Skatole

Nitrogen Compounds -> Indoles

Waste-water effluent contaminant

LogP= 2.60

2.60

CHARACTERISTIC FECAL ODOR AT HIGH LEVELS, BECOMING PLEASANT, SWEET, AND WARM AT VERY LOW LEVELS

Fecal odor

LEAVES FROM PETROLEUM ETHER; WHITE-BROWN SCALES

White crystalline substance, browning upon aging.

SOL IN HOT WATER, ALC, BENZENE, CHLOROFORM, ETHER

SOL IN ACETONE, WATER, ETHANOL, ETHER

0.498 mg/mL

Soluble in boiling water

Soluble (in ethanol)

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

265-266 °C @ 755 MM HG

265.00 to 266.00 °C. @ 755.00 mm Hg

95 °C

97.5 °C

This chemical does not meet GHS hazard criteria for 76% (304 of 400) of all reports.

Warning

H315 (19.5%): Causes skin irritation [Warning Skin corrosion/irritation]

P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 400 reports by companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Chemical: 1H-Indole, 3-methyl-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

Status: Cease Manufacture Update: 21-11-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/23505

1H-Indole, 3-methyl-: Does not have an individual approval but may be used under an appropriate group standard

Caused no irritation in humans following 24 hour closed patch test (2% in petrolatum); [HSDB] Lethal doses by intravenous and oral routes produced pulmonary lesions in cattle; [RTECS] Safe when used as a flavoring agent in food; [JECFA] See Indole.

CHEM SCRUBBING SYSTEMS ARE ATTRACTIVE FOR CONTINUOUSLY HANDLING LARGE VOL OF GAS CONTAINING VERY LOW CONCN OF POTENT ODORANTS. THESE SYSTEMS USUALLY FUNCTION BY OXIDN OF THE ODORANT. THE ODOR CONTROL OF SKATOLE IS DISCUSSED FOR EACH OF THE OXIDIZERS: NAOCL, CL2, KMNO4, AND O3.

TWO TYPES OF AIR WASHERS, CROSS-CURRENT AND COUNTERCURRENT, WERE INSTALLED IN THE VENTILATION OF THE EXHAUST SYSTEM IN LIVESTOCK AND POULTRY FARMS, TO DEODORIZE THE AIR. ACTIVATED SLUDGE FROM A SEWAGE PLANT WAS ADDED TO THE CIRCULATING WATER. WASH WATER SAMPLES CONTAINED SKATOLE.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

TERRESTRIAL FATE: A methanogenic consortium, enriched from wetland soil completely mineralized 13 mg of 3-methylindole within 35 days(1). Based on a recommended classification scheme(2), an estimated Koc value of 600(SRC), indicates that 3-Methylindole will have low mobility in soil(SRC). Volatilization of 3-methylindole may occur slowly from moist soil surfaces(SRC) given an estimated Henry's Law constant of 2.1X10-6 atm-cu m/mole(SRC), using a fragment constant estimation method(3).

AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 600(SRC), determined from a structure estimation method(2), indicates that 3-methylindole is expected to adsorb to suspended solids and sediment in water(SRC). 3-Methylindole will volatilize from water surfaces(1,SRC) based on an estimated Henry's Law constant of 2.1X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Estimated half-lives for a model river and model lake are 20 and 148 days, respectively(1,SRC). According to a classification scheme(5), an estimated BCF value of 56(1,SRC), from an experimental log Kow(4), suggests that bioconcentration in aquatic organisms is moderate, not high(SRC). When exposed to natural sunlight 3-methylindole may undergo photo-oxidative degradation. The aqueous rate constant for the photolysis of 3-methylindole was measured as 0.18 hr-1 with a half life of 3.8 hours(6). The major product of the aqueous photo-oxidative degradation of 3-methylindole is thought to be o-(N-formyl)aminoacetophenone(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 3-Methylindole, which has an extrapolated vapor pressure of 0.005 mm Hg at 25 °C(4,SRC), will exist primarily as a vapor in the ambient atmosphere. Vapor-phase 3-methylindole 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 about 0.64 hours(3,SRC).

The Koc of 3-methylindole is estimated as approximately 600(SRC), using an experimental log Kow of 2.60(1,SRC) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that 3-methylindole has low mobility in soil(SRC). The value of Koc may be influenced by the pH of the soil for this compound due to the basic nature of the amine group(SRC).

...AFRICAN CIVET CAT; CELTIS RETICULOSA, A JAVANESE TREE.

