Phenacetin

179.21600

179.22

200-533-0

ER0CTH01H9

2100

757401|7651

3077

DTXSID1021116

C44432

Monoclinic prisms|Crystalline scales or powder|Solid|WHITE, GLISTENING CRYSTALS, USUALLY SCALES, OR AS FINE WHITE, CRYSTALLINE POWDER

N - Nervous system

2924291000

38.33000

2.11670

Phenacetin is an odorless fine white crystalline solid with a lightly bitter taste. Used as an analgesic medicine.

1.21 g/cm³

134-135 °C

132 °C / 4mmHg

149.5±28.4 °C

1.505 (20ºC)

H2O: 0.076 g/100 mL

2-8ºC

6.29X10-7 mm Hg at 25 deg C

LD50 orally in rats: 1.65 g/kg (Boyd)

ODORLESS

Slightly bitter

SATURATED SOLN IS NEUTRAL TO LITMUS

Henry's Law constant = 2.13X10-10 atm-cu m/ mol at 25 °C (est)

139.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|140.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 1.75X10-11 cu cm/molec-sec at 25 °C (est)

Insoluble in water.

Amides and Imides

PHENACETIN react with oxidizing agents, iodine and nitrating agents. (NTP, 1992)

NONH for all modes of transport

3

R22; R45

S45-S53

AM4375000

T

Stable. Incompatible with strong oxidizing agents, strong acids.

P201-P308 + P313

H302-H350

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U187, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.|A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 °C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 °C and residence times of seconds for liquids and gases, and longer for solids.|PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for PHENACETIN (7 total), please visit the HSDB record page.

Oxidizing agents, iodine and nitrating agents.

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: phenacetin is included in digestive aid drug products; weight control drug products; internal analgesic drug products; and orally administered menstrual drug products..

Bach PH, Bridges JW; Chemically Induced Renal Papillary Necrosis and Upper Urothelial Carcinoma. Part 2.; CRC Crit Rev Toxicol 15 (4): 331-441 (1985).|Clissold SP; Paracematol and Phenacetin Drugs 32 (4): 46-59 (1986)|WHO; Environmental Health Criteria 119: Principles and Methods for the Assessment of Nephrotoxicity Associated with Exposure to Chemicals (1991)|National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Phenacetin (62-44-2) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s143phen.pdf]

Flash point data for this compound are not available but it is probably combustible. (NTP, 1992)

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 158 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P281, P301+P312, P307+P311, P308+P313, P314, P321, P330, P405, and P501|P201, P202, P260, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this chemical under refrigerated temperatures, and keep it away from oxidizing materials. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)|PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Poisonous gases including nitrogen oxides are produced in fire. Use any extinguishing agent suitable for surrounding fire. If material of contaminated runoff enters waterways, notify downstream users of potentially contaminated waters. Notify local health and fire officials and pollution control agencies. If employees are expected to fight fires, they must be trained and equipped in OSHA 1910.156.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for PHENACETIN (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

The major hazards encountered in the use and handling of phenacetin stem from its toxicologic properties. Exposure to this odorless, white crystalline substance can occur from its manufacture, handling, and use as an analgesic medication, and stabilizer for hydrogen peroxide in hair bleaching preparations. Effects from exposure may include light-headedness, skin rash, methemoglobinemia, hemolytic anemia, renal papillary necrosis, convulsions, and coma. Also, the International Agency for Research on Cancer (IARC) has designated phenacetin as a Group 2A carcinogen, meaning, "The agent is probably carcinogenic to humans." Mechanical ventilation which employs a high efficiency particulate arrestor (HEPA) should be used to minimize airborne levels of phenacetin. In activities and situations where over-exposure may occur, wear a protective suit and a carefully fitted respirator. Smoking, drinking, and eating should be prohibited in phenacetin work areas, and cleanliness following the handling of phenacetin should be emphasized. Phenacetin should be stored in a securely sealed, watertight container, which should be enclosed in a second, unbreakable, leakproof container. Phenacetin is a potential candidate for rotary kiln and fluidized bed forms of incineration.

