightness) may be delayed up to 24 or 48 hours following exposure.
Brief exposures to 6 mg/m3 o-cresol vapour/aerosol produced dryness, nasal constriction and throat irritation in 8/10 volunteers.(19) Exposure concentrations are not well documented in this study. One report describes life-threatening lung injury (pulmonary edema) in an employee who splashed heated cresol on him. Signs of pulmonary edema (shortness of breath and chest pain) were not observed until 4 days after the accident. The temperature of the cresol was unknown, but was probably less than 100 deg C.(10)

Skin Contact:
Cresol (mixed isomers) is corrosive and can cause burns, blisters and permanent scarring and can cause death. Soon after contact with concentrated solutions, sensations of prickling and intense burning occur, followed by loss of feeling. The affected skin becomes soft, wrinkled and discoloured. Later, gangrene may occur. Dilute solutions can cause redness, blistering and ulceration. Numerous cases of burns due to skin contact with cresol have been reported.(16)
In one case report, a man fell into a vat containing "ardrox", a cresylic acid derivative. He suffered burns to 15% of his body and developed kidney failure after 36 hours. He died due to congestive heart failure after 9 days.(5) Another report describes 13 cases of accidental burns, some caused by cresol. The burns were diagnosed as first and second degree, covering a relatively small area (0.5-10% of body surface). Skin discolouration (white, red, brown and black) was followed by crusting and tissue death. The victims were treated immediately following exposure by washing the affected area. Full recovery, with no scarring, was reported for 12/13 victims.(2, original not available in English)
Cresol can cause toxic effects following absorption through the skin. The rate of absorption depends on exposed surface area and on concentration. Symptoms are expected to be similar to those described under "Ingestion".(1)
Dermal absorption of cresol appears to be responsible for the death of a man who worked with an antiseptic solution containing concentrated mixed cresols for 2 days prior to becoming ill. Harmful changes to the blood (methemoglobinemia, Heinz body formation and massive hemolysis) were observed.(1,2, original not available in English) Acute renal failure was observed in a male technician accidentally exposed to cresol (mixed isomers). He experienced dizziness, pain and numbness of the burnt skin and abdominal pain followed by reduced urination 1 day after exposure. Follow-up revealed decreased pulse rate, urinary volume, and blood urea nitrogen. Burnt skin was light brown in colour and there was slight swelling. Full recovery occurred within 27 days.(2, original not available in English) In another case, an employee accidentally poured a hot cresol solution over his upper trunk. The actual temperature of the cresol is unknown, but it was probably less than 100 deg C. A deep burn involving about 40% of the body surface developed, as well as signs of kidney failure within the first 24 hours. The victim was hospitalized for 38 days and had permanent scarring.(10)

Eye Contact:
Direct contact is expected to produce corrosive injury, based on human and animal information. Permanent eye injury, including blindness could result.
Eye burns have been reported following contact with a product containing cresol (Lysol). In one case, a splash of 2.5% Lysol solution caused swelling of the eye with clouding of the cornea. After several months, the effects partially cleared, but there was permanent impairment of vision.(4, unconfirmed)

Ingestion:
Ingested cresol (mixed isomers) can cause mouth and throat burns, and irritation and corrosion of the gastrointestinal tract. The damage may be permanent and deaths have been reported following intentional or accidental non-occupational ingestion of disinfectants containing cresols. Effects have included abdominal pain, vomiting, initial central nervous system (CNS) stimulation followed by CNS depression, unconsciousness, laboured breathing, increased blood pressure, possible circulatory or respiratory collapse, blood cell damage and destruction (e.g. methemoglobinemia and hemolytic anemia), and kidney damage.(1,2)
Ingestion is not a significant route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

Skin:
Cresol (mixed isomers) may cause red, dry, cracked skin (dermatitis) following repeated exposure to very dilute solutions. One limited report describes dermatitis developing on the hands and face in six synthetic resin plant employees following exposure to phenol and cresol.(2,6) There are no further details available in English.