Common naturally occurring sources of 3-methylindole are feces, beetroot, and nectrandra wood(1,2).

TESTED AT 2% IN PETROLATUM IT PRODUCED NO IRRITATION AFTER A 48-HR CLOSED-PATCH TEST ON HUMAN SUBJECTS.

SKATOLE AND ITS METABOLIC INTERMEDIATES MAY BE RELATED TO HUMAN PATHOLOGICAL CONDITIONS, INCL MALABSORPTION SYNDROMES AND CERTAIN ANEMIAS AND HEPATIC COMA. 6-HYDROXYSKATOLE, THE MAJOR METABOLITE OF SKATOLE IN MAN, MAY BE A PSYCHOTROPIC SUBSTANCE; IT IS EXCRETED AS THE SULFATE IN ELEVATED AMOUNTS IN THE URINE OF SOME SCHIZOPHRENIC PT.

An estimated BCF value of 56 was calculated for 3-methylindole(SRC), using an experimental log Kow of 2.60(4) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is moderate, not high(SRC).

The Henry's Law constant for 3-methylindole is estimated as 2.1X10-6 atm-cu m/mole(SRC) from its extrapolated value for vapor pressure, 0.005 mm Hg(1), and experimental water solubility, 498 mg/l(2). This value indicates that 3-methylindole will volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 20 days(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 148 days(3,SRC). 3-Methylindole's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces will not be important(SRC).

IN FROGS, THE MINIMUM LETHAL DOSE OF SKATOLE ADMIN SC OR INTO THE ABDOMINAL LYMPH SAC WAS 1 G/KG; A PARALYTIC ACTION ON THE CENTRAL NERVOUS SYSTEM RESULTED IN A COMPLETE ABOLITION OF SPONTANEOUS REFLEX AND RESP MOVEMENTS. AN ORAL DOSE OF 0.3 G SKATOLE/KG GIVEN TO GOATS PRODUCED DIFFUSE PULMONARY EDEMA WHICH RESULTED IN DEATH, AND ORAL OR IV ADMIN TO COWS CAUSED PULMONARY LESIONS. DEATH FROM PULMONARY EDEMA & EMPHYSEMA RESULTED IN 3/3, 0/2 AND 1/3 COWS GIVEN 0.2 (ORAL), 0.1 (ORAL) AND 0.06 G/KG (IV IN PROPYLENE GLYCOL), RESPECTIVELY.

MICE TREATED ORALLY WITH 100 MG SKATOLE/KG SHOWED NO SIGNS OF PULMONARY DISEASE. ORAL INGESTION OF 200 MG/KG BY MICE ALSO FAILED TO INDUCE PULMONARY EMPHYSEMA, BUT PULMONARY CONGESTION DID OCCUR, AS SHOWN BY A REDUCTION IN THE PHOSPHOLIPID CONTENT OF THE LUNG AND INCREASES IN HEMOGLOBIN CONTENT. ...WHEN MICE WERE GIVEN SKATOLE (10 MG/KG BODY WT) IP FOR 15 CONSECUTIVE DAYS...LESIONS OF THE LIVER, SPLEEN, KIDNEY AND LUNGS WERE PRESENT BUT SHOWED MARKED REGENERATION AFTER THE DOSE WAS STOPPED.

RABBITS INJECTED IN THE KNEE JOINT WITH A SINGLE DOSE OF SKATOLE (0.26 MMOL IN 1 ML AQUEOUS 50% PROPYLENE GLYCOL) DEVELOPED ACUTE ARTHRITIS AND AN ACUTE INFLAMMATION ORIGINATING IN THE SYNOVIAL TISSUE, WHILE RABBITS INJECTED IN THE KNEE JOINT WITH 0.04-0.26 MMOL SKATOLE ONCE WEEKLY FOR 6 WK DEVELOPED CHRONIC ARTHRITIS, THE SEVERITY INCREASING WITH INCREASING DOSAGES. ...SKATOLE APPLIED FULL STRENGTH TO INTACT OR ABRADED RABBIT SKIN FOR 24 HR UNDER OCCLUSION WAS NOT IRRITATING.