U187; A toxic waste when a discarded commercial chemical product, or manufacturing chemical intermediate, or an off-specification commercial chemical product, or manufacturing chemical intermediate.

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).

U187; As stipulated in 40 CFR 261.33, when phenacetin, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Phenacetin was identified in leachate from a sanitary landfill in Barcelona, Spain(1). The compound has also been identified, not quantified (detection limit of 1.0 ug/L) in tire leachates following an experiment whereby tire plugs 10.25 cm in diameter where soaked in 16 L of Lake Mead, Nevada water for a period of 31 days(2).

Acute oral toxicity (LD50): 866 mg/kg [Mouse].

Sodium 3-hydroxy-4-iodo-2-naphthoate and sodium 1-hydroxy-4-bromo-naphthoate inhibited phenacetin absorption in the rat intestine. The blood, brain and kidney levels of phenacetin decreased and the liver level increased in rats following simultaneous oral administration of phenacetin and either one. The blood levels of phenacetin in rabbits were decreased by both but were increased by sodium 1-hydroxy-2-naphthoate, sodium tetrahydro-1-hydroxy-2-naphthoate, and sodium tetrahydro-3-hydroxy-2-naphthoate. All derivatives tested decreased the in vitro metabolism of phenacetin by rat or rabbit liver slices.|The transformation of acetophenetidin to n-acetyl-p-aminophenol was increased in the liver from rats treated with caffeine or antipyrine. The lung and intestine were also capable of metabolizing acetophenetidin to form this metabolite, and this pathway was increased by exposure to cigarette smoke. Following a test dose of acetophenetidin to human subjects, the plasma levels of acetophenetidin were lower in people who smoke cigarettes than in nonsmokers. Thus, in addition to the liver, the lung and intestine may have important roles in the metabolism of acetophenetidin.|The principal route of metabolism and the total absorption of phenacetin in humans were not affected by combined ingestion of 324.0 mg phenacetin with aspirin (453.6 mg), caffeine citrate (64.8 mg) and codeine phosphate (16.2 mg) in pills taken 3 times at 2-hour intervals. The proportion of the phenacetin dose metabolized to 2-hydroxyphenetidine was increased from 1.9 to 3.4% when the drug was ingested with aspirin, caffeine, and codeine.|/Phenacetin/ potentiates the effect of caffeine on the central nervous system.|For more Interactions (Complete) data for PHENACETIN (6 total), please visit the HSDB record page.

LD50 Wistar rat (male) oral about 4 g/kg|LD50 Guinea pig oral 2.6 g/kg|LD50 Rat oral 1.65 g/kg

Anemia is usually severe & may be accompanied by intravascular hemolysis, hemoglobinuria, & acute anuria. These reactions may occur in patient with glucose-6-phosphate dehydrogenase deficiency in erythrocytes or as immunological reaction ... .

Phenacetin is not known to occur in nature(1).

Phenacetin's former production and use in the US as an analgesic(1) may have resulted in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 170(SRC), determined from a log Kow of 1.58(2) and a regression-derived equation(3), indicates that phenacetin is expected to have moderate mobility in soil(SRC). Volatilization of phenacetin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.1X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.92X10-7 mm Hg(3), and water solubility, 766 mg/L(4). Phenacetin is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). A theoretical BOD of 8.4% in activated sludge and using the Japanese MITI test(5), suggests that biodegradation is not a fast environmental fate process in soil(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 170(SRC), determined from a log Kow of 1.58(2) and a regression-derived equation(3), indicates that phenacetin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.1X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.92X10-7 mm(Hg(5), and water solubility, 766 mg/L(6). According to a classification scheme (7), a BCF of <30(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A theoretical BOD of 8.4% in activated sludge and using the Japanese MITI test(8), suggests that biodegradation is not a fast environmental fate process in water(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phenacetin, which has a vapor pressure of 6.92X10-7 mm Hg at 25 deg(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase phenacetin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hrs(SRC), calculated from its rate constant of 1.75X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase phenacetin may be removed from the air by wet or dry deposition(SRC). Phenacetin does not absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of phenacetin with photochemically-produced hydroxyl radicals has been estimated as 1.75X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Phenacetin is expected to be inert to reaction with naturally occurring oxidants found in water (alkylperoxy radicals and singlet oxygen)(2). Phenacetin absorbs at wavelengths >250 nm (ethanol) and 285 nm(chloroform and isooctane); therefore, it is not expected to be susceptible to direct photolysis by sunlight(3).

