Absorption, Distribution and Excretion
The absorption, distribution and excretion of radioactivity have been determined after a 6-hour topical application with 0.5 mg/kg bw of ring-labeled (14)C-musk ketone (in a mixture of phenylethyl alcohol and ethanol) to the shaven backs of 21 male rats (16 CD Sprague- Dawley and 5 Long-Evans). The dose was applied evenly over an area of 9 sq cm. The application rate was 0.01 mg/sq cm ... In CD rats and Long-Evans rats 14.6-26.3% and 13.3%, respectively, of the radiolabeled dose was absorbed from the shaven backs during 6 hours. After removal of the (14)C-musk ketone at 6 hours of application 16% of the dose remained on the skin which continued to be absorbed. This is supported by data obtained on animals killed at later times which show a steady decrease in the amount of material found on the treated skin from 7.2-9.85% of the dose at 8 hours to 3.1-4.1% after 24 hr and 2.0-3.4% after 48 hours. The actual absorption at 8 hours was approximately 19%, at 24 hours 25.1-28.3%, and at 48 hours 26.2-32.7%. After 48 hours, absorption essentially ceased while approximately 3% of the dose remained unabsorbed on the skin. In Long-Evans rats the disposition of radioactivity was similar with absorption of (14)C-musk ketone rising to 29.3-40.2% of the dose between 48 and 120 hours. The mean proportion of the dose remaining on the treated skin after 24 hours was approximately 3%.
The absorption, distribution and excretion of radioactivity have been determined after a 6-hour topical application with 0.5 mg/kg bw of ring-labeled (14)C-musk ketone (in a mixture of phenylethyl alcohol and ethanol) to the shaven backs of 21 male rats (16 CD Sprague- Dawley and 5 Long-Evans). The dose was applied evenly over an area of 9 sq cm. The application rate was 0.01 mg/sq cm ... After 6 hr application the dressing and foil were removed and the remaining dose at the treated area was wiped off ... In CD rats means of 7.3% and 17.2% of the applied dose had been excreted in the urine and feces, respectively, after 120 hours. In Long-Evans rats the rate of elimination was comparable with 10.8% and 27.2% of the dose excreted during 5 days in the urine and feces, respectively. Most radioactivity was eliminated in the first 48 hr after start of dosing. No radioactivity was detected in expired air.
The absorption, distribution and excretion of radioactivity have been determined after a 6-hour topical application with 0.5 mg/kg bw of ring-labeled (14)C-musk ketone (in a mixture of phenylethyl alcohol and ethanol) to the shaven backs of 21 male rats (16 CD Sprague- Dawley and 5 Long-Evans). The dose was applied evenly over an area of 9 sq cm. The application rate was 0.01 mg/sq cm ... After 6 hr application the dressing and foil were removed and the remaining dose at the treated area was wiped off ... In the bile duct cannulated CD rats only 1.8% of the dose was eliminated in the urine in 48 hours, while 25.3% was collected in the bile (of which 15.8% within 24 hours). The non-cannulated rat excreted 8% of the dose in the urine in 48 hours. These results indicate that the predominant route of excretion for (14)C-musk ketone is via the bile, and therefore that most of the radioactivity in the urine of cannulated animals is due to material that had been reabsorbed from the gastro-intestinal tract. In bile, at least six drug-related components were present as beta-glucuronic acid conjugates which were apparently deconjugated and further metabolized in the gastro-intestinal tract to other more polar components, some of which were at least partially reabsorbed giving rise to a complex profile of urinary metabolites. Radioactivity was detected in nearly all the tissues of animals killed at 1-120 hours after start of dose application. Concentrations were highest at about 6 hours after start of dosing in all tissues. Between 8 and 120 hr the concentration of radioactivity declined steadily in all tissues so that at 120 hours after start of dosing the concentration of radioactivity in each tissue was in general less than 20% of its peak value. Throughout the study the highest concentrations of radioactivity were found in the gastro-intestinal tract, liver, adipose tissue, adrenals, thyroid and kidneys, which at 6 hours after start of dosing contained means of 0.645 ug musk ketone equivalents/g, 0.32 ug/g, 0.19 ug/g, 0.12 ug/g, 0.10 ug/g and 0.08 ug/g, respectively, in CD rats. The distribution of radioactivity in the tissues of Long-Evans rats was similar with the highest peak concentrations of radioactivity at 6 hr after start of dosing in the gastro-intestinal tract (0.47 ug musk ketone equivalents/g), liver (0.26 ug/g), adrenals (0.1 ug/g), thyroid (0.18 ug/g) and fat (0.16 ug/g).
Ring-labeled (14)C-musk ketone (in phenylethyl alcohol and ethanol) was applied under occlusion to the shaven backs (area about 9 sq cm) of 10 male Sprague-Dawley CD rats up to fourteen daily 24-hour doses of 0.5 mg/kg bw. The skin remained unrinsed between the applications. Two rats were killed for whole-body autoradiography, one 24 hours after the first dose, and the other 24 hours after the 14th dose. From the remaining 8 rats, urine and feces were collected at several time points, and at sacrifice samples of blood, treated skin, brain, kidney, liver, thyroid, and fat were taken. Whole-body autoradiography showed that at 24 hours after the first dose radioactivity was not widely distributed throughout the body. Relatively high concentrations were present at the site of application and in the caecal contents, large intestine contents, and bile ducts. Lower levels were present in the small intestine contents and liver. Tissues of the rat killed at 24 hours after the 14th dose generally contained more radioactivity, although the highest concentrations were still associated with the site of application and the gastro-intestinal tract and lower levels were present in liver, blood, and thyroid. Hence, the absorption of radioactivity was incomplete, given the large amounts of the applied radioactivity remaining at the site of application. Means of 1.48 and 2.34 ug musk ketone equivalents were excreted in urine and feces, respectively, in the 24 hours following the application of dose 1. The mean rate of excretion in the urine increased to 6.54 ug/day during the 24 hours following the application of dose 14. The mean rate of excretion in feces increased to maxima of about 14.8 ug/day in the 24 hours following application of both dose 12 and dose 14. At sacrifice, the concentration of radioactivity in treated skin was high, whereas the total radioactivity present in blood and selected tissues was only a very small proportion of the total of 14 applied doses (0.22-0.37% in liver, and even less in fat, blood, kidneys, brain, and thyroid).
For more Absorption, Distribution and Excretion (Complete) data for Musk ketone (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Ubiquitous occurrences of synthetic nitro musks are evident in the literature. The in vivo analysis of musk xylene (MX) and musk ketone (MK)-protein adducts in trout liver has been performed by gas chromatography-mass spectrometry using selected ion monitoring (GC-SIM-MS). Biotransformation, dose-response and toxicokinetics studies of 2-amino-MX (2-AMX), 2-amino-MK (2-AMK) and 4-amino-MX (4-AMX) metabolites, covalently bound to cysteine amino acids in proteins in fish liver, formed by enzymatic nitro-reduction of MX and MK, have been described. Trout were exposed to single exposures of 0.010, 0.030, 0.10, and 0.30 mg/g MX and/or MK. Forty-two fish liver samples were collected from exposed- and control-fish subsequent to exposure intervals of 1 day, 3 days, and 7 days and were composited as per exposure schedules and times. Alkaline hydrolysis released bound metabolites from exposed liver composites that were extracted into n-hexane and then concentrated and analyzed by GC-SIM-MS. The presence of the metabolites in liver extracts was confirmed based on agreement of similar mass spectral properties and retention times with standards. In the dose-response study, the maximum adduct formation was 492.0 ng/g for 2-AMX, 505.5 ng/g for 2-AMK and 12588.5 ng/g for 4-AMX in liver at 0.03 mg/g MX and MK fish in 1 day after exposure. For toxicokinetics investigation, the highest amount of the target metabolites was found to be the same concentration as observed in the dose-response study for 1 day after exposure with 0.03 mg/g MX and MK fish and the half-lives of the metabolites were estimated to be 2-9 days based on assumption of first-order kinetics. Average recoveries exceeded 95% with a relative standard deviation (RSD) around 9%, and the limit of detection (LOD) ranged from 0.91 to 3.8 ng/g based on a signal to noise ratio of 10 (S/N=10) could be achieved for the metabolites. No metabolites were detected in the controls and exposed non-hydrolyzed liver extracts. This is the first report on dose-response and toxicokinetics of nitro musk-cysteine-protein adducts in fish liver.
Two healthy male volunteers received an application of 2.2 mg ring-labeled (14)C-musk ketone (in a mixture of phenylethyl alcohol and ethanol) on the unshaven skin of the upper left quadrant of the chest for 6 hours. The dose was applied evenly over an area of 100 sq cm. The application rate was 0.02 mg/sq cm. ... When urine samples were treated with beta-glucuronidase and extracted with ethyl acetate the recovery was about 5-fold larger, indicating that a large proportion of the metabolites of musk ketone in human urine were present as glucuronide conjugates. Extracts of beta-glucuronidase treated human urine contained a single major (unidentified) metabolite which was probably also present as a minor constituent of rat bile extract.