3-METHYLINDOLE (3MI) WAS ORALLY ADMIN AS A SINGLE DOSE OF 0.1-0.2 G/KG WHICH THEN PRODUCED ACUTE PULMONARY EDEMA IN CATTLE. LUNG TISSUE COLLECTED AFTER 72 HR REVEALED VESICULATION AND DESQUAMATION OF ALVEOLAR TYPE I CELLS AS WELL AS HYPERPLASIA OF THE ALVEOLAR TYPE II CELLS. HYALINE MEMBRANE FORMATION, ALONG WITH MASSIVE ACCUMULATION OF TUBULAR MYELIN IN THE ALVEOLAR SPACES, WAS OBSERVED. PULMONARY CAPILLARIES WERE OCCLUDED WITH MICROTHROMBI, AND LEUKOCYTES INFILTRATED THE INTERSTITIUM AS WELL AS THE ALVEOLI. ACCUMULATION OF LARGE AGGREGATES OF GLYCOGEN IN THE ALVEOLAR TYPE II CELLS WERE THE MOST UNUSUAL CHANGES SEEN IN EXPTL ANIMALS.

THE PATHOLOGIC FEATURES OF BRONCHIOLITIS WERE STUDIED IN HORSES AND PONIES FROM 30 MIN TO 27 DAYS AFTER AN ORAL DOSE OF 3-METHYLINDOLE (3MI). FROM 30 MIN TO 3 HR, LESIONS WERE LIMITED TO NONCILIATED BRONCHIOLAR EPITHELIAL (CLARA) CELLS, WHICH LOST APICAL CAPS AND CYTOPLASMIC GRANULES AND HAD DILATED SMOOTH ENDOPLASMIC RETICULUM (SER). AT 12 HR, NECROTIC CLARA CELLS WERE EXFOLIATED; DEGENERATION AND NECROSIS WERE EVIDENT, IN BRONCHIOLAR CILIATED CELLS. RARE EPITHELIAL CELLS WITH HYPERPLASTIC SER APPEARED ON THE DENUDED BASAL LAMINA AT 24 HR. INFLAMMATORY CELLS, EPITHELIA, FIBROBLASTLIKE CELLS, COLLAGEN, AND DEBRIS OCCLUDED MANY BRONCHIOLAR LUMENS FROM 3 TO 6 DAYS. REORGANIZATION RESULTED IN A SIMPLE COLUMNAR BRONCHIOLAR EPITHELIUM WITH RELATIVELY NORMAL CILIATED CELLS AND FEWER FIBROBLASTLIKE CELLS. HOWEVER, MATURE CLARA CELLS WERE RARE AT 27 DAYS, AND COLLAGENOUS BANDS STILL DIVIDED BRONCHIOLAR LUMENS.

When exposed to natural sunlight the aqueous rate constant for the photolysis of 3-methylindole was measured as 0.18 hr-1 with a half life of 3.8 hours(1). The major product of the photo-oxidative degradation of 3-methylindole is thought to be o-(N-formyl)aminoacetophenone(1). The vapor-phase reaction of 3-methylindole with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(2,SRC). This corresponds to an atmospheric half-life of about 0.64 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(3,SRC).

NUCLEOPHILIC THIOL AGENTS, GLUTATHIONE, L-CYSTEINE AND N-ACETYL-L-CYSTEINE, PROTECTED MICROSOMAL PROTEINS AGAINST ALKYLATION BY THE REACTIVE METABOLITE OF 3-METHYLINDOLE. THE CYTOSOL FRACTION FROM THE LUNGS OF CATTLE INCR THE PROTECTIVE EFFECT OF THESE THIOL AGENTS. PRETREATMENT OF SHEEP WITH DIETHYLMALEATE, WHICH DEPLETES GLUTATHIONE, INCR THE SEVERITY OF THE PNEUMOTOXIC EFFECT OF 3-METHYLINDOLE, WHEREAS PRETREATMENT WITH L-CYSTEINE DECR THE SEVERITY OF THIS EFFECT. THESE FINDINGS ARE CONSISTENT WITH A HYPOTHESIS THAT AN ELECTROPHILIC REACTIVE METABOLITE OF 3-METHYLINDOLE IS RESPONSIBLE FOR ITS PNEUMOTOXIC EFFECT AND IMPLIES THAT GLUTATHIONE AND GLUTATHIONE S-TRANSFERASES ARE INVOLVED IN THE DETOXIFICATION OF THIS REACTIVE METABOLITE.

INCUBATION OF VARIOUS INDOLIC COMPD WITH GOAT LUNG MICROSOMES SHOWED THAT ONLY 3-METHYLINDOLE WAS ABLE TO GENERATE A FREE RADICAL IN THE NADPH-DEPENDENT MICROSOMAL SYSTEM, AS TESTED BY SPIN-TRAPPING. ENZYMIC RADICAL FORMATION FROM 3-METHYLINDOLE SUGGESTS A MICROSOMAL-ACTIVATED FREE RADICAL MECHANISM FOR THE SPECIFICITY OF 3-METHYLINDOLE-INDUCED PULMONARY TOXICITY.