Skin Sensitization:
It is not possible to conclude that cresol (mixed isomers) is a skin sensitizer based on the limited information available.
There are insufficient details available to evaluate a historical report which describes dermatitis developing on the fingers of silk mill employees who used an anti-mildew solution containing crude cresol.(7) Negative results were obtained in one animal study.

Blood/Blood Forming System:
There are insufficient details available to evaluate a Russian report of 174 female production workers aged 20-50 exposed mainly to cresol (mixed isomers), with 70% exposed for at least 10 years. Concentrations averaged 1.4 mg/m3, with maximum recorded 3.6-5.0 mg/m3. Reported effects included circulatory disturbances and minor blood system changes (decreases in red blood cell count, white blood cell count and platelets).(2, original not available in English)

Carcinogenicity:

There is no human or animal information available on the cancer-causing potential of cresol (mixed isomers). Limited animal information suggests that cresols may promote the formation of tumours if applied to the skin with a known carcinogen.

The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.

The American Conference of Governmental Industrial Hygienists (ACGIH) has not assigned a carcinogenicity designation to this chemical.

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

Teratogenicity and Embryotoxicity:
There is no human information available. Developmental effects have been reported in animals following the oral administration of cresols, but only at doses that also caused toxicity in the mothers.

Reproductive Toxicity:
No conclusions can be drawn from two limited Russian studies.(8,9) The available animal information does not suggest that cresols affect reproductive performance.

Mutagenicity:
The available information does not suggest that cresol (mixed isomers) is mutagenic. No human studies were located. Negative results have been obtained in a study using live mice. Positive results have been obtained in cultured mammalian cells. Negative results have been obtained in bacteria, both with and without metabolic activation.

Toxicologically Synergistic Materials:
No specific information is available. It has been suggested that cresols could interact with phenol on the nervous system to cause convulsions and coma, and on the red blood cells to produce methemoglobinemia. It has also been suggested that the oxidizing effect of cresol on red blood cells could be enhanced in the presence of other oxidizing agents, such as hydroquinone.(1)

Potential for Accumulation:
Cresols are absorbed following inhalation, ingestion and skin contact. Absorption following ingestion or skin contact is considered rapid and extensive. Cresols are distributed to all major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor pathways include hydroxylation of the benzene ring and side-chain oxidation. The main route of elimination is excretion of conjugates in the urine.(1,2)


SECTION 4. FIRST AID MEASURES

Inhalation:
If symptoms are experienced, remove source of contamination or move victim to fresh air. If breathing is difficult, oxygen may be beneficial if administered by trained personnel, preferably on a doctor's advice. DO NOT allow victim to move about unnecessarily. Symptoms of pulmonary edema can be delayed up to 48 hours after exposure. Obtain medical attention.

Skin Contact:
Avoid direct contact. Wear chemical protective clothing, if necessary. Flush contaminated area with lukewarm, gently flowing water for at least 20-30 minutes, by the clock. If irritation persists, repeat flushing. Under running water, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). 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. 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 20-30 minutes, by the clock, while holding the eyelid(s) open. Neutral saline solution may be used as soon as it is available. DO NOT INTERRUPT FLUSHING. If necessary, keep emergency vehicle waiting. Take care not to rinse contaminated water into the unaffected eye or onto the face. If irritation persists, repeat flushing. Quickly transport victim to an emergency care facility.

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 to dilute material in stomach. If milk is available, it may be administered AFTER the water is given. If vomiting occurs naturally, rinse mouth and repeat administration of water. 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. Quickly transport victim to an emergency care facility.

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.
Some recommendations in the above sections may be considered medical acts in some jurisdictions. These recommendations should be reviewed with a doctor and appropriate delegation of authority obtained, as required.
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:
82 deg C (179.6 deg F) (closed cup) (1,2,20)

Lower Flammable (Explosive) Limit (LFL/LEL):
Less than or equal to 1.35% at 149 deg C (300 deg F) (24)

Upper Flammable (Explosive) Limit (UFL/UEL):
Not determined (o-, m- and p-cresols) (27)

Autoignition (Ignition) Temperature:
Not available. Range for individual isomers: 558-599 deg C (1038-1100 deg F) (27)

Sensitivity to Mechanical Impact:
Probably not sensitive. Stable material.

