Methapyrilene

261.387

261.39

202-099-8

A01LX40298

1851

DTXSID2023278

LIQUID

R - Respiratory system

47.6

2.74 (est).

Methapyrilene is a clear colorless liquid. (NTP, 1992)

1.1388 (rough estimate)

25°C

173-175 °C @ Press: 3 Torr

INDEX OF REFRACTION: 1.5915 @ 20 °C/D; MAX ABSORPTION (WATER): 238 NM (LOG E= 4.17), 304 NM (LOG E= 3.60)|INDEX OF REFRACTION: 1.5842 @ 25 °C/D, 1.5835 @ 25 °C/D

Water solubility: 879 mg/l (est).

7.0X10-4 mm Hg at 25 deg C (extrapolated from vapor pressure data at higher temperatures, SRC)

LD50 in mice, guinea pigs (mg/kg): 182.2 ±12.8, 374.9 ±34.5 orally; in mice (mg/kg): 19.85 ±0.69 i.v. (Lee)

8.85(at 20 °C)

8.85 (at 20 °C)

1 G DISSOLVES IN: ABOUT 0.5 ML WATER, 3 ML CHLOROFORM, 5 ML ALCOHOL; PRACTICALLY INSOL IN ETHER, BENZENE; MP: 162 °C; MAX ABSORPTION: 238 NM (E= 623, 1%, 1 CM), MIN: 272 NM. /METHAPYRILENE HYDROCHLORIDE/|WHITE CRYSTALLILNE POWDER; USUALLY FAINT ODOR. /METHAPYRILENE HYDROCHLORIDE/|ITS SOLN ARE SLIGHTLY ACID TO LITMUS, HAVING PH OF ABOUT 5.5. /METHAPYRILENE HYDROCHLORIDE/|Henry's Law Constant 2.74X10-7 atm-cu m/mole (calc)

No rapid reaction with air. No rapid reaction with water.

Amines, Phosphines, and Pyridines

An amine, organosulfide. Organosulfides are incompatible with acids, diazo and azo compounds, halocarbons, isocyanates, aldehydes, alkali metals, nitrides, hydrides, and other strong reducing agents. Reactions with these materials generate heat and in many cases hydrogen gas. Many of these compounds may liberate hydrogen sulfide upon decomposition or reaction with an acid. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

III

6.1(b)

UN 1851

UT1400000

Stable. Incompatible with strong oxidizing agents.

P264, P270, P301+P310, P321, P330, P405, P501

H301

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U155, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.|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. 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 liquid injection incineration at a temperature range of 650 to 1,600 °C and a residence time of 0.1 to 2 seconds.

Lijinsky W; Chronic Toxicity Tests of Pyrilamine Maleate and Methapyrilene Hydrochloride in F344 rats; Food and Chemical Toxicology 22 (1): 27-30 (1984).

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

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory.

Fires involving this compound should be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Excerpt from ERG Guide 151 [Substances - Toxic (Non-combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

Excerpt from ERG Guide 151 [Substances - Toxic (Non-combustible)]: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. (ERG, 2016)

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)

The major hazards encountered in the use and handling of methapyrilene stem from its toxicologic properties. Primarily toxic by ingestion, exposure to this liquid may occur from its production or veterinary use (parenteral or topical application) on domestic animals to treat histamine associated allergies or hypersensitivities. Effects from exposure may include tachycardia, CNS depression, hallucinations, toxic psychosis, cerebral edema, deep coma, cardio-respiratory collapse, or death.

U155; 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 5,000 lb or 2270 kg. The toll free telephone number of the NRC is (800) 424-8802; in the Washington metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.6 (see section IV. D.3.b).

U155; As stipulated in 40 CFR 261.33, when methapyrilene, 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).

A CASE OF FATAL POISONING WITH SOMINEX (METHAPYRILENE HYDROCHLORIDE, COMBINATION, SCOPOLAMINE AMINOXIDE HYDROBROMIDE & SALICYLAMIDE) CAPSULES IS REPORTED.

The hydrochloride and fumarate salts of methapyrilene have been used in the past as an antihistamine(1). The compound may no longer be used as a drug based upon a report that it was being withdrawn due to possible carcinogenicity(1).

