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Description of key information

Short description of key information on bioaccumulation potential result: 
Acetone appears in the human and mammalian organism as an endogenous product of normal metabolism with considerably increased levels during altered physiological states.
Acetone from dermal, inhalative and oral exposure is rapidly absorbed. The relative uptake from the airways was about 50 % in humans. Passage into blood occurs within several minutes. Acetone is not selectively absorbed in any tissue but is more evenly distributed in the body water.
The metabolic fate of exogenous acetone is independent of the route of uptake and involves three separate gluconeogenic pathways at low doses with acetol (1-hydroxyacetone), methylglyoxal and 1,2-propanediol as intermediary products. Both methylglyoxal and propanediol are oxidised to pyruvate which is the basic building block for the biosynthesis of many endogenous biochemicals. At high doses, an alternate metabolic pathway appears with cleavage of 1,2-propanediol to acetate and formate. Elimination of acetone is effective even at high internal doses and occurs via metabolic transformation to endogenous biochemicals, as acetone vapour via the airways and the skin surface, via exhalation of CO2 and in urine as acetone or acetol, methylglyoxal or as D-lactoyl-GSH. Acetone turnover rates were linear up to plasma concentration of 5 mM (260 mg/L) with a turnover rate of ca. 9 µmol/kg bw/min = ca. 0.52 mg/kg bw/min corresponding to a daily turnover of 750 mg/kg bw/d. Studies with repeated daily exposures of 6 or 8 hrs confirmed that bioaccumulation is not expected to occur up to ca. 1,000 ppm (ca. 2,400 mg/m3 for 8 h/d and 5 d/w) in humans, and during 14-day daily exposure of rats of up to 11,000 ppm (26,550 mg/m3). For oral application to rats as a single bolus by gavage, acetone elimination appeared to be saturated when blood levels rise above 300-400 mg/L corresponding to a dose of about 200 mg/kg bw.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Endogenous levels

Acetone appears in the human and mammalian organism as an endogenous product of normal metabolism (Information summarised from review articles (Kalapos, 2003; Morgott, 2001) and experimental studies of human volunteers (e.g.: Jones et al., 1993; Kawai et al., 1992; Owen et al., 1982; Reichard et al. 1979, 1986; Wang et al., 1994) and animals (e.g.: Casazza et al., 1994; López-Soriano and Argilés, 1985).

In healthy human subjects acetone levels in blood covered a range of 0.15-15.4 mg/L with arithmetic means ranging from 0.29 - 1.59 mg/L. Urinary excretion of acetone in normal unexposed subjects was in the range of 0.127-9.350 mg/L with an arithmetic mean of 0.842 mg/L. Acetone levels, found in the body without external exposure, reflect acetoacetate production from the biotransformation of acetyl coenzyme A which is in turn affected by the use of free fatty acids in the liver.

Consequently, altered physiological states or disease states can appreciably increase ketogenesis and the body burden of acetone to several fold the normal level. These physiological states include pregnancy and lactation, perinatal and postnatal development, and conditions of high fat consumption, e.g. during fasting, starvation and physical exertion. Disease states with increased acetone levels are alcoholism, diabetes mellitus, hypoglycemia, eating disorders, prolonged vomiting, acute trauma, and inborn errors of metabolism.

For instance, infants, pregnant women, and exercising humans can have ketone body levels that are elevated 2- to 20-fold above normal due to the ketogenesis from their higher energy requirements. Fasting subjects show blood acetone levels up to ca. 100 mg/L. Patients who have severe diabetic ketoacidosis can have plasma acetone levels as high as 750 mg/L which is more than 300 times the normal limit (Key studies: Owen et al., 1982; Reichard et al. 1979, 1986).

In normal virgin and pregnant (day 20 of gestation) rats average plasma levels of 1.60 mg/L were at a comparable level as in human subjects. In virgin rats, a 48-hr fasting period increased plasma levels about 10-fold, while tissue levels in liver and kidney decreased by about 20 %. In contrast, fasted pregnant rats presented strong increases of levels in plasma (254 mg/L, 160-fold), in liver (ca. 150 µg/g tissue, ca. 10-fold) and in kidney (ca. 160 µg/tissue, ca. 20-fold). Fasting increased plasma levels in fetuses from maternal levels about 200-fold to ca. 320 mg/L and tissue levels (whole fetus) from ca. 4 to 80 µg/g (ca. 20-fold), while the concentration in the placenta increased from 4.6 to 133 µg/g (ca. 30-fold) (López-Soriano and Argilés, 1985). Newborn rats showed an increase of serum levels of at least 20-fold on the first day post partum compared to prebirth levels on gestation day 20. After 10 days, serum levels of the offspring were still at least 2-fold that of their mothers (Casazza et al., 1994). These data indicate, that endogenous production of acetone takes place in the fetus and the newborn rat itself in a considerable amount.


