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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 118
CCOHS Chemical Name: Phenolphthalein

Synonyms:
3,3-Bis(4-hydroxyphenyl)-1-(3H)-isobenzofuranone
3,3-Bis(4-hydroxyphenyl)phthalide
3,3-Bis(p-hydroxyphenyl)phthalide
alpha-Di-(p-hydroxyphenyl)phthalide
Phenolphtaleine
alpha-(p-Hydroxyphenyl)-alpha-(4-oxo-2,5-cyclohexadien-1-ylidene)-o-toluic acid

CAS Registry Number: 77-09-8
RTECS Number(s): SM8380000
EU EINECS/ELINCS Number: 201-004-7
Chemical Family: Phthalein dye / triphenylmethane derivative
Molecular Formula: C20-H14-O4

SECTION 2. DESCRIPTION

Appearance and Odour:
White or yellowish-white crystals; odourless.(1)

Odour Threshold:
Odourless.

Warning Properties:
POOR - phenolphthalein is odourless.

Composition/Purity:
Commercially available as the pure solid and as alcohol solutions (ethanol, methanol and isopropanol). This record provides information for the solid form. For solutions in alcohol, the hazard would also relate to the type and concentration of alcohol present.

Uses and Occurrences:
Used as an acid-base (pH) indicator in colorimetric and titrimetric determinations; laboratory reagent.(1,5) Formerly used as a laxative- cathartic, but recently has been substituted due to concerns regarding potential carcinogenicity.


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
White or yellowish-white, odourless crystals. Solid is not combustible, but may burn if strongly heated. POTENTIAL COMBUSTIBLE DUST HAZARD. Powdered material may form explosive dust-air mixtures. POSSIBLE CANCER HAZARD - may cause cancer, based on animal information. POSSIBLE MUTAGEN - may cause genetic damage, based on animal information.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Pure phenolphthalein is a dust with an extremely low tendency to form a vapour. Health effects following short-term inhalation exposures have not been described in the literature. In general, high concentrations of dust may cause coughing and mild, temporary irritation.

Skin Contact:
The dust is probably not irritating. There is no specific human or animal information available.

Eye Contact:
In general, dusts may cause tearing, blinking and mild temporary pain as the solid material is rinsed from the eye by tears. There is one unconfirmed human case report of swelling of the eyelids and effects on the inner eyelids, but these effects were related to a widespread skin reaction and may have been an allergic response.(2) There is no animal information available.

Ingestion:
Phenolphthalein has been widely used therapeutically as a laxative for many years; doses of 30 to 195 mg are typical. Animal toxicity data suggests that phenolphthalein has low short-term toxicity. Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

The medical literature contains references to a number of different health effects which have resulted from abuse of phenolphthalein in laxatives or accidental ingestion of large amounts by children. Animal toxicity information suggests that it would not be harmful at low doses. Rare, but potentially serious, allergic reactions may occur from ingestion of phenolphthalein in laxative products.(1,3) These effects are not relevant to occupational exposures.

Carcinogenicity:

Phenolphthalein is considered possibly carcinogenic to humans, based on animal information.
Two human population studies showed no statistically significant increased risk of colorectal cancer in phenolphthalein laxative users.(1) There is inadequate evidence for the carcinogenicity of phenolphthalein in humans.(13)

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

The American Conference of Governmental Industrial Hygienists (ACGIH) has no listing for this chemical.

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

Teratogenicity and Embryotoxicity:
There is no human information available. Phenolphthalein was not teratogenic in one unconfirmed animal study.

Reproductive Toxicity:
There is no human information available. No conclusions can be drawn regarding effects on fertility. One animal study has shown testicular and sperm effects at very high doses.

Mutagenicity:
There is no human information available. Positive results have been obtained in studies using live animal. Both positive and negative results have been obtained in cultured mammalian cells. Negative results have been obtained in bacteria.

Toxicologically Synergistic Materials:
There is no information available.

Potential for Accumulation:
Phenolphthalein is absorbed from the intestine and is excreted primarily in the bile, urine, feces and milk. In animal studies, it has been shown that once absorbed, phenolphthalein is conjugated with glucoronic acid and widely and evenly distributed throughout the body. There is some evidence that it may cross the placenta. Animal studies have shown that it is largely eliminated as conjugated material within 48-72 hours of ingestion. Small doses of phenolphthalein in humans (30-60 mg) are excreted entirely as metabolites in the urine and feces, while larger doses (300 mg) result in the excretion of both the free and conjugated compound.(1)


SECTION 4. FIRST AID MEASURES

Inhalation:
This chemical is a possible carcinogen. Take proper precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment). If symptoms are experienced, remove source of contamination or have victim move to fresh air. If symptoms persist, obtain medical advice.