30.20|A BCF of <30 was calculated in fish for phenacetin, using orange-red killifish (Oryzias latipes) which were exposed to a test concentration of 0.03 ppm over an 8-week period(1). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of phenacetin is estimated as 170(SRC), using a log Kow of 1.58(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that phenacetin is expected to have moderate mobility in soil.

The Henry's Law constant for phenacetin is estimated as 2.1X10-10 atm-cu m/mole(SRC) derived from its vapor pressure, 6.92X10-7 mm Hg(1), and water solubility, 766 mg/L(2). This Henry's Law constant indicates that phenacetin is expected to be essentially nonvolatile from water surfaces(3). The potential for volatilization of phenacetin from dry soil surfaces may exist(SRC) based upon its vapor pressure(1).

EXPERIMENTAL: Phenacetin was found in breast milk of nursing mothers 0.5 to 24 hours after ingestion of an analgesic containing this compound(1).|Phenacetin is excreted into breast milk, appearing along with its major metabolite, acetaminophen.|Phenacetin enters /breast/ milk in small quantities. /From table/

NIOSH (NOES Survey 1981-1983) has statistically estimated that 18,808 workers (15,338 of these are female) were potentially exposed to phenacetin in the US(1). An additional estimated 869 workers (617 are female) were exposed to phenacetin powder(1). Occupational exposure to phenacetin may have occurred through inhalation of dust and dermal contact with this compound at workplaces where phenacetin was produced or used(SRC), particularly in the benzidene dye industry(2). Monitoring data indicate that the general population may have been exposed to phenacetin via dermal contact with this compound and other products containing phenacetin(SRC). Exposure to phenacetin among the general US population may have been limited to those administered the drug(SRC).

Phenacetin was found in breast milk of nursing mothers 0.5 to 24 hours after ingestion of an analgesic containing this compound(1).

Used principally as an analgesic.

Analgesics, Non-Narcotic; Enzyme Inhibitors|MEDICATION (VET): Analgesic & antipyretic (eg, for treatment of muscle pain); analgesic & antipyretic in veterinary medicine.|Medication: It is mainly used for mild to moderate pain associated with the musculo-skeletal system.|The so-called coal tar analgesics, phenacetin and its active metabolite acetaminophen, are effective alternatives to aspirin as analgesic-antipyretics; however, unlike aspirin, their anti-inflammatory activity is weak and seldom clinically useful.|Acetaminophen and phenacetin have analgesic and antipyretic effects that do not differ significantly from those of aspirin. However ... They have only weak anti-inflammatory effects. The pharmacological effects of phenacetin are a combination of its inherent activity and those of acetaminophen, its major metabolite.

Individuals with genetically determined limitation in ability to metabolize phenacetin to acetaminophen convert greater fraction of phenacetin to toxic metabolites, possibly with propensity for serious methemoglobin formation & hemolysis.|Since single 2-g dose of phenacetin in adults converts only 1-3% of total hemoglobin to methemoglobin, methemoglobinemia produced by therapeutic doses... Is not usually of clinical significance. However, in acute overdosage or during chronic abuse, methemoglobinemia may contribute to total toxicity.|Repeated administration is contraindicated in patient with anemia or cardiac, pulmonary, renal, or hepatic disease.|Phenacetin has been said to cause relaxation, drowsiness, euphoria, stimulation, & incr efficiency; such effects have been thought to contribute to its abuse liability.|For more Drug Warnings (Complete) data for PHENACETIN (10 total), please visit the HSDB record page.