The rates and routes of acetone metabolism are well examined, both in humans and laboratory animals (Argilés, 1996; ATSDR, 1994; Casazza et al., 1984; Kalapos, 2003; Kosugi et al., 1986; Mandl et al., 1995; Morgott, 2001; WHO, 1998). Acetone is a normal product of intermediary metabolism. The metabolic fate of exogenous acetone is independent of the route of uptake and involves three separate gluconeogenic pathways.

The biotransformation of acetone takes place in three consecutive steps:

First step: intrahepatic cytochrome P450IIE1-dependent oxidation (acetone monooxygenase) of acetone to acetol; rate-limiting step controlling the overall accumulation and elimination of acetone from the body

Second step: includes 2 different pathways

(A)  methyl glyoxal pathway: intrahepatic cytochrome P450IIE1-dependent oxidation (acetol monooxygenase)  of acetol to methylglyoxal

(B)  propanediol pathway: extrahepatic reduction of acetolphosphate by propanediolphosphate dehydrogenase to 1,2-propanediol

Third step: both methylglyoxal and propanediol are oxidised to pyruvate which is the basic building block for the biosynthesis of many endogenous biochemicals. For instance, glucose, amino acids, glycogen, fatty acids and cholesterol contain the carbon atoms from orally or intravenously administered acetone.

High dose metabolism

When large doses of acetone are absorbed an alternate metabolic pathway appears with cleavage of 1,2-propanediol to acetate and formate.

Eliminated metabolites

Acetone is eliminated in urine as acetol, methylglyoxal oras D-lactoyl-GSH after conjugation of methylglyoxal with glutathione.

A portion of the carbon atoms of acetone is further found as carbon dioxide in exhaled air being generated from products of intermediary metabolism (see above).

Induction of metabolism

Physiological status (e.g. diabetes, fasting, pregnancy) or genetic status may alter the metabolism of acetone changing the metabolic capacity of certain pathways of biotransformation.

Acetone regulates its own metabolism via induction of cytochrome P450 leading to an increased rate of enzymatic elimination. Thereby acetone also potentiates the toxicity of numerous other chemicals by enhancing the metabolism to reactive intermediates, which depends on cytochrome P-450IIE1.

Acetone treatment induced cytochrome subfamilies P450IA, P450IIIA2, P450IIB, and P450IIE in several tissues of rats, mice, hamsters and rabbits asin liver, kidney, bone marrow, and olfactory mucosa.A cytochrome P450 from human liver and from acetone-treated rats showed high structural similarities (Casazza et al., 1994;Chen and Ueng, 1997; Ding and Coon, 1990;Forkert et al., 1991, 1994;Hong et al., 1987;Johansson et al., 1986, 1988; Koop et al., 1991; Koop and Casazza, 1985;Longo et al., 1993;Menicagli et al., 1990; Patten et al., 1986; Porter et al., 1989; Puccini et al., 1990; Robinson et al., 1989; Ronis and Ingelman-Sundberg, 1989; Ronis et al., 1991, 1998; Schnier et al., 1989; Song et al., 1989; Ueng et al., 1991).Acetone exposure was shown to induce phase-II-metabolism, especially glutathione-S-transferase, UDP-glucuronosyltransferase (UGT) and bilirubin UGT (Braun et al., 1998;Sippel et al., 1991).

Toxicokinetic data from humans

Short-term inhalation experiments (wash-in of 12 breaths, wash-out of 10 breaths) with human volunteers showed that the dissolvation of acetone in the mucous membranes of the airways due to its high water solubility leads to lower alveolar concentrations and deviating excretion behaviour compared to poorly soluble gases. The epithelial tissue lining the conducting airways constitutes a reservoir from which acetone is resumed both by the inspired and the expired air so that systemic uptake and expiration continue even after termination of exposure (Key study: Schrikker et al., 1985). These dissolution and resolution processes determine the time course of uptake and excretion of acetone which has been investigated in detail as the following publications with similar findings show.