Skin Contact:
Avoid direct contact. Wear chemical protective clothing, if necessary. Quickly and gently blot or brush away excess chemical. Wash gently and thoroughly with water and non-abrasive soap for 5 minutes or until the chemical is removed. If symptoms persist, obtain medical advice. Discard contaminated clothing, shoes and leather goods.

Eye Contact:
Avoid direct contact. Wear chemical protective gloves, if necessary. Do not allow victim to rub eye(s). Let the eye(s) water naturally for a few minutes. Have the victim look right and left, and then up or down. If particle/dust does not dislodge, flush with lukewarm, gently flowing water for 5 minutes or until the particle/dust is removed, while holding the eyelid(s) open. If irritation persists, obtain medical attention. DO NOT attempt to manually remove anything stuck to the eye(s).

Ingestion:
If irritation or discomfort occur, obtain medical advice.

First Aid Comments:
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:
Not combustible

Lower Flammable (Explosive) Limit (LFL/LEL):
Not available

Upper Flammable (Explosive) Limit (UFL/UEL):
Not available

Autoignition (Ignition) Temperature:
Not available

Sensitivity to Mechanical Impact:
Not sensitive. Stable compound.

Combustion and Thermal Decomposition Products:
Incomplete combustion may produce phenols, acrid smoke and fumes.(1,7)

Flammable Properties:

Specific Hazards Arising from the Chemical:
During a fire irritating/toxic gases may be formed.

Extinguishing Media:
Does not burn. Use extinguishing media suitable for the surrounding fire.

Fire Fighting Instructions:
Phenolphthalein will not burn and does not support combustion. However, the thermal decomposition products may be combustible. Evacuate area and fight fire from a safe distance or a protected location. Approach fire from upwind to avoid toxic decomposition products.
If possible, isolate materials not yet involved in the fire, and move containers from fire area if this can be done without risk, and protect personnel. Otherwise, water spray or fog can be used to absorb heat, keep fire-exposed containers or tanks cool and protect exposed material.
The thermal combustion products of phenolphthalein may be hazardous to health. Do not enter without wearing specialized protective equipment suitable for the situation. Firefighter's normal protective equipment (Bunker Gear) will not provide adequate protection. Chemical resistant clothing (e.g. chemical splash suit) and positive pressure self-contained breathing apparatus (MSHA/NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Comments:
NFPA has no listing for this chemical in Codes 49 or 325.


SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 318.33

Conversion Factor:
Not applicable

Physical State: Solid
Melting Point: 262-263 deg C (504-505 deg F) (1,9)
Boiling Point: Not available
Relative Density (Specific Gravity): 1.3 at 25 deg C (water=1) (8)
Solubility in Water: Practically insoluble. The solubility is pH dependent and does not exceed 6 mg/100 mL.(1)
Solubility in Other Liquids: Very soluble in acetone; soluble in toluene; moderately soluble in ethanol (8.5 g/100 mL), and diethyl ether (1 g/100 mL); very slightly soluble in chloroform; insoluble in benzene and petroleum ether.(1,5,8,9)
Coefficient of Oil/Water Distribution (Partition Coefficient): Not applicable
pH Value: 8.2-10.0 (0.05 g in 50 mL ethanol and 50 mL water) (9)
Vapour Density: Not applicable
Vapour Pressure: Extremely low
Saturation Vapour Concentration: Not applicable
Evaporation Rate: Extremely low
Critical Temperature: Not available

Other Physical Properties:
ACIDITY: Weak acid; pKa = 9.4 at 25 deg C (8)
TRANSITION INTERVAL: pH 8.2 (colourless) to pH 9.8 (pink to red) (0.1% phenolphthalein in 96% ethanol) (9,10)


SECTION 10. STABILITY AND REACTIVITY

Stability:
Stable at normal temperatures when protected from light.(1)

Hazardous Polymerization:
Does not occur

Incompatibility - Materials to Avoid:

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


STRONG OXIDIZING AGENTS (e.g. perchlorates, peroxides, permanganates) - can react rapidly and violently with the risk of fire and/or explosion.
STRONG REDUCING AGENTS (e.g. phosphorus, tin (II) chloride, metal hydrides) - may react vigorously or violently.

Hazardous Decomposition Products:
None reported

Conditions to Avoid:
Generation of dust, high temperatures, sources of ignition.

Corrosivity to Metals:
Not corrosive


SECTION 11. TOXICOLOGICAL INFORMATION

There are no standard toxicity values available.