Bioactivation of 3-methylindole (3MI), a highly selective pneumotoxin in goats, was investigated in human lung and liver tissues in order to provide information about the susceptibility of humans to 3MI toxicity. Human lung microsomes were prepared from eight organ transplantation donors and liver microsomes from one of the donors were /selected/. The 3MI turnover rate with human lung microsomes was 0.23 +/- 0.06 nmol/mg/min, which was lower than the rate with the human liver microsomes (7.40 mnol/mg/min). The activities were NADPH dependent and inhibited by l-aminobenzotriazole, a potent cytochrome p450 suicide substrate inhibitor. Covalent binding of 3MI reactive intermediates to human tissues was determined by incubation of (14)C-3MI and NADPH with human lung and liver microsomal proteins. Although human lung microsomes displayed measurable covalent binding activity (2.74 +/- 2.57 pmol/mg/min), the magnitude of this reaction was only 4% as large as that seen with human liver microsomes and also was inhibited by l-aminobenzotriazole. Therefore, the bioactivation of 3MI to covalently binding intermediates is catalyzed by cytochrome p450 in human pulmonary tissues. These activities were compared to those activities measured with tissues from goats. Proteins from goat and human pulmonary and hepatic microsomal incubations were incubated with radioactive 3MI, and radioactive proteins were analyzed by SDS-PAGE and HPLC and visualized by autoradiography and radiochromatography, respectively. The results showed that a 57-kDa protein was clearly the most prominently alkylated target associated with 3MI reactive intermediates. These data suggest that humans may be susceptible to 3MI mediated toxicities and that the specificity of covalent binding and the extent of binding to target proteins may play important roles in organ and species selective susceptibilities to 3MI pneumotoxicity.

SKATOLE IS PRODUCED IN THE GI TRACT (SMALL INTESTINE AND RUMEN) BY THE BACTERIAL DEGRADATION OF DIETARY TRYPTOPHAN RESIDUES...

MATURE BEEF COWS GRAZING ON DRY SUMMER RANGE WERE MOVED TO LUSH GREEN PASTURE TO INDUCE ACUTE BOVINE PULMONARY EDEMA AND EMPHYSEMA (ABPE) AND TO DETERMINE WHETHER PLASMA AND RUMINAL FLUID 3-METHYLINDOLE (3MI) CONCN ARE RELATED TO THE DEVELOPMENT OF ABPE. IN VITRO PRODN OF 3MI WAS OBSERVED IN CULTURE MEDIA INOCULATED WITH RUMINAL FLUID, DEMONSTRATING THAT MICROORGANISMS CAPABLE OF PRODUCING 3MI WERE IN THE RUMEN. APPARENTLY RUMINAL MICROORGANISMS OF CATTLE CONVERT TRYPTOPHAN (CONTAINED IN LUSH FORAGE) TO 3MI, WHICH UPON ABSORPTION BY THE ANIMAL MAY RESULT IN THE ONSET OF ABPE.

FORMED FROM INDOLE-3-ACETIC ACID. YIELDS O-FORMAMIDOACETOPHENONE IN RAT, WHEAT; FRYDMAN RB ET AL; FEBS LETTERS 17: 273 (1971). YIELDS 5-HYDROXYSKATOLE, 7-HYDROXYSKATOLE IN RAT; DALGLIESH CE ET AL; BIOCHEM J 70: 13P (1958). YIELDS 6-HYDROXYSKATOLE IN RABBIT; JEPSON JB ET AL; BIOCHIM BIOPHYS ACTA 62: 91 (1962). YIELDS SALICYLIC ACID IN PSEUDOMONAS; PROCTOR MM; NATURE (LONDON) 181: 1345 (1958). /FROM TABLE/

GOATS WERE GIVEN JUGULAR INFUSIONS OF (14)C-3-METHYLINDOLE (3MI). A MAJOR ROUTE OF METABOLISM INVOLVED FORMATION OF 3-METHYLOXINDOLE AND SUGGESTS THAT A MIXED FUNCTION OXIDASE, PYRROLOOXYGENASE, MAY BE THE MAJOR METABOLIC SYSTEM INVOLVED. A MINOR ROUTE OF METABOLISM INVOLVED OXIDATION OF THE METHYL CARBON OF 3MI.

