4'-methylacetophenone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Review article on ADME studies in the context of the Flavor and Extract Manufacturers Association (FEMA) risk assessment

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

The FEMA GRASS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavour ingredients

Author:

Adams TB, McGowen MM, Williams MC, Cohen SM, Feron VJ, Goodman JI, Marnett LJ, Munro IC, Portoghese PS, Smith RL, Waddell WJ

Year:

2007

Bibliographic source:

Food and Chemical Toxicology 45(2): 171-201

Reference 2

Reference Type:

publication

Title:

Studies in detoxication. 69. The metabolism of alkylbenzenes: n-propylbenzene and n-butylbenzene with further observations on ethylbenzene.

Author:

El Masry AM, Smith JN, Williams RT

Year:

1956

Bibliographic source:

Biochem J 64: 50-57

Reference 3

Reference Type:

publication

Title:

Quantitative studies of beta-oxidation. II The metabolism of phenylvaleric acid, phenyl-alpha, beta-penetic acid, phenyl-beta-gamma-penetic acid, mandelic acid, phenyl-beta-hydroxypropionic acid and acetophenone in dogs

Author:

Quick AJ

Year:

1928

Bibliographic source:

J Biol Chem 80: 515-526

Reference 4

Reference Type:

publication

Title:

Studies in detoxication. 59. The metabolism of alkylbenzenes: the biological reduction of ketones derived from alkylbenzenes

Author:

Smith JN, Smithies RH, Williams RT

Year:

1954

Bibliographic source:

Biochem J 57: 74-76

Reference 5

Reference Type:

publication

Title:

Reaction pathways of in vivo stereoselective conversion of ethylbenzene to (-)-mandelic acid

Author:

Sullivan HR, Miller WM, McMahon RE

Year:

1976

Bibliographic source:

Xenobiotica 6: 49-54

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Acetophenone

EC Number:

202-708-7

EC Name:

Acetophenone

Cas Number:

98-86-2

IUPAC Name:

1-phenylethanone

Test animals

Species:

other: rat, mouse, rabbit, dog

Administration / exposure

Route of administration:

other: oral (gavage, feeding); intraperitoneal

Results and discussion

Preliminary studies:

Acetophenone is absorbed, metabolized and excreted as polar metabolite within 24 h.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

rapidly absorbed from the gut

Main ADME results 2

Type:

distribution

Results:

aromatic ketones administered orally undergo essentially complete first-pass hepatic clearance in mice and rats

Main ADME results 3

Type:

metabolism

Results:

by the liver

Main ADME results 4

Type:

excretion

Results:

primarily in the urine and to a very minor extent, in the feces

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Acetophenone administered to rabbits via variety of different routes or to dogs in the diet is primarily reduced to alpha-methylbenzyl alcohol. In other studies, alpha-methylbenzyl alcohol is, in part, oxidized to acetophenone in rats or a metabolite of acetophenone in rabbits.
Rabbits given single doses of 240 mg acetophenone/kg bw excreted 19 % as hippuric acid. In rabbits, approximately 50 % of a single oral dose of 450 mg/kg bw alpha-methylbenzyl alcohol was excreted as the glucuronic acid conjugate in the urine within 24 h. Other urinary metabolites included hippuric acid (30 %) and mendelic acid (1-2 %). Under similar conditions, acetophenone exibits essentially the same metabolic fate. A 450 mg/kg bw oral dose of acetophenone was excreted in the 24-h urine as the glucuronic acid conjugate of alpha-methylbenzyl alcohol (47 %) and, to a lesser extent, as hippuric acid (17 %).
The major urinary metabolites remained the glucuronic acid conjugate of alpha-methylbenzyl alcohol (35 %) and hippuric acid (24 %) when rabbits were administered single subcutaneous doses of 500-1400 mg acetophenone/kg bw. Small amounts were excreted as mandelic acid or unchanged.
When dogs were administered single oral doses of 500 mg acetophenone/kg bw, 35 % was recovered in the urine as the glucuronic acid conjugate of alpha-methalbenzyl alcohol while 20 % was excreted as hippuric acid. Much of the remainder was excreted unchanged.
Single intraperitoneal doses of racemic labelled [3H-C1]-alpha-methylbenzyl alcohol given to rats (8/group) resulted in the excretion of mandelic acid in the urine. The isolated acid was the (-)-enantiomer but did not contain the tritium [3H-] label, suggesting that the alcohol was oxidized to acetophenone prior to formation of mandelic acid. Acetophenone is concluded to be the precursor of optically active mandelic acid given that either stereoisomer or the racemic alpha-methylbenzyl alcohol forms only the (-) enantiomer of mandelic acid. Formation of benzoic acid from acetophenone was confirmed when, in male rats (8/group), 30 % of a single 100 mg/kg bw dose of [methyl-14C]-acetophenone was exhaled as 14CO2 within 30 h. The intermediacy of alpha-hydroxyacetophenone in the formation of benzoic acid and mandelic acid is supported by the observation that incubation of acetophenone in microsomes of rat hepatocytes yields mainly alpha-hydroxyacetophenone

