Mci-186

Cosmetic ingredients (Phenyl Methyl Pyrazolone) -> CIR (Cosmetic Ingredient Review)

Hair dyeing

MONOCLINIC PRISMS FROM WATER

WHITE POWDER OR CRYSTALS

less than 1 mg/mL at 73 °F (NTP, 1992)

SOL IN HOT WATER & HOT ALCOHOL; SLIGHTLY SOL IN BENZENE; INSOL IN PETROLEUM ETHER

25.4 [ug/mL] (The mean of the results at pH 7.4)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

549 °F at 105 mmHg (NTP, 1992)

191 °C @ 17 MM HG; 287 °C @ 105 MM HG

261 to 266 °F (NTP, 1992)

127 °C

128.9 °C

less than 0.01 mmHg at 68 °F (NTP, 1992)

LESS THAN 0.01 MM @ 20 °C

1-phenyl-3-methyl-5-pyrazolone appears as white to off-white powder or crystals. (NTP, 1992)

White solid; [Merck Index] Light yellow odorless powder; [Alfa Aesar MSDS]

This chemical does not meet GHS hazard criteria for 7.7% (16 of 209) of reports.

Warning

H302 (26.8%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P272, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P333+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 209 reports by companies from 25 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

Chemical: 3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-

Status: Active Update: 15-10-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/22541

3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-: Does not have an individual approval but may be used under an appropriate group standard

Emergency treatment: Irritants; [HSDB] A skin, eye, and mucous membrane irritant; [CAMEO] Causes no to mild skin and eye irritation in rabbits; Not sensitizing to guinea pig skin; [IUCLID] No teratogenicity observed in experimental animals, but reduced birth weight and fetal loss seen at high doses; [REPROTOX] No evidence for carcinogenicity in mice or rats; [NTP] A mild eye irritant; Causes changes in liver and spleen in intravenous studies of dogs; [RTECS]

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.

Acute Tox. 4 (26.8%)

Skin sensitisation - category 1

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.

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.

5.7 [mg/m3]

63 [mg/m3]

380 [mg/m3]

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Serum aminotransferase elevations occur in a small proportion of patients on edaravone therapy, but the frequency, timing of onset, duration and severity of these elevations has not been defined. The rates of abnormal liver tests during edaravone therapy were said to be similar to those during placebo treatment. Most elevations resolved spontaneously, and there were no reports of drug discontinuation for serum enzyme elevations. Clinically apparent liver injury due to edaravone was not reported in the prelicensure trials and has not been reported with subsequent clinical use of edaravone, but the numbers of patients treated have been few. Thus, clinically apparent liver injury from edaravone must be rare if it occurs at all.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=89-25-8]

1-Phenyl-3-methyl-5-pyrazolone

TR-141: Bioassay of 1-Phenyl-3-methyl-5-pyrazolone for Possible Carcinogenicity (CASRN 89-25-8) (1978 )

06/29/78

No Evidence

No Evidence

No Evidence

Drug Induced Liver Injury Rank (DILIrank 2.0)

Edaravone

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

A bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3Fl mice. l-Phenyl-3-methyl-5-pyrazolone was admin in the feed, at either of two concn, to groups of 49 or 50 male and 50 female animals of each species. The high and low concn of 1-phenyl-3-methyl-5-pyrazolone utilized were, respectively, 5,000 and 2,500 ppm for rats and 15,000 and 7,500 ppm for mice. Twenty animals of each species and sex were placed on test as controls. After a 103 wk period of chemical admin, there was an additional observation period of 2 wk for rats. A 102 wk period of chemical admin was followed by an additional 2 wk observation period for mice. In both species adequate numbers of animals survived sufficiently long to be at risk from late developing tumors. ... Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 1-phenyl-3-methyl-5-pyrazolone to Fischer 344 rats or B6C3Fl mice. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative.