Toxicity Summary
IDENTIFICATION AND USE: Musk ketone forms yellow crystals. It is a fragrance. Musk ketone is widely used as a fixative in blossom and fantasy compositions. HUMAN STUDIES: Musk ketone failed to elicit a sensitization reaction after 48 and 72 hours in a maximization test with human volunteers. A case described patient with chronic actinic dermatitis whose photopatch tests revealed reactions to musk ketone and musk ambrette, both of which were found in his aftershave lotion. Musk ketone at doses of 0.068 to 68 uM did not induce sister chromatid exchanges in human lymphocytes with or without metabolic activation. In an in vitro micronucleus test, musk ketone at doses up to 136 and 250 uM did not increase the frequency of micronuclei in human lymphocytes and in the human hepatoma cell line Hep G2, respectively. ANIMAL STUDIES: Musk ketone did not produce dermal irritation or systemic toxicity in rabbits. It was a mild eye irritant in rabbit's eyes. Musk ketone did not produce contact sensitivity in guinea pigs. Musk ketone treatment in mice resulted in dose-related increases in relative liver weight at dose levels of 50 mg/kg bw, up to 50% at 500 mg/kg bw. Musk ketone also caused histological changes in the liver, primarily centrilobular hepatocellular hypertrophy, and at the highest dose panlobular hepatocellular hypertrophy. Pregnant rats received by gavage 0, 60, 200, 600 or 2,000 mg musk ketone/kg bw/day during days 7-17 of gestation. Observations after caesarean sectioning showed decreases in fetal body weights, litter sizes and live fetuses and increases in early and late resorptions and percent resorbed conceptuses at 200 mg/kg bw and higher. No gross external fetal alterations were observed. Musk ketone negatively affects reproduction and early life-stage survival in zebrafish. Musk ketone was tested in 5 strains of Salmonella typhimurium and found to be negative with and without activation. ECOTOXICITY STUDIES: Cytochromes P450 are potentially sensitive targets of synthetic musk substances in fish.