TERRESTRIAL FATE: If methapyrilene is released to soil, it will be expected to exhibit low mobility in soil(1,SRC) based upon an estimated Koc of 737(2-3,SRC). Methapyrilene, therefore, may very slowly leach through soil to groundwater(3,SRC). It should not hydrolyze in moist soil(2). Based upon an estimated Henry's Law constant of 2.74X10-7 atm-cu m/mole (which was calculated from an estimated water solubility(2-3,SRC) and an extrapolated vapor pressure(4,SRC), volatilization of methapyrilene from moist near-surface soil should not be significant(2,SRC). It is not known whether methapyrilene biodegrades in soil(SRC).|AQUATIC FATE: If methapyrilene is released to water, it may be susceptible to direct photolysis in the atmosphere since the compound absorbs light at wavelengths >290 nm(1). It should not hydrolyze(2), bioconcentrate signficantly in aquatic organisms(2-3,SRC), or strongly adsorb to sediment or suspended sediments(2-3,SRC). Based upon an estimated Henry's Law constant of 2.74X10-7 atm-cu m/mole (which was calculated from an estimated water solubility(2-3,SRC) an an extrapolated vapor pressure(4,SRC), volatilization of methapyrilene from water should not be significant(2,SRC). It is not known whether methapyrilene biodegrades in natural water(SRC).|ATMOSPHERIC FATE: If methapyrilene is released to the atmosphere, it will be expected to exist in both vapor and particulate phases, based upon(2) a vapor pressure of 7.0X10-4 mm Hg at 25 °C which was extrapolated from vapor pressure data at higher temperatures(4,SRC). It may be susceptible to direct photolysis in the atmosphere since the compound absorbs light at wavelengths >290 nm(1). It should react rapidly with photochemically produced hydroxyl radicals based upon an estimated rate constant for this process of 185X10-12 cu cm/molecule-sec at 25 °C which corresponds to an atmospheric half-life of 2.1 hr at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2,SRC).

Methapyrilene may be susceptible to direct photolysis since the compound absorbs light at wavelength >290 nm(1). The rate constant for the vapor-phase reaction of methapyrilene with photochemically produced hydroxyl radicals has been estimated to be 185X10-12 cu cm/molecule-sec at 25 °C which corresponds to an atmospheric half-life of 2 hr at an atmospheric concentration of 5X10+5 hdyroxyl radicals per cu cm(2,SRC). Hydrolysis is not expected to be significant under normal environmental conditions (pH 5-9)(3).

An estimated BCF of 71 can be calculated(2,SRC) from an estimated log Kow of 2.74(1) using a recommended regression equation(2,SRC). Based upon this estimated BCF, methapyrilene will not be expected to significantly bioconcentrate in aquatic organisms (SRC).

741.31 L/kg|An estimated Koc of 737 can be calculated(2,SRC) from an estimated log Kow of 2.74(1) using a recommended regression equation(2,SRC). Based upon this estimated Koc, methapyrilene will be expected to exhibit low mobility in soil(3,SRC).

Based upon an estimated water solubility of 879 mg/l(1,3,SRC) and a vapor pressure of 7.0X10-4 mm Hg at 25 °C which was extrapolated from vapor pressure data at higher temperatures(2,SRC), the Henry's Law Constant for methapyrilene has been calculated to be 2.74X10-7 atm-cu m/mole(SRC). Volatilization of methapyrilene from water and moist soil should not be significant based upon the low value for the Henry's Law constant(3,SRC).

Exposure to methapyrilene in the past may have been mainly via oral ingestion of medications which contained the compound as an antihistamine(1,SRC). It may no longer be used as a drug based upon a report that it was being withdrawn due to possible carcinogenicity(1). Current exposure may be very limited since no information concerning possible current manufacture or uses were found(SRC).

Methapyrilene was found in the blood of 16 persons who died of non-drug related causes in Maryland between 1975 and 1980 at concn ranging from 0.1 to 7.2 mg/l and at an avg concn of 1.8 mg/l(1). It also was found in the blood of 2 persons who had apparently committed suicide by ingesting unknown amounts of methapyrilene; the range of concn found in these suicide victims was 0.5-9.8 mg/l and the average concn was 5.2 mg/l(1).