Sensitivity to Static Charge:
No specific information available. Probably not sensitive.

Electrical Conductivity:
The individual isomers have electrical conductivities ranging from 1.27 X 10(5) to 1.4 X 10(6) pS/m.(28)

Minimum Ignition Energy:
Not available

Combustion and Thermal Decomposition Products:
Aromatic degradation products and other irritating toxic fumes and gases.(27,29)

Fire Hazard Summary:
COMBUSTIBLE LIQUID. Can form explosive mixtures with air at, or above 82 deg C. During a fire irritating/toxic fumes and gases may be formed. Closed containers may rupture violently or explode 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.(27,29) 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 protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products.
Closed containers may rupture violently when exposed to the heat of the fire. Stay away from ends of tanks involved in fire, 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 the 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. Application should begin as soon as possible (within the first several minutes) and should concentrate on any unwetted portions of the container. Apply water from the side and from a safe distance until well after the fire is out. Take care not to get water inside container. 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 knock down and disperse the vapours and to protect personnel attempting to stop a leak. Water spray can be used to dilute spills to nonflammable mixtures and flush spills away from ignition sources. 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. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank. Tanks or drums should not be approached directly after they have been involved in a fire, until they have been completely cooled down.

Protection of Fire Fighters:
Cresol (mixed isomers) is corrosive to skin and a serious skin absorption 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: 3 - Short exposure could cause serious temporary or residual injury.
NFPA - Flammability: 2 - Must be moderately heated or exposed to relatively high ambient temperatures before ignition can occur.
NFPA - Instability: 0 - Normally stable, even under fire conditions, and not reactive with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 108.14 (varies with composition)

Conversion Factor:
1 ppm = 4.41 mg/m3; 1 mg/m3 = 0.23 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: 11-35 deg C (51.8 -95 deg F) (1,2,20); may supercool (exist as a liquid below the Freezing Point) (25,26)
Boiling Point: 191-203 deg C (375.8-397.4 deg F) (1,2,20)
Relative Density (Specific Gravity): 1.03-1.047 at 20 deg C (1); 1.03-1.038 at 25 deg C (2,20,21) (water = 1)
Solubility in Water: Moderately soluble (about 2 g/100 g water) (21)
Solubility in Other Liquids: Soluble in all proportions in ethanol, benzene, diethyl ether, glycerol and petroleum ether; soluble in vegetable oils and fixed alkali hydroxide solutions.(21,24)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = 1.95 (experimental) (average of isomers) (30,31)
pH Value: Not available
Acidity: Weak acid (25,26)
Dissociation Constant: pKa = 10.2 at 25 deg C (31)
Viscosity-Dynamic: Not available at normal temperatures.
Surface Tension: Not available at normal temperatures.
Vapour Density: 3.72 (air = 1) (2)
Vapour Pressure: 0.023 kPa (0.17 mm Hg) at 25 deg C (31)
Saturation Vapour Concentration: Approximately 225 ppm (0.022%) at 25 deg C (calculated)
Evaporation Rate: Very low
Henry's Law Constant: 6.27 X 10(-2) Pa.m3/mol (cited as 6.19 X 10(-7) atm.m3/mol) at 25 deg C (31); log H = -4.6 (dimensionless constant; calculated)

SECTION 10. STABILITY AND REACTIVITY

Stability:
Normally stable. Cresol (mixed isomers) darkens with age or on exposure to air and light as a result of slow oxidation.(21,26,27)

Hazardous Polymerization:
Will 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. calcium hypochlorite, permanganates, perchlorates, peroxides, nitric acid) - reaction may be vigorous or violent. Increased risk of fire and explosion.(27,29,35)
STRONG ACIDS (e.g. chlorosulfonic acid, oleum) - mixing in a closed container caused the temperature and pressure to rise.(27)

Hazardous Decomposition Products:
None reported

Conditions to Avoid:
Temperatures greater than 82 deg C.