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Interactions
... 13 patients, suspected to suffer from a photoallergic contact dermatitis, were screened by means of a questionnaire and clinical tests. Dermal sensitivity to UV light was pre-tested after which nitromusks (amount and vehicle not specified) were applied on the skin under occlusive patches (two sites per substance). After 24 hours of contact the patches were removed under dim light and the skin examined for any signs of contact-dermatitis. Half of the contact sites were covered again and the other half was irradiated with ultra-violet light. All persons studied showed a photoallergic reaction to musk ambrette. In one person also a photoallergic reaction to musk ketone was observed. No reaction was seen at the non-irradiated site. The study is inconclusive as to whether this patient shows either cross-photoallergy between musk ambrette and musk ketone or that this patient shows a concomittant independent photo-allergy to two nitromusks. The study is also inconclusive as to the prevalence of the condition.
... When the cells were treated simultaneously with MK (5-5000 ng/mL) and 0.2 ug/mL benzo(a)pyrene, no synergistic effects were detected; benzo(a)pyrene (B(a)P) itself caused an 1.5-fold increase of MN over the spontaneous background frequency (60 versus 39 MN/1000 binucleated cells). ...
When tested in an in vitro micronucleus test with metabolically competent human hepatoma cells (Hep G2 line), a cogenotoxic effect of musk ketone was observed when the cells were pre-treated with musk ketone for 28 hours and subsequently exposed to B(a)P, but not when the cells were simultaneously treated with musk ketone and B(a)P. Pretreatment with musk ketone resulted in a significant increase in B(a)P-induced micronuclei. This amplification of B(a)P genotoxicity was seen with 500-5,000 ng/mL musk ketone, concentrations that were effectively inducing CYP1A-activities (as was shown by EROD measurements in the Hep G2 cells), i.e. enzymes playing a key role in the activation of B(a)P.

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Non-Human Toxicity Values
LD50 Rat oral >10 g/kg
LD50 Rabbit dermal >10 g/kg

[1]. Identification of musk xylene and musk ketone in freshwater fish collected from the Tama River, Tokyo. Bull Environ Contam Toxicol. 1981 May;26(5):656-62.

[2]. Musk ketone enhances benzo(a)pyrene induced mutagenicity in human derived Hep G2 cells. Mutat Res. 2001 Aug 22;495(1-2):89-96.

[3]. Musk Ketone Induces Neural Stem Cell Proliferation and Differentiation in Cerebral Ischemia via Activation of the PI3K/Akt Signaling Pathway. Neuroscience. 2020 May 21;435:1-9.

[4]. Effects of musk xylene and musk ketone on rat hepatic cytochrome P450 enzymes. Toxicol Lett. 1999 Dec 20;111(1-2):105-15.

[5]. Musk ketone induces apoptosis of gastric cancer cells via downregulation of sorbin and SH3 domain containing 2. Mol Med Rep. 2021 Jun;23(6):450.

Musk ketone is a light yellow crystalline solid. Insoluble in water. (NTP, 1992)
4'-tert-Butyl-2',6'-dimethyl-3',5'-dinitroacetophenone is an aromatic ketone.
Musk ketone has been reported in Moschus with data available.
See also: ... View More ...

C14H18N2O5

294.31

294.121

81-14-1

6669

White to off-white solid powder

1.2±0.1 g/cm3

369.0±42.0 °C at 760 mmHg

135-139 °C(lit.)

153.2±20.7 °C

0.0±0.8 mmHg at 25°C

1.548

3.86

0

5

2

21

418

0

WXCMHFPAUCOJIG-UHFFFAOYSA-N

InChI=1S/C14H18N2O5/c1-7-10(9(3)17)8(2)13(16(20)21)11(14(4,5)6)12(7)15(18)19/h1-6H3

1-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)ethanone

NSC-15339; NSC 15339; Musk ketone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 125 mg/mL (~424.74 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)