For more Metabolism/Metabolites (Complete) data for 3-METHYLINDOLE (6 total), please visit the HSDB record page.

3-methylindole has known human metabolites that include 3-methyleneindolenine and 3-methylindole-2,3-epoxide.

AFTER ADMIN OF SKATOLE TO CATTLE IN A DOSE OF 0.1-0.2 G SKATOLE/KG INTRARUMINALLY OR 0.06 G/KG BY JUGULAR INFUSION, THE MEAN PLASMA CONCN OF SKATOLE BECAME MAXIMAL AT 3 AND 9 HR, RESPECTIVELY.

GOATS WERE GIVEN A 2 HR JUGULAR INFUSION OF 3-METHYLINDOLE (3MI) CONTAINING (14)C-3MI USING PROPYLENE GLYCOL AS THE VEHICLE. 3MI WAS RAPIDLY CLEARED FROM BLOOD PLASMA AND TISSUES AFTER INFUSION, AND 81% OF THE RADIOACTIVITY WAS EXCRETED IN THE URINE BY 24 HR. MAX CONCN OF UNMETABOLIZED 3MI IN THE TISSUES RANGED FROM 2.6 TO 15 UG 3MI/G, INCL 7.5 UG 3MI/G IN THE LUNG. THE LUNG CONTAINED THE HIGHEST PROPORTION OF METABOLITES. THE DATA DEMONSTRATE THAT 3MI DOES NOT SELECTIVELY CONCENTRATE IN THE LUNG AND THAT THE CONCN ARE LOWER THAN THOSE USUALLY ASSOC WITH DIRECT MEMBRANE DAMAGE.

Used in perfume fixatives, artificial civet (musk), food flavoring, and experimental veterinary medications; [HSDB]

IN PERFUMERY (FIXATIVE), ARTIFICIAL CIVET

FLAVORING FOOD ADDITIVE

MEDICATION

OBTAINED BY FUSING EGG ALBUMIN WITH POTASSIUM HYDROXIDE.

SYNTHESIZED...BY HEATING GLYCEROL AND ANILINE IN THE PRESENCE OF ZINC CHLORIDE; ALSO BY TREATING THE PHENYLHYDRAZONE OF PROPIONIC ALDEHYDE WITH A CALCULATED AMT OF ZINC CHLORIDE IN AN OIL BATH @ 180 °C...

...BY CYCLIZATION OF O-TOLUIDIDES.

Fragrance Ingredients

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

1H-Indole, 3-methyl-: ACTIVE

SKATOLE (0.001-0.1% IN THE DIET) ADVERSELY AFFECTED LARVAL GROWTH AND DEVELOPMENT AND THE SUBSEQUENT REPRODUCTIVE CAPACITY OF THE BOLLWORM, HELIOTHIS ZEA. IT IS AN ATTRACTANT FOR THE PALM WEEVIL RHYNCHOPHORUS PALMARUM AND FOR HIPPELATES EYE GNATS. ... SKATOLE HAS BEEN SHOWN TO...CAUSE, AT LEVELS OF 0.2-0.4 MG/ML, TOTAL INHIBITION OF LATERAL GROWTH BY SCLEROTINA TRIFOLIORUM, THE CLOVER ROT FUNGUS, TO EFFECT IN 100 PPM CONCN GREATER THAN 75% INHIBITION AGAINST THE RUBBER-TREE MOLDY-ROT FUNGUS MYCELIUM...

SKATOLE ACTS AS A PLANT HORMONE SHOWING AUXINIC EFFECTS IN LENS CULINARIS ROOTS AND AFFECTING SEED GERMINATION AND GROWTH OF STELLARIA MEDIA AND HYPTIS SUAVEOLENS AS WELL AS THE GROWTH OF PLANT TISSUES IN VITRO.

SYNTHETIC FLAVOR INGREDIENTS- SKATOLE: FLAVOR USEFUL IN CHEESE, GRAPE, BERRY, NUT, EGG.

REPORTED USES: NON-ALCOHOLIC BEVERAGES, 0.75 PPM; ICE CREAM, ICES, ETC, 1.0 PPM; CANDY, 0.78 PPM; BAKED GOODS, 0.80 PPM; GELATINS AND PUDDINGS, 0.01 PPM; CHEWING GUM, 0.10 PPM.

For more General Manufacturing Information (Complete) data for 3-METHYLINDOLE (7 total), please visit the HSDB record page.