Anti-Allergic Agents; Histamine H1 Antagonists; Sedatives, Nonbarbiturate|CERTAIN ANTIHISTAMINES (EG, METHAPYRILENE ... ) ARE PROMOTED AS SEDATIVE-HYPNOTICS THROUGHOUT WORLD. AMONG NONPRESCRIPTION SEDATIVE-HYPNOTIC DRUGS IN USA, METHAPYRILENE IS MOST ... USED DRUG, & THEY ARE EMPLOYED IN COMBINATION IN ABOUT HALF PRODUCTS. ... DOSES OF SOME ... ARE TOO LOW TO BE EFFECTIVE.|FOR SYMPTOMATIC TREATMENT OF SEASONAL & PERENNIAL ALLERGIC RHINITIS, VASOMOTOR RHINITIS, ALLERGIC CONJUNCTIVITIS DUE TO INHALANT ALLERGENS & FOODS, MILD UNCOMPLICATED ALLERGIC SKIN MANIFESTATIONS OF URTICARIA & ANGIOEDEMA, & FOR AMELIORATION & PREVENTION OF ALLERGIC REACTIONS TO BLOOD OR PLASMA. /METHAPYRILENE HYDROCHLORIDE/|IT IS WIDELY EMPLOYED IN PROPRIETARY SLEEP MEDICATION BECAUSE OF ITS MILD SEDATIVE PROPERTIES. IT ALSO HAS SOME LOCAL ANESTHETIC PROPERTIES. /METHAPYRILENE HYDROCHLORIDE/|For more Therapeutic Uses (Complete) data for METHAPYRILENE (6 total), please visit the HSDB record page.

Methapyrilene has ... been shown to enhance liver tumor development when administered either before or after a genotoxic liver carcinogen.

A death has been reported from an oral dose as small as 12 mg/kg, but others have survived after 80 mg/kg.

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475) (See all compounds classified as Anti-Allergic Agents.)|Drugs that selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions of endogenous histamine. Included here are the classical antihistaminics that antagonize or prevent the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and some other smooth muscles, and are used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce somnolence. The effects of blocking central nervous system H1 receptors are not as well understood. (See all compounds classified as Histamine H1 Antagonists.)|Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety. (See all compounds classified as Hypnotics and Sedatives.)

DURATION OF ACTION: 4-6 HR. /METHAPYRILENE HYDROCHLORIDE, FROM TABLE/|25 MG METHAPYRILENE TO NORMAL SUBJECT PRODUCED PLASMA CONCN LESS THAN 10 NG/ML OVER 5 HR FOLLOWING INGESTION WITH PEAK CONCN OCCURRING 3 HR AFTER INGESTION. URINE CONCN @ MAX OF 172 NG/ML @ 24 HR; 24 HR URINARY EXCRETION WAS 0.2% OF ADMIN DOSE.

The metabolism of methapyrilene, was examined in vivo by glc and glc-mass spectrometric analysis of rat urinary extracts. Dosing the animals with tetradeuterium labeled methapyrilene helped identify 7 different metabolites of methapyrilene in the urine, including (5-hydroxylpyridyl)-methapyrilene, which was identified by comparison with a synthetic reference standard. After 4 weeks of treatment with methapyrilene, rats also excrete detectable amounts of the 3- and (6-hydroxylpyridyl)-methapyrilene metabolites suggesting that pretreatment with methapyrilene alters the metabolism of the pyridine ring. Metabolic removal of the 2-thienylmethylene moiety is also facile, as large amounts of N'-(2-pyridyl)-N,N-dimethylethylenediamine and its metabolite N'-(2(5-hydroxylpyridyl))-N,N-dimethylethylenediamine are excreted under all dosing regimens. Urinary concn of both methapyrilene and metabolites decline with time, despite continuous dosing, indicating a change in absorption, metabolism, and/or excretion of methapyrilene on repeated dosing.|Rats were fed 100 or 1000 ppm methapyrilene in their diet for 1, 2, 4, 8 or 16 weeks. Liver microsomes were prepared from both control and treated rats. After incubation with 1 mM methapyrilene, eight metabolites were detected and six were quantitated. Five of the metabolites have been previously identified as 2-hydroxymethyl-thiophene, thiophene-2-carboxylic acid, N-(2-thienylmethyl)-2-aminopyridine, N-2-pyridyl-N'N'-dimethylethylenediamine, and 2-aminopyridine. Three other metabolites have been tentatively identified based on their mass spectral fragmentation patterns as normethapyrilene, (5-hydroxypyridyl)methapyrilene, and methapyrileneamide. The same metabolites were found in both control and treated animals, the most abundant being normethapyrilene and N-2-pyridyl-N'N'-dimethylenethylenediamine. Pretreatment with methapyrilene resulted in inhibition of both consumption of methapyrilene and formation of some metabolites. However increases in the formation of all of the metabolites also occurred under different treatment conditions. In both control and treated tissue, the preliminary mass balance was less than 55%, except in incubations with tissue from rats treated with 1000 ppm for 8 or 16 weeks where it was 92 and 89%, respectively. Dramatic increases in the fraction of N-(2-thienylmethyl)-2-aminopyridine, methapyrileneamide, normethapyrilene and (5-hydroxypyridyl)methapyrilene relative to methapyrilene consumed account for the increase in the mass balance after 8 weeks pretreatment with 1000 ppm methapyrilene, and increases in the amounts of N-2-pyridyl-N'N'-dimethylenediamine, (5-hydroxypyridyl)methapyrilene and thiophene-2-carboxylic acid account for the higher mass balance after 16 weeks.