Phenacetin was the first NSAID and fever reducer to go on the market. It acts as an analgesic at the spinal cord as well as a negative inotrope at the heart. It can be used to treat subacute rheumatoid arthritis, intercostal neuralgia, and ataxias.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS. (See all compounds classified as Analgesics, Non-Narcotic.)

Oral absorption of phenacetin is markedly influenced by particle size in the preparation, & plasma concentration of phenacetin & acetaminophen are correspondingly variable.|Peak concentration of phenacetin in plasma usually occurs in about 1 hr, & that of acetaminophen derived there from in 1-2 hr.|Absorption following oral administration is rapid ... duration of effect is about 4 hr.|Up to 45% of (14)C was recovered in 16 hr urine & 1% in feces of rats given [acetyl-(14)C]phenacetin per oral.|For more Absorption, Distribution and Excretion (Complete) data for PHENACETIN (9 total), please visit the HSDB record page.

Metabolised in the body to paracetamol.|Acetaminophen & phenacetin are metabolized primarily by hepatic microsomal enzymes. ... In normal individual, 75 to 80% of administered phenacetin is rapidly metabolized to acetaminophen.|... Phenacetin is converted to at least a dozen other metabolites, by n-deacetylation to para-phenetidin & by hydroxylation & further metabolism of phenacetin & para-phenetidin. An unknown metabolite, but an oxidizing agent, is responsible for methemoglobin formation & hemolysis of red blood cells ... .|Phenacetin is metabolized ... to p-acetamidophenol, which is excreted as glucuronide and sulfate conjugate ... .|... N-hydroxyphenacetin has been identified as metabolite in ... man.|For more Metabolism/Metabolites (Complete) data for PHENACETIN (15 total), please visit the HSDB record page.|Phenacetin has known human metabolites that include N-Hydroxyphenacetin and acetaminophen.