N - Nervous system

QN - Nervous system

Oxidative stress and reactive oxygen species (ROS) production have been implicated in various neurological disorders, such as amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Oxidative stress caused by excess ROS damages endothelial cells in the cerebral vasculature as well as neuronal cell membranes, leading to neuronal cell death. Edaravone is a free radical scavenger that scavenges and suppresses the generation of hydroxyl radicals and peroxynitrite radicals. The exact mechanism of action of edaravone in ALS has not been fully elucidated; however, edaravone is thought to mediate therapeutic effects via its antioxidant properties. Since oxidative stress has been implicated in the pathophysiology of ALS and cerebral ischemia, inhibiting lipid peroxidation, suppressing endothelial cell damage induced by lipid peroxides, and scavenging free radicals may lead to neuroprotective effects. Edaravone has no effect on superoxide production. It is suggested that edaravone may also possess anti-inflammatory properties, as it inhibited neutrophil activation and suppressed inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) expression in animal models. It was also shown to ameliorate ROS-induced inflammatory oxidative stress after ischemic brain reperfusion.

The metabolites of edaravone have not been fully characterized. Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases. Oral edaravone results in 1.3- and 1.7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to intravenously-administered edaravone because of first-pass metabolism.

Substances that eliminate free radicals. Among other effects, they protect PANCREATIC ISLETS against damage by CYTOKINES and prevent myocardial and pulmonary REPERFUSION INJURY.

Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.

One study investigated the absorption of edaravone in healthy adults, who either received a single oral (105 mg/mL) or intravenous (60 mg/60 min) dose. The mean Cmax (CV%) and Tmax were 1656 (44.3) ng/mL and 0.5 hours, respectively, following oral administration. The absolute oral bioavailability is about 57% because of first-pass metabolism. The mean Cmax (CV%) and Tmax were 1253 (18.3) ng/mL and one hour, respectively, following intravenous administration. When intravenously administered, the maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. The Cmax and area under the concentration-time curve (AUC) of edaravone increases more than dose-proportional over the dose range of 30 to 300 mg. Edaravone does not accumulate in plasma with once-daily or multiple-dose administration. The Cmax and AUC decreased when the oral suspension formulation of edaravone was administered with a high-fat meal.

In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate (60-80% of the dose up to 48 hours). Approximately 6-8% of the dose was recovered in the urine as the sulfate conjugate, and <1% of the dose was recovered in the urine as the unchanged drug. _In vitro_ studies suggest that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the kidney before excretion into the urine.

After intravenous administration, edaravone has a mean volume of distribution of 63.1 L, suggesting substantial tissue distribution. Edaravone has an apparent volume of distribution of 164 L following oral administration. Edaravone readily crosses the blood-brain barrier.

Following intravenous administration, the total clearance of edaravone is estimated to be 35.9 L/h. The apparent total clearance of edaravone is estimated to be 67.9L/h following oral administration.

CIR ingredient: Phenyl Methyl Pyrazolone

Used as an intermediate for dyes and drugs, reagent to detect cyanide, and developer for diazotized direct dyes; [HSDB] Used in the treatment of strokes; [Merck Index] Used for synthesis in the chemical industry and in the textile processing industry; [IUCLID] Used in hair dyes; [ExPub: EC]

Textiles (Printing, Dyeing, or Finishing) [Category: Industry]

INTERMEDIATE FOR DYES & DRUGS; SENSITIVE REAGENT FOR DETECTION OF CYANIDE

CHEM INT FOR DYES (EG, FOR PYRAZOLONE PIGMENTS), DRUGS (EG, ANTIPYRINE & AMINOPYRINE), DEVELOPER FOR DIAZOTISED DIRECT DYES, REAGENT FOR DETECTION OF CYANIDE

(1977) No Data

(1979) No Data

(1977) 6.01X10+7 GRAMS (PRINCPL CUSTMS DISTS)

(1979) 1.55X10+8 GRAMS (PRINCPL CUSTMS DISTS)

(1976) 5.90X10+6 GRAMS (SALES)

(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS

CONDENSATION OF PHENYLHYDRAZINE WITH ETHYL ACETOACETATE

BY CONDENSATION OF PHENYLHYDRAZINE WITH ETHYLACETOACETATE.