Corrosivity to Metals:
Cresol (isomer not specified) is corrosive to bronze, brass, cast iron and lead.(36) It is not corrosive to 300 series and 400 series stainless steels, aluminum, nickel, nickel-base alloys, such as Hastelloy, and titanium.(36,37,38)

Corrosivity to Non-Metals:
Cresol (mixed isomers) attacks elastomers, such as butyl rubber, chloroprene, ethylene-propylene, ethylene vinyl acetate (EVA), isoprene, natural rubber, nitrile buna-N (NBR), nylon, low density polyethylene, polyurethane, polyvinyl chloride (PVC), silicone rubbers and styrene-butadiene.(38) Cresol (isomer not specified) attacks many plastics, such as acrylonitrile-styrene-butadiene (ABS), acrylics, polyesters and polypropylene; and coatings, such as coal tar epoxy, polyester and vinyls.(39) Cresol (mixed isomers) does not attack Teflon, Viton A, other fluorocarbon polymers, ethylene-propylene terpolymer, fluorosilicone and ultra high molecular weight (UHMW) polyethylene.(38,39)


SECTION 11. TOXICOLOGICAL INFORMATION

LD50 (oral, rat): 1454 mg/kg (mixed o-, m- and p-cresol in corn oil) (17)
LD50 (oral, mouse): 561 mg/kg (mixed o-, m- and p-cresol in corn oil) (17)

LD50 (dermal, rabbit): 1782 mg/kg (mixed o-, m- and p-cresol; undiluted) (17); 2000 mg/kg (mixed isomers) (12)

Eye Irritation:

Extreme irritation has been observed in rabbits.

Using the Draize method, maximum scores ranging from 87.3 to 93/110 (depending on the isomer tested) were obtained in rabbits. These scores indicate that the cresols are extremely irritating (scores exceeding 80).(3, original not available)

Skin Irritation:

Corrosive injury has been observed in rabbits.

Covered application of 0.5 mL of a technical mixture of all 3 cresol isomers (o-, m- and p-) for 4 hours caused corrosive injury (visible tissue destruction) in rabbits.(12)

Effects of Short-Term (Acute) Exposure:

m- and p-Cresol in food produced increased liver and kidney weights in rats and mice exposed to high doses, as well as mild irritant effects in the stomachs of rats. Signs of irritation of the nasal cavity of rats and mice were also observed, probably due to irritation by cresol vapours. Ingestion of cresol isomers in corn oil produced signs of central nervous system (CNS) depression such as reduced activity, laboured respiration and, then, increased activity. High doses (450 mg/kg/day) have caused deaths.

Inhalation:
Rats survived an 8-hour exposure to substantially saturated cresol vapour concentrations at room temperature.(18)

Ingestion:
Rats and mice were exposed to 0, 300, 1000, 3000, 10000 or 30000 ppm m- and p-cresol (60:40 mixture) in their feed for 28 days. Approximate doses were 20, 60, 180, 600 or 1800 mg/kg/day for male rats; 15, 50, 150, 500 or 1500 for female rats; 35, 120, 360, 1200 or 3600 mg/kg/day for mice. There were no deaths. Mean final body weight was reduced in high dose male rats, high dose male and female mice, probably due to reduced food intake. Clinical signs of toxicity (e.g. hair loss, dehydration, hunched posture, reduced body temperature, and lethargy) were observed in high dose mice. Relative kidney weights were significantly higher in rats exposed to the two highest doses and in female mice given the high dose. Relative liver weights were increased for male rats and female mice exposed to 3000 ppm and above, and in male mice and female rats exposed to 1000 ppm and above. Atrophy (wasting away) and increased cell growth was observed in the nasal cavity of rats and mice and in the bronchioli of high dose mice. These effects were due to irritant vapours given off from the cresol mixture. At 3000 ppm and above, minimal to mild increased cell growth was observed in the esophagus, and forestomach in rats.(15) Unpublished studies have shown central nervous system effects (reduced activity, laboured breathing and then increased activity) in animals orally exposed to the cresol isomers (o-, p- or m-cresol). The lowest dose at which nervous system effects were reported was 50 mg/kg/day. Convulsions and deaths were observed in pregnant rats given 450 mg/kg/day o-, m- and p-cresol in corn oil.(1,2 citing unpublished studies)