0.28 Days|The elimination half-life (t1/2)beta varied from 37 to 74 minutes.

The present study was aimed to test the possible cyclooxygenase (COX)-1/COX-2 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine, which exhibits high renal toxicity. Paracetamol (acetaminophen), the main metabolite of phenacetin with low renal toxicity, and indomethacin were selected as reference compounds. Collagen-stimulated platelet thromboxane B2 (TxB2) production and phorbol 12-myristate-13-acetate (PMA)-induced neutrophil prostaglandin E2 (PGE2) synthesis were used as indicators for COX-1 and COX-2 activity, respectively. Phenacetin was even less potent than paracetamol to reduce the production of both TxB2 and PGE2, and no clear preference for either of the COX-enzymes was seen. P-phenetidine was a more potent inhibitor, already at nanomolar level, of the synthesis of these prostanoids than indomethacin and showed some preference to COX-2 inhibition. Somewhat higher, micromolar, concentrations of p-phenetidine also reduced COX-2 expression in neutrophils. We suggest that the very potent inhibitory activity of p-phenetidine on PGE2 synthesis combined with the reduction of COX-2 expression could explain the renal papillary necrosis in phenacetin kidney.|Analgesic nephropathy is a unique drug-induced kidney disease characterized pathologically by renal papillary necrosis and chronic interstitial nephritis, and is the result of excessive consumption of combination antipyretic analgesics. The clinical features of the disorder relate mainly to the papillary necrosis, renal colic, and obstructive uropathy and the development of chronic renal failure in a small percentage of patients. There are significant geographic variations in the clinical features that may be related to the differing combinations of analgesics. The pathogenesis of the disease is in part related to the kidneys' ability to concentrate drugs in the papillae. The following sequence of events presents a plausible explanation for the evolution of the disease. If a combination of phenacetin and aspirin is ingested, the following steps occur. Phenacetin is converted in the gut and liver to acetaminophen by first-pass metabolism. Acetaminophen is then taken up by the kidney and excreted. During its excretion, acetaminophen becomes concentrated in the papillae of the kidney during physiologic degrees of antidiuresis, the concentration being up to five times the intracellular concentration of other tissues. Acetaminophen undergoes oxidative metabolism by prostaglandin H synthase to a reactive quinoneimine that is conjugated to glutathione. If acetaminophen is present alone, there is sufficient glutathione generated in the papillae to detoxify the reactive intermediate. If the acetaminophen is ingested with aspirin, the aspirin is converted to salicylate and salicylate becomes highly concentrated in both the cortex and papillae of the kidney. Salicylate is a potent depletor of glutathione. The mechanism is not completely understood; however, the inhibition of the production of NADPH via the pentose shunt is a possible explanation. With the cellular glutathione depleted, the reactive metabolite of acetaminophen then produces lipid peroxides and arylation of tissue proteins, ultimately resulting in necrosis of the papillae.|The mechanism of analgesic action has not been fully determined. Acetaminophen may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and, to a lesser extent, through peripheral action by blocking pain impulse generation. The peripheral action may also be due to inhibition of of the synthesis or actions of other substances that sensitive pain receptors to mechanical or chemical stimulation. /Acetaminophen/|Acetaminophen probably produces antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating, and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. /Acetaminophen/

Phenacetin is available in the US as a USP grade containing 98-101% active ingredient on a dried basis and a maximum of 0.03% para-chloracetanilide. In the European Pharmacopoeia ... specifications, sulphated ash is limited to 0.1%.

SYMPTOMS: Symptoms following exposure to this compound may include weakness, dizziness, depression, collapse, cyanosis, sweating, gastric irritation, chills, fall in blood pressure, jaundice, coma, convulsions, weight loss, insomnia, shortness of breath, aplastic anemia, and damage to the liver, kidneys, heart and central nervous system. ACUTE/CHRONIC HAZARDS: This compound is moderately toxic by ingestion. When heated to decomposition it emits toxic fumes. (NTP, 1992)|Carcinogens

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aniline and related compounds/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aniline and related compounds/

/HUMAN EXPOSURE STUDIES/ Group of 623 women known regularly to ingest phenacetin-containing analgesics were compared over 4-yr period with group of 621 controls. High intake of phenacetin analgesics was assoc with increased serum creatinine levels & low urine specific gravity ... . /Phenacetin analgesics/|/HUMAN EXPOSURE STUDIES/ Chronic ingestion of large doses of analgesics (e.g., 1 kg or more of phenacetin [no longer commercially available in the US] and/or salicylate over any period of time) has been associated with analgesic nephropathy which is characterized by papillary necrosis and subsequent chronic interstitial nephritis, with or without pyelonephritis. Analgesic nephropathy frequently has been associated with ingestion of large amounts of combinations of aspirin, phenacetin, and caffeine (combinations containing phenacetin no longer are commercially available in the US). Because phenacetin previously was a component of many analgesic drug mixtures, this drug has been implicated as the causative agent of renal damage. Many clinicians, however, believe that nephropathy may be caused by a combination of several analgesics rather than a single drug. Cancer of the renal pelvis has been reported in patients with analgesic nephropathy and in patients following chronic ingestion of phenacetin-containing analgesic mixtures. Splenomegaly has also been associated with abuse of phenacetin-containing mixtures.|/SIGNS AND SYMPTOMS/ Renal tubular necrosis ... may ... occur. Phenacetin may cause methemoglobinemia & hemolytic anemia as form of acute toxicity, but more commonly as a consequence of chronic overdosage. Lethal doses of phenacetin are ... associated ... with cyanosis, respiratory depression, and cardiac arrest.|/SIGNS AND SYMPTOMS/ The /hemolytic/ anemia /assoc with chronic ingestion/ is usually mild, with slight reticulocytosis, but may be progressive & severe in presence of uremia or other exacerbating factors. Splenomegaly has been reported. Methemoglobinemia, sulfhemoglobin formation, & heinz bodies are not consistently present ... .|For more Human Toxicity Excerpts (Complete) data for PHENACETIN (25 total), please visit the HSDB record page.