Uptake and excretion of acetone was investigated in an experimental set-up with 2-hr exposures to1309 mg/m3 at rest or ca. 725 mg/m3 including a 90-min exercise period. Althoughabsolute uptake increased in a workload-dependent manner, due to increased pulmonary ventilation, the relative uptake accounted to 44 % of the amount administered irrespective of physical activity state. Due to dissolution of acetone in the mucous membranes of the respioratory tract, the acetone concentration in expired alveolar air remained constant at 30-40 % of the concentration in inspired air. The low concentration of acetone in the airstream at the lower respiratory tract supports the release of acetone from the mucous membranes and subsequently the excretion with the expired air. The acetone concentration in blood increased linearly as absolute uptake increased, showing no tendency to equilibrate with the concentration in inspired air.After termination of exposure the half-time of acetone in alveolar air was about 4 hrs, and in venous and arterial blood it was about 6 and 4 hrs, respectively. Elimination via the lungs corresponded to about 20 % of the total uptake, whereas only 1 % was excreted via the urine as unchanged acetone. After 20 hrs, acetone levels in alveolar air, in blood and in urine had dropped to endogenous levels indicating absence of a potential to bioaccumulate(Key study: Wigaeus et al., 1981).

Following 2 to 4 hours of inhalation of 56 - 500 mg acetone/m3 at rest or slight physical exercise, average values were about 53 % for relative uptake and about 0.28 for the ratio of alveolar concentration to inspired concentration.After termination of exposure, elimination decreased rapidly in expired air and urine (decrease by 85 % within 10 min and 20 hrs, respectively) (Key study: Pezzagno, et al., 1986).

Linear relationships between acetone levels in exhaled alveolar air, blood, or urine and environmental concentrations were observed in many studies, both for experimentally exposed subjects and occupationally exposed workers (e.g.:Matsushita, 1969; Pezzagno, et al., 1986; Satoh et al. 1995, 1996). Uptake (including both acetone dissolved in airways and acetone absorbed systemically) increased with increasing intensity of physical activity and of respiratory depth (supporting studies: Jakubowski and Wieczorek, 1988; Teramoto et al., 1987).

Acetone blood levels increased during a 2-hr exposure to 250 ppm (600 mg/m3 with light exercise), with almost no tendency to level off. The calculated steady state level was 1.01 mmol/L (59 mg/L). The net respiratory uptake accounted to 11.0 mmol or 640 mg. The relative uptake was 43 %. A low bioaccumulation potential is indicated from elimination kinetics, as blood acetone appeared to follow a monoexponential decay curve with a half-time of 4.3 hrs reaching background levels of about 2 mg/L within 20 hrs. Urinary excretion was reduced to 10% of the initial post-exposure level. Respiratory excretion accounted to 16.3 % of the net respiratory uptake and cumulative respiratory excretion reached a value of 1.79 mmol (104 mg) (Key study: Ernstgard et al., 1999).

Excretion of acetone vapour was shown to occur also via the skin surface with a dermal excretion rate of 40 µg acetone/min and m2 of skin surface after oral ingestion of 80 mg/kg bw (total dose 5440 mg) by a test person. During 30 to 140 min after oral intake, dermal excretion accounted to 25 % of exhaled acetone (8 and 32 mg) (Supporting study: Parmeggiani and Sassi, 1954).

Investigations in subjects with increased plasma levels of acetone, due to endogenic production during starvation or diabetic ketoacidosis (mean levels of 0.3-5 mM or 17-290 mg/L), demonstrated that the human organism is capable of effective metabolism and excretion also of increased acetone levels (Key studies: Owen et al., 1982; Reichard et al. 1979, 1986). At low plasma concentrations < 2 mM (ca. 160 mg/L), metabolic elimination is the main path for the disappearance of acetone accounting to ca. 70-90 %. In contrast, it decreases linearily to ca. 20 % when plasma concentration rises to 8 mM (ca. 480 mg/L) while excretion of acetone via breath increases simultaneously from ca. 20 to 70 %. Urinary excretion of acetone accounted to ca. 1 to 7 % at plasma levels ranging from 0.3 to ca. 8.5 mM. Marked renal reabsorption or back-diffusion in urinary tract tissues may occur. Metabolic elimination with conversion to endogenous biological compounds is an important disposal mechanism with up to ca. 40% of total plasma14C found in glucose, lipids, and proteins. Besides 1-hydroxyacetone and 1,2-propanediol were detected in plasma. Acetone turnover rates were linear up to plasma concentration of 5 mM (260 mg/L) with a turnover rate of ca. 9 µmol/kg bw/min = ca. 0.52 mg/kg bw/min corresponding to a daily turnover of 750 mg/kg bw/d. Acetone excretion rates at plasma levels of 1.55-8.91 mM accounted to 28 - 239 µmol/1.73 m2/min in breath and 5 - 31 µmol/1.73 m2/min in urine. Elimination via breath, occurred either as unchanged acetone or after oxidation to CO2(1- 21% of an external dose).