Effects of Long-Term (Chronic) Exposure:

m- and p-Cresol in food produced signs of decreased liver function in male rats exposed to 1800 mg/kg/day and female rats exposed to 750 and 1500 mg/kg/day for 13 weeks. Irritation of the nasal cavity was observed in mice and rats, probably due to irritation by cresol vapours. In unpublished studies, ingestion of lower doses (50 mg/kg/day and above) has produced nervous system effects such as muscle incoordination, increased activity, then decreased activity and tremors.

Ingestion:
In a 13-week study, rats were fed an m- and p-cresol mixture (60:40) in their diet at doses of 1880, 3750, 7500, 15000, or 30000 ppm. Approximate doses were 115, 225, 450, 900 or 1800 mg/kg/day for males and 95, 190, 375, 750 or 1500 mg/kg/day for females. There were no deaths. Decreased body weight was observed at the two high doses, probably due to reduced food consumption. Clinical signs of toxicity (rough hair coat and urine-stained fur) were observed at the high dose. Males exposed to 7500 ppm and above and females exposed to 30000 ppm had increased relative kidney weights. At 7500 ppm and above, both sexes had increased liver weights. Relative testis weights were increased in males exposed to 15000 ppm and above. Signs of liver injury were observed on day 5 in high dose animals. This injury appeared to resolve. Signs of decreased liver function (elevation of total bile acids) were observed in males exposed to the high dose and females exposed to 15000 ppm and above. Dose-related increased cell growth was observed in the nasal respiratory epithelium in all exposure groups.(15) In a 13-week study, mice were fed an m- and p-cresol mixture (60:40) in their diet at doses of 625, 1250, 2500, 5000 or 10000 ppm. Approximate doses were 75, 150, 300, 600, or 1200 mg/kg/day. There were no deaths. Mean final body weights were decreased for all high dose animals, probably due to reduced food consumption. Clinical signs of toxicity (rough hair coat) as observed in 3/10 high dose females. Relative liver weights were increased for males exposed to 5000 ppm and above and females exposed to 10000 ppm. Increased cell growth was observed in the nasal respiratory epithelium in males exposed to 5000 ppm and above and females exposed to 2500 ppm and above.(15) In unpublished 13-week studies, oral exposure produced nervous system effects. Stimulation of the central nervous system was observed at 50 mg/kg/day, muscle incoordination, decreased activity and tremors were observed at 175 mg/kg/day and coma and convulsions at 450 or 600 mg/kg/day. Increased mortality was observed following exposure to 600 mg/kg/day o-cresol. Exposure to 450-600 mg/kg/day p- or m-cresol did not produce deaths. In a two-generation reproductive toxicity study, 12-60% mortality was observed in both generations of rats exposed to 450 mg/kg/day o-, p- or m-cresol.(1 citing unpublished studies)

Skin Sensitization:
The available information does not suggest that cresols are skin sensitizers.
Repeated application of a 7.5% solution of a mixture of m- and p-cresol did not produce sensitization in guinea pigs.(3,unconfirmed)