Acetophenetidin

Butalbital|Fiorinal, Butalbital with aspirin|2100|Schedule III - Substances in the DEA Schedule III have a potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence.|No

Grades: Technical; USP, as phenacetin.|Apcabuff contains 2.5 g phenacetin per tablet.|Pharmex Flu capsules contain 2.5 g phenacetin per tablet.|Phencaset contains 150 mg phenacetin per tablet.|For more Formulations/Preparations (Complete) data for PHENACETIN (6 total), please visit the HSDB record page.

Acetamide, N-(4-ethoxyphenyl)-: ACTIVE|S - indicates a substance that is identified in a final Significant New Use Rule.|Gives pasty mass with phenol, chloral hydrate or pyrocatechol, strong acids or alkalies, salicylic acid, oxidizers, iodine, spirit nitrous ether.|... Use of phenacetin by itself has been restricted to prescription in some countries.|Phenacetin has been employed only in analgesic mixtures. In recent years, it has been removed from almost all such mixtures. In some instances acetaminophen has been included to replace it.|A non-prostaglandin synthase inhibitor. It was utilized extensively in a wide variety of analgesic mixtures, but its causal role in analgesic-abuse nephropathy led to its withdrawal from the market. (From Smith and Reynard, Textbook of Pharmacology,1991, p431)|For more General Manufacturing Information (Complete) data for PHENACETIN (6 total), please visit the HSDB record page.

Chromatographic method is used for determination of phenacetin in mixtures of analgesic drugs.|... HIGH PRESSURE LIQUID CHROMATOGRAPHIC METHOD FOR THE SEPARATION AND QUANTIFICATION OF MUSCLE RELAXANT-ANALGESIC MIXTURES. A CARISOPRODOL, PHENACETIN & CAFFEINE MIXTURE WAS SELECTED TO DEMONSTRATE THE UTILITY OF /METHOD/.|PHOTOMETRIC DETERMINATION OF PHENACETIN IN DRUG FORMULATIONS.|EPA Method 8250. Packed Column Gas Chromatography/Mass Spectrometry Technique for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soil, and groundwater. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride and capable of being eluted without derivatization as sharp peaks from a gas chromatographic packed column. For phenacetin the method detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix.|For more Analytic Laboratory Methods (Complete) data for PHENACETIN (6 total), please visit the HSDB record page.

... UV SPECTROPHOTOMETRIC METHOD ... IN BIOLOGICAL MATERIALS ... GAS CHROMATOGRAPHIC METHOD ... IN URINE & PLASMA ... .|... HPLC METHOD IS SENSITIVE ENOUGH TO DETECT 0.05 MG/L OF PHENACETIN & 0.25 MG/L OF ACETAMINOPHEN /IN RAT BLOOD/.|A PROCEDURE FOR QUANTITATION OF PHENACETIN IN PLASMA BY RADIOIMMUNOASSAY.|GAS CHROMATOGRAPHIC METHOD HAS BEEN USED FOR DETERMINATION OF PHENACETIN AND ITS METABOLITES IN BLOOD PLASMA OF ANIMALS.|For more Clinical Laboratory Methods (Complete) data for PHENACETIN (10 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Health Hazards -> Carcinogens|Pharmaceuticals -> Animal Drugs -> Approved in Taiwan|Cosmetics -> Stabilizing