Also in cases of severe acetone intoxication, elimination from blood was shown to be high. In a severely intoxicated 30 month-old infant (dose ca. 10 g/kg bw), serum levels declined from initially 4,450 mg/L to 265 and 4 mg/L within 17 and 72 hrs, respectively. The estimated half-life was 19 hrs in the early stage of intoxication and 13 hrs in the later stages (Gamis and Wasserman, 1988).In a 53 -year old female patient with oral intake of at least 150 g acetone,elimination from blood appeared to follow first-order kinetics with a half-life of 31 hrs. The rate of elimination was found to be determined by the respiratory excretion rate (expected half-life of 25 hrs), while metabolic elimination accounted to only ca. 25 % of total elimination and urinary excretion was minimal (Ramu et al., 1978).

Further studies confirm that the bioaccumulation potential of acetone is low.

Several studies with 4-hr exposures of volunteers to up to 990 ppm or 2,350 mg/m3, showed that acetone levels in blood return to background values and urinary excretion is essentially completed within 20 hrs after termination of exposure (supporting studies: Brown et al., 1987; Dick et al., 1989; Seeber et al., 1992; Vangala et al., 1991).During a single 6-hr exposure of volunteers to 0, 100, 250, 500, and 1000 ppm acetone (240, 600, 1,200 and 2,400 mg/m3) blood and urine levels of acetone increased throughout the 6-hr exposure in a dose-dependent manner reaching levels of 6, 20, 48, and 60 mg/L in blood and of 3, 18, 30, and 52 mg/L in urine. At 250, 500, and 1000 ppm acetone, background levels of about 2 mg/L in blood and urine were reached within 24, 32 and 48 hrs after start of exposure (supporting study: Matsushita, 1969).

Effective elimination of acetone was also observed during a 6 day exposure, 6 hrs/day of volunteers to 250 and 500 ppm. At 250 ppm, both blood and urine levels (daily maximum 20 mg/L) returned to background after each daily exposure. At 500 ppm, levels increased due to accumulation during the 6 exposure days (blood 62 mg/L, urine 42 mg/L) but dropped to approximately the background levels (2 mg/L in blood, 0.2 mg/L in urine) within an exposure-free period being comparable to a work-free weekend. Consequently, bioaccumulation is not expected to occur up to 500 ppm during a typical workplace situation with a weekly exposure of 5 days(supporting study: Matsushita, 1969).

Following two previous days without work, acetone concentrations in workplace air, alveolar air, blood and urine were monitored in 110 acetone-exposed workers in acetate fiber plants during two working days with 8-hr exposures each. The mean time-weighted average was 361.4 ppm (872 mg/m3) with a range of ca. 5 - 1,200 ppm (12 - 2,890 mg/m3) for single workers. Ranges of acetone concentrations were 1 – 476 ppm (2.4 - ca. 1,150 mg/m3) in alveolar air, 1 – 225 mg/L in blood, and 0.8 – 212 mg/L in urine, compared to pre-exposure values on the first day of 2.95 ppm (7 mg/m3), 3.8 mg/L and 2.44 mg/L for alveolar air, blood and urine, respectively. The background value in urine of unexposed workers was 1.3 mg/L. Based on data from the individual workers significant correlations were found between acetone exposure levels and acetone levels in exhaled alveolar air, blood and urine. The maximal urine concentration was reached within 8 to 13.5 hrs after start of the 8-hr exposure. Urinary acetone levels did not decline to background levels until start of the next working shift when exposure concentrations exceeded 300 ppm (725 mg/m3). Despite this effect, the urinary acetone level at the end of the second workshift was not substantially affected by the previous days exposure up to ca. 1000 ppm (ca. 2400 mg/m3) indicating a low potential for bioaccumulation (Supporting study: Fujino et al., 1992; Satoh et al., 1995, 1996).

Toxicokinetic data from experimental animal studies

Inhalative exposure

Absolute deposition of acetone in the upper respiratory tract, measured as disappearance of acetone from the airstream, increased significantly with increasing inspiratory flow rate while the deposited fraction decreased simultaneously. Deposition efficiency was independent of inspired acetone concentration over a concentration range of 1,500 - 20,000 mg acetone/m3, however, significant species differences were found (Sprague-Dawley rat > Fischer rat, B6C3F1 mouse > guinea pig, hamster). The existing lack of saturation of deposition efficiency suggests that inspired acetone was not metabolized in nasal tissues in vivo. In vitro acetone was found to be metabolised by nasal tissue homogenates of mice but not of hamsters (Supporting studies: Morris, 1991;Morris and Cavanagh, 1986, 1987; Morris et al., 1986, 1991).