Carcinogenicity:
No cancer studies have been conducted. Despite limitations in study design, results of a cancer promotion study in mice suggest that cresol isomers (o-, p- or m-) may be cancer promoters following dermal application with a known carcinogen. Limitations include the observation of obvious toxicity in the animals and the use of benzene as the carrier.(1,2,11)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Developmental effects have been reported following the oral administration of cresols, but only at doses that also caused toxicity in the mothers.
In a 2-generation, continuous breeding study, mice were exposed to 0.25, 1.0 and 1.5% of a mixture of m- and p-cresol in their food (approximately 370, 1500 and 2100 mg/kg/day). At 1.5%, parental toxicity was seen in both generations (F0 and F1). At 1.0%, parental toxicity was also seen in the F1 generation. Signs of developmental toxicity, such as decreased number of live pups/litter (F0), and decreased pup weight/litter (F0 and F1) were seen at the 1.5%.(13,14) Fetotoxicity was observed in another two-generation rat study, but only at doses that cause toxicity to the parents. Administration of 450 mg/kg/day of o- and p-cresol produced overt toxicity in the parents and the F1 offspring had reduced body weight 4-6 weeks after birth. m-Cresol produced fetotoxicity (body weight effects and reduced survival) at 30 mg/kg/day. Parental toxicity was also reported at this dose.(1,2 citing an unpublished study) Maternal toxicity (reduced body weight and food consumption and clinical signs) was observed in rats orally dosed with 450 mg/kg/day throughout pregnancy. At this dose, o- and p-cresol produced slight fetal toxicity (increased incidences of dilated lateral ventricles in the brain and minor skeletal variations, respectively). No effects were observed at lower doses. m-Cresol had no effect, even at maternally toxic doses.(1,2 citing an unpublished study) Maternal toxicity (audible respiration and reduced activity) was observed in rabbits orally exposed to 50 mg/kg/day and above throughout pregnancy. At 100 mg/kg, o-cresol produced slight fetotoxicity (e.g. poorly ossified sternebrae). No developmental effects were observed for p- or m-cresol.(1,2 citing an unpublished study)

Reproductive Toxicity:
The available information does not suggest that cresols affect reproductive performance.
In a 2-generation, continuous breeding study, mice were exposed to 0.25, 1.0 and 1.5% in their food (approximately 370, 1500 and 2100 mg/kg/day). At 1.5%, parental toxicity was seen in both generations (F0 and F1). At 1.0%, parental toxicity was also seen in the F1 generation. At 1.5% (F0) and 1.0% (F0 and F1), seminal vesicle weight was reduced, but there were no changes in sperm endpoints. No effects were observed on the female fertility cycle.(13,14) Mice and rats were exposed to a m- and p-cresol mixture (60:40) in their diet for 13 weeks. No adverse effects on sperm motility or concentration were observed. Minimal to mild uterine atrophy was noted among females exposed to 15000 ppm and above. An increase in length of the fertility cycle was observed in female rats exposed to 7500 and 30000 ppm. There were no effects observed in the fertility cycle in mice.(15) Rats were exposed to 0, 0.6 or 4.0 mg/m3 of a mixture of o-, m- and p-cresols for 4 months. At 4.0 mg/m3, harmful effects on the function and structure of the ovaries were noted (effects on the fertility cycle, decreased number of primary follicles and increased atresia). Similar, but less pronounced changes, were observed at 0.6 mg/m3.(2, original not available in English) There are no further details available. No effects on reproductive parameters were observed in unpublished studies using rats and mink.(1)