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Acetophenone is absorbed, metabolized and excreted as polar metabolite within 24 h, therefore no bioaccumulation potential may be expected. In animals, alpha-methylbenzyl alcohol and acetophenone are interconvertible. alpha-Metyhlbenzyl alcohol is excreted in the urine predominantly as the glucuronic acid conjugate. To lesser extent, acetophenone underges alpha-oxidation to yield alpha-hydroxyacetophenone. Subsequent stereoselective reduction of the ketone function and oxidation of the terminal alcohol yields mandelic acid. Oxidation of the secondary alcohol only yields the corresponding ketoacid which undergoes oxidative decarboxylation to yield benzoic acid which is then excreted as hippuric acid.

Executive summary:

Simple aromatic ketones have been shown to be rapidly absorbed from the gut, metabolized by the liver and excreted primarily in the urine, and to very minor extent, in the feces. Pharmacokinetic data suggest that aromatic ketones administered orally undergo essentially complete first-pass hepatic clearance in both mice and rats. It was shown that acetophenone is absorbed, metabolized and excreted as polar metabolite within 24 h (Quick, 1928; Smith et al, 1954). Approximately half of the 450 mg/kg oral dose of acetophenone administered to rabbits by gavage was excreted within the urine 24 h after administration (Smith et al, 1954). Likewise, approximately half of a 500 mg/kg bw dose of acetophenone added to the food of dogs was accounted for in the first 24-h and following 12-h urine samples (Quick, 1928).

Acetophenone administered to rabbits via variety of different routes or to dogs in the diet is primarily reduced to alpha-methylbenzyl alcohol. In other studies, alpha-methylbenzyl alcohol is, in part, oxidized to acetophenone in rats or a metabolite of acetophenone in rabbits. Rabbits given single doses of 240 mg acetophenone/kg bw excreted 19 % as hippuric acid (El Masry et al, 1956). In rabbits, approximately 50 % of a single oral dose of 450 mg/kg bw alpha-methylbenzyl alcohol was excreted as the glucuronic acid conjugate in the urine within 24 h. Other urinary metabolites included hippuric acid (30 %) and mendelic acid (1-2 %). Under similar conditions, acetophenone exibits essentially the same metabolic fate. A 450 mg/kg bw oral dose of acetophenone was excreted in the 24-h urine as the glucuronic acid conjugate of alpha-methylbenzyl alcohol (47 %) and, to a lesser extent, as hippuric acid (17 %) (Smith et al, 1954). The metabolic fate of the alcohol or ketone is not significantly affected by either the mode of administration of the test material or the animal species tested. The major urinary metabolites remained the glucuronic acid conjugate of alpha-methylbenzyl alcohol (35 %) and hippuric acid (24 %) when rabbits were administered single subcutaneous doses of 500-1400 mg acetophenone/kg bw. Small amounts were excreted as mandelic acid or unchanged. When dogs were administered single oral doses of 500 mg acetophenone/kg bw, 35 % was recovered in the urine as the glucuronic acid conjugate of alpha-methylbenzyl alcohol while 20 % was excreted as hippuric acid. Much of the remainder was excreted unchanged (Quick, 1928).

Single intraperitoneal doses of racemic labelled [3H-C1]-alpha-methylbenzyl alcohol given to rats (8/group) resulted in the excretion of mandelic acid in the urine. The isolated acid was the (-)-enantiomer but did not contain the tritium [3H-] label, suggesting that the alcohol was oxidized to acetophenone prior to formation of mandelic acid. Acetophenone is concluded to be the precursor of optically active mandelic acid given that either stereoisomer or the racemic alpha-methylbenzyl alcohol forms only the (-) enantiomer of mandelic acid. Formation of benzoic acid from acetophenone was confirmed when, in male rats (8/group), 30 % of a single 100 mg/kg bw dose of [methyl-14C]-acetophenone was exhaled as 14CO2 within 30 h. The intermediacy of alpha-hydroxyacetophenone in the formation of benzoic acid and mandelic acid is supported by the observation that incubation of acetophenone in microsomes of rat hepatocytes yields mainly alpha-hydroxyacetophenone (Sullivan et al, 1976).

Based on these observations it is concluded that, in animals, alpha-methylbenzyl alcohol and acetophenone are interconvertible. alpha-Metyhlbenzyl alcohol is excreted in the urine predominantly as the glucuronic acid conjugate. To lesser extent, acetophenone underges alpha-oxidation to yield alpha-hydroxyacetophenone. Subsequent stereoselective reduction of the ketone function and oxidation of the terminal alcohol yields mandelic acid. Oxidation of the secondary alcohol only yields the corresponding ketoacid which undergoes oxidative decarboxylation to yield benzoic acid which is then excreted as hippuric acid.