Effects of Short-Term (Acute) Exposure:

Ingestion:
No harmful effects were observed in rats or mice fed high doses of phenolphthalein for 14 days (approximately 310-5000 mg/kg/day for rats and 940-15000 mg/kg/day for mice).(1)

Effects of Long-Term (Chronic) Exposure:

Ingestion:
Harmful effects have been observed in rats and mice fed very large doses for 13 weeks or 2 years, but effects have not been observed at low doses. Rats and mice were fed high doses of phenolphthalein for 2 years (approximately 500-2500 mg/kg/day for rats and 300-1200 mg/kg/day for mice). The most significant effects were kidney damage (nephropathy) in rats and effects on the testes in male mice (degeneration of the germinal epithelium).(1) Effects on the bone marrow and blood cell formation were observed in male mice, but not in females, fed approximately 3750 or 7500 mg/kg/day for 13 weeks. Little evidence of toxicity was observed in rats fed approximately 150-2500 mg/kg/day for the same duration.(4) No harmful effects were observed in female mice fed 5-50 mg/kg/day for 135 days.(1)

Carcinogenicity:
The International Agency for Research on Cancer has concluded there is sufficient evidence for the carcinogenicity of phenolphthalein in experimental animals.(13)
Carcinogenic effects were observed in rats and mice fed phenolphthalein for 2 years (approximately 500-2500 mg/kg/day for rats and 300-1200 mg/kg/day for mice). Treatment-related neoplasms were observed in the kidney and adrenal medulla in male rats, adrenal medulla in female rats, hematopoietic system in female mice and ovary of female mice. The authors concluded that there was clear evidence of carcinogenicity in mice and in male rats and that there was some evidence of carcinogenicity in female rats.(1)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Phenolphthalein was not teratogenic in mice fed approximately 250 mg/kg/day in a three-generation study.(1,5, unconfirmed)

Reproductive Toxicity:
No conclusions can be drawn from the available information. Testicular effects and sperm abnormalities were observed in mice fed high doses (450-7500 mg/kg/day) of phenolphthalein for 13 weeks, but not in rats fed somewhat lower doses for the same duration.(4) There are insufficient details available to evaluate one study which reported harmful effects on fertility (a decrease in the number of fertile mating pairs and in the number of litters per fertile pair) in mice fed high doses (approximately 1050-4500 mg/kg/day) for 105 days.(6, unconfirmed)

Mutagenicity:
Phenolphthalein is mutagenic, based on positive results (chromosomal aberrations) observed in mice.
Positive results (chromosome aberrations) have been obtained following the oral administration of high doses (greater than 2000 mg/kg/day) phenolphthalein to mice.(4,6)
Positive results (chromosome aberrations) have also been obtained in cultured mammalian cells, with metabolic activation. Negative results (sister chromatid exchanges) have been observed in cultured mammalian cells and bacteria, both with and without metabolic activation.(1)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) National Toxicology Program. Toxicology and carcinogenesis studies of phenolphthalein (CAS no. 77-09-8) in F344/N rats and B6C3F1 mice (feed studies). NTP Technical Report No. 465. US Department of Health and Human Services, Nov. 1996
(2) Grant, W. M. et al. Toxicology of the Eye. 4th ed. Charles C. Thomas, 1993. p. 1136
(3) Gosselin, R.E., et al. Clinical toxicology of commercial products. 5th ed. Williams and Wilkins, 1984. p. II-404
(4) Dietz, D.D., et al. Subchronic (13-week) toxicity studies of oral phenolphthalein in Fischer 344 rats and B6C3F1 Mice. Fundamental and Applied Toxicology. Vol. 18, no. 1 (Jan. 1992). p. 48-58
(5) HSDB record for phenolphthalein. Last revision date: 97/03/17
(6) Witt, K.L. Phenolphthalein: induction of micronucleated erythrocytes in mice. Mutation research. Vol. 341, no. 3 (1995). p. 151-160
(7) The Sigma-Aldrich library of chemical safety data. Ed. II. Vol. 2. Sigma-Aldrich Corporation, 1988. p. 2745D
(8) Dean, J.A. Lange's handbook of chemistry. 14th ed. McGraw-Hill, Inc., 1992. p. 1.279, 8.63
(9) Weast, R.C., ed. Handbook of chemistry and physics. 66th ed. CRC Press, 1985-1986. p. C-416, D-148
(10) Ross, E., et al. Indicator reagents. In: Ullmann's encyclopedia of industrial chemistry. 5th completely revised ed. Vol. A 14. VCH Verlagsgesellschaft, 1989. p. 127-131
(11) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002
(12) Report on Carcinogens. 11th ed. US Department of Health and Human Services, Public Health Service, National Toxicology Program
(13) International Agency for Research on Cancer (IARC). Phenolphthalein. In: IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 76. Some antiviral and antineoplastic drugs, and other pharmaceutical agents. World Health Organization, 2000.

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: 1998-05-27

Revision Indicators:
Carcinogenicity 2003-07-09
Toxicological info 2003-07-09
WHMIS detailed classification 2003-07-09
WHMIS proposed classification 2003-07-09
WHMIS health effects 2003-07-09
WHMIS disclosure list 2003-07-09
Emergency overview 2003-07-09
First aid inhalation 2003-07-09
First aid skin 2003-07-09
First aid eye 2003-07-09
Engineering controls 2003-07-09
Handling 2003-07-09
Bibliography 2005-02-02



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