Mutagenicity:
The available information suggests that cresol (mixed isomers) is not mutagenic.
A mixture of m- and p-cresol (60:40) produced negative results (micronuclei in peripheral blood erythrocytes) in mice exposed to up to 20000 ppm in their diets for 13 weeks.(15)
A mixture of o-, m-, p-cresol (1:1:1) produced positive results in cultured mammalian cells (forward mutations in mouse lymphoma cells, with metabolic activation; sister chromatid exchanges in Chinese hamster ovary cells, with and without metabolic activation; and cell transformation in mouse BALB/C-3T3 cells, with activation).(1,2 citing an unpublished study) A mixture of o-, m-, p-cresol (1:1:1) produced negative results in bacteria, both with and without metabolic activation.(1,2 citing an unpublished study) A mixture of m- and p-cresol (60:40) produced negative results in bacteria, with and without metabolic activation.(15)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for cresols: o-cresol, m-cresol, p-cresol. TP-91/11. Public Health Service, US Department of Health and Human Services, July, 1992
(2) International Programme on Chemical Safety (IPCS). Cresols. Environmental Health Criteria; 168. World Health Organization, 1995
(3) Stouten, H. DECOS and SCG basis for an occupational standard. Cresols (o-, m-, p-). Arbete Och Halsa. Vol. 27 (1998)
(4) Grant, W.M., et al. Toxicology of the eye. 4th ed. Charles C. Thomas, 1993. p. 475-477
(5) Cason, J.S. Report on three extensive industrial chemical burns. British Medical Journal. Vol. 1 (Mar. 1959). p. 827-829
(6) Zalecki, M. The results of examination of the employees of Cracow plants for detection of occupational skin diseases. [In Polish, English abstract] Medycyna Pracy. Vol. 16, no. 5 (1965). p. 385-393 (NIOSHTIC 00031811)
(7) Goodman, H. Silk handler's disease of the skin. Medical Journal and Record. Vol. 138 (1933). p. 349-350
(8) Pashkova, G.A. Condition of the function of the ovaries of female workers in the production of tricresyl phosphate. [English Translation] Voprosy Gigieny Truda Profpatologii Toksikologii Proizvodstvo Ispol'zovanie Forsfororg. Plastif. Moskovskii Nauchno-Issledovatez'skii Instit. Gigieny, 1973. p. 62-65 {NIOSHTIC Control Number: 00151644)
(9) Syrovadko, O.N., et al. Work conditions and their effect on certain specific functions among women who are engaged in the production of enamel-insulated wire. [English Translation] Gigiena Truda Professional'nye. No. 4 (1977). p. 25-28 (NIOSHTIC Control Number: 00103223)
(10) Lin, C.H. et al. Chemical burn with cresol intoxication and multiple organ failure. Burns. Vol. 18, no. 2 (1992). p. 162-166
(11) Boutwell, R.K., et al. The tumor-promoting action of phenol and related compounds for mouse skin. Cancer Research. Vol. 19 (May 1959). p. 413-424
(12) Vernot, E.H., et al. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicology and Applied Pharmacology. Vol. 42, no. 2 (1977). p. 417-423
(13) Heindel, J., et al. m-/p-Cresol. NTP reproductive assessment by continuous breeding study. Environmental Health Perspectives. Vol. 105, Suppl. 1 (Feb., 1997). p. 295-296
(14) Izard, M.K., et al. Reproductive toxicity of cresol isomers administered in feed to mouse breeding pairs. (Abstract). Toxicologist. Vol. 12 (1992). p. 198
(15) NTP report on the toxicity studies of cresols (CAS Nos. 95-48-7, 108-39-4, 106-44-5) in F344/N rats and B6C3F1 mice (feed studies). NTP TOX 9. US Department of Health and Human Services, Feb. 1992
(16) National Institute for Occupational Safety and Health (NIOSH). NIOSH Criteria for recommended standard, occupational exposure to cresol. US Department of Health, Education and Welfare, Feb. 1978
(17) Back, K.C., et al. Reclassification of materials listed as transportation health hazards. Suppl. US National Technical Information Service. NTIS PB 225 283. Sept. 1973
(18) Smyth, Jr., H.F. Improved communication - hygienic standards for daily inhalation. American Industrial Hygiene Association Quarterly. Vol. 17 (1956). p. 129-185