VERY LITTLE IS KNOWN ABOUT MODE OF CNS ACTION OF THESE NONPRESCRIPTION DRUGS. IT HAS BEEN SUGGESTED THAT CENTRAL ANTIMUSCARINIC ACTION IS COMMON TO ALL. /NONPRESCRIPTION SEDATIVE-HYPNOTIC DRUGS/

ACUTE/CHRONIC HAZARDS: This material is highly toxic by ingestion. (NTP, 1992)

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)

SIMILAR TO OTHER ANTIHISTAMINICS IN ACUTE TOXICITY. OVERDOSES PRODUCE EXCITEMENT, CONVULSIONS, HYPERPYREXIA, CEREBRAL EDEMA, DEPRESSION, & OCCASIONALLY RENAL TUBULAR NECROSIS. DEATH HAS BEEN REPORTED FROM ORAL DOSE AS SMALL AS 12 MG/KG, BUT OTHERS HAVE SURVIVED AFTER 80 MG/KG. /METHAPYRILENE HYDROCHLORIDE/|OVER THE COUNTER HYPNOTIC PREPN CONTAINING METHAPYRILENE IMPLICATED IN 21 CASES OF PSYCHOTROPIC DRUG OVERDOSE. 10 PATIENTS SHOWED CENTRAL ANTICHOLINERGIC TOXICITY: HALLUCINATIONS, DELIRIUM & CONFUSION. CONCLUDED THAT THE PREPN PRODUCES TOXIC PSYCHOSIS WHICH IS TEMPORARY & BENIGN.|METHAPYRILENE TOXIC PSYCHOSIS MIMICKING ECLAMPSIA.|FATALITY DUE TO METHAPYRILENE IN 38-YR-OLD WOMAN IS DESCRIBED.|7 CASES OF METHAPYRILENE OVERDOSE, 5 OF WHICH PROVED FATAL, ARE PRESENTED & EXTRACTION & ASSAY FROM BIOL FLUIDS ARE REPORTED. IN 5 CASES, MULTIPLE DRUG INGESTION INCL ETHANOL WAS DIAGNOSED.

Lullamin

SYRUP NF: 30 MG/5 ML /METHAPYRILENE FUMARATE/|CAPSULES, 25 & 50 MG; INJECTION; SYRUP /METHAPYRILENE HYDROCHLORIDE; FROM TABLE/

Spectrophotometric method is used for determination of Methapyrilene in expectorants.|Ion exchange chromatography is used for determination of methapyrilene in selected drug combinations.|Spectrophotometry method can be used for determination of methapyrilene at a wavelength of 235 nm.|Liquid chromatography is used for the determination of methapyrilene.|EPA Method A121. Gas Chromatography/Mass Spectrometry method can be applied for the determination of methapyrilene extracted from organic liquids. This method has a detection method of 5-20 ng.

GLC ANALYSIS OF METHAPYRILENE IN HUMAN PLASMA & URINE USING A SULFUR-SPECIFIC FLAME PHOTOMETRIC DETECTOR.

Pharmaceuticals