(19) Uzhdavini, E.R., et al. Inhalation toxicity of o-cresol. [Translation] Tr. Ufimskogo Nauchno-Issledovatel'skogo Instituta Gigiyeny Profzabolevaniya. Vol. 7 (1972). p. 115-119
(20) Cresol, all isomers. In: Documentation of threshold limit values and biological exposure indices. 7th ed. A-D. American Conference of Governmental Industrial Hygienists (ACGIH), 2001
(21) Cresol. The Merck index: an encyclopedia of chemicals, drugs and biologicals. Edited by M.J. O'Neil, et al. 13th ed. Merck and Company, 2001. p. 451
(22) Gingell, R, et al. Phenol and phenolics. In: Patty's toxicology. 5th ed. Edited by E. Bingham, et al. Vol. 4. Hydrocarbons; organic nitrogen compounds. John Wiley and Sons, 2001. p. 433-447
(23) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 15, 52
(24) US National Library of Medicine. Cresol. Last revision date: 2002-01-14. In: Hazardous Substances Data Bank (HSDB). CHEMpendium. [CD-ROM]. Canadian Centre for Occupational Health and Safety (CCOHS). Also available at: <ccinfoweb.ccohs.ca/chempendium/search.html>
(25) Fiege, H. Cresols and xylenols. In: Ullmann's encyclopedia of industrial chemistry. 5th completely revised ed. Vol. A 8. VCH Publishers, 1987. p. 25-59
(26) Lorenc, J.F., et al. Alkylphenols. In: Kirk-Othmer encyclopedia of chemical technology. 4th ed. Vol. 2. John Wiley and Sons, 1992. p. 113-143
(27) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 49; NFPA 491
(28) Britton, L.G. Using material data in static hazard assessment. Plant/Operations Progress. Vol. 11, no. 2 (Apr. 1992). p. 56-70
(29) Cresol mixture of isomers, crude. In: Sigma-Aldrich Fine Chemicals: technical library [online]. Sigma-Aldrich Corporation. MSDS. Valid 2002-08 - 2002-10. Available at: <www.sigma-aldrich.com/saws.nsf/Technical+Library?OpenFrameset> (Password required)
(30) Syracuse Research Corporation. Interactive LogKow (KowWin) Database Demo [online]. Date unknown. Available at: <esc-plaza.syrres.com/interkow/kowdemo.htm>
(31) Syracuse Research Corporation. The Physical Properties Database (PHYSPROP). Interactive PhysProp Database Demo. Date unknown. Available at: <esc-plaza.syrres.com/interkow/physdemo.htm>
(32) Lide, D.R., ed. Handbook of chemistry and physics. [CD-ROM]. Chapman and Hall/CRCnetBASE, 1999
(33) Dean, J.A. Lange's handbook of chemistry. 15th ed. McGraw-Hill, Inc., 1999. p. 1.154, 5.93, 5.141, 8.36
(34) Jasper, J.J. Surface tension of pure liquid compounds. In: Compilation of data of some 2200 pure liquid compounds. Journal of Physical and Chemical Reference Data. Vol. 1, no. 4 (1972). p. 940
(35) o-Cresol. In: NIOSH pocket guide to chemical hazards. National Institute for Occupational Safety and Health, June, 1997
(36) Pruett, K.M. Chemical resistance guide to metals and alloys: a guide to chemical resistance of metals and alloys. Compass Publications, 1995. p. 110-121
(37) Corrosion data survey: metals section. 6th ed. National Association of Corrosion Engineers, 1985. p. 42-8 to 43-8
(38) 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. 893-896
(39) Pruett, K.M. Chemical resistance guide for elastomers II. Compass Publications, 1994. p. C-98 to C-103
(40) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002
(41) European Economic Community. Commission Directive 93/72/EEC. Sept. 1, 1993
(42) Occupational Safety and Health Administration (OSHA). Phenol and Cresol. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc>
(43) National Institute for Occupational Safety and Health (NIOSH). 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: 2003-03-21

Revision Indicators:
Bibliography 2003-04-16
Personal hygiene 2003-05-05
PEL-TWA transitional 2004-01-22
PEL transitional comments 2004-01-22
PEL-TWA final 2004-01-22
PEL final comments 2004-01-22
Resistance of materials for PPE 2004-04-09
Bibliography 2004-04-09
Synonyms 2004-12-03



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