After exposure of mice to 1,200 mg/m3 (14C-labeled acetone tracer) for up to 24 hours, and for 1, 3 or 5 days for 6 hrs/day, 14C-label as unchanged acetone and as total radioactivity (14C-acetone plus metabolites) was determined in blood and tissues, as well as elimination via expiration of 14C-acetone or14CO2for 12 hours (Key study: Wigaeus et al., 1982). In all tissues, unchanged acetone increased during the first 6 hrs and was then fairly constant throughout the 24-hr exposure with highest steady-state levels of ca. 60 µg/g in blood, lung, and kidney. Tissue concentrations of metabolized acetone showed a similar time course except for liver and brown adipose tissue with a steady increase during exposure. After 24 hrs the highest metabolite concentration of 278 µg acetone equivalents/g was found in liver. Unchanged acetone represented the minor part of total radioactivity with ca. 30-35 % in blood, muscle and brain, 25 % in lung, 19 % in kidney and ca. 15 % in liver and adipose tissues, whereas metabolites represented the major part with up to 85 % in liver and adipose tissues. Total 14C-activity as acetone equivalents reached 110-170 µg/g in blood, lung, liver, kidney, brain, and muscle after 3 hrs of exposure and of 190-230 µg/g after 24 hrs (except 120 µg/g in muscle). Intraperitoneal and subcutaneous tissue exhibited the lowest levels of total acetone (75 µg acetone equivalents/g at 24 hrs) throughout the exposure. Other tissues, namely pancreas, spleen, thymus, heart, testis, and vas deferens showed their maximum radioactive label after 6 hrs of exposure (ca. 120 -210 µg acetone equivalents/g tissue). After repeated daily exposures of 6 hrs, most tissues showed no or only a small additional increase of radiolabel on day 3 and 5 compared to day 1 with tissue levels ranging from ca. 140-200 µg total acetone equivalents/g tissue except 120-145 µg/g in muscle: Tissues with continued accumulation of radioactivity were the liver (244 and 215 µg/g on day 3 and 5) and adipose tissues (especially brown adipose tissue up to 4.5-fold) presumably due to high metabolic turnover and the presence of 14C-labeled fragments.

After termination of a 6-hour exposure, fastest elimination occurred in blood, kidneys, lung, brain, and muscles with half-times of about 2-3 hrs. Elimination was slowest from subcutaneous adipose tissue with a half-time slightly longer than 5 hrs. 12 hrs after termination of exposure the liver had the highest14C-activity, 10 times higher the blood concentration. After 24 hrs, unchanged acetone had reached endogenous levels (1.16-5.8 µg/g tissue), whereas radiolabel located in metabolites was still detectable in lung, liver, kidney, brain, and brown adipose tissue in levels ranging from 12-35 µg/g tissue. Expiration as the major route of excretion occurred as unchanged acetone (about 52 % of expired 14C-activity within 6 hrs) and as carbon dioxide (39 % within 6 hrs, 48 % within 12 hrs) accounting to 2,500 µg of 14C-acetone and 2,260 µg of 14CO2 (both as µg acetone equivalents) within 12 hrs post exposure.

These data indicate that acetone is not selectively absorbed in any tissue but is more evenly distributed in the body water. After 3 to 6 hrs of exposure a steady state plateau of tissue concentrations was reached indicating that equilibrium had been obtained with the actual air concentrations. Within 24 hrs after a single 6-hr exposure, all tissue concentrations of acetone had reached the endogenous background level, and after up to 5 repeated exposures total radioactivity increased slightly at most except for tissues with high turnover of 14C-derived metabolites. Consequently, acetone is not likely to accumulate in mice at repeated exposures at 1,200 mg/m3 (ca. 500 ppm) (Key study: Wigaeus et al., 1982).

During a 3-day inhalative exposure (8 hrs/d) of rats to 1,000 pppm or 2,400 mg/m3, daily plasma levels at 30 min post exposure reached values of 107 to 125 mg/L. After the 3-day inhalation period, plasma elimination of acetone was by first order kinetics, with a half-life of 4.5 hrs and an AUC of 960 µg x hr/mL. Tissue concentrations of acetone after 10 daily 3-hr exposures to 2,400 mg/m3 were at 11.4, 13.2 and 21.8 µg/g in lung, liver and kidney, respectively, amounting to 40, 40 and 65 % of the level in plasma (35.3 µg/g) (Supporting study: Scholl and Iba, 1997).

Toxicokinetic investigations with rats with inhalative exposures to initial concentrations of ca. 6,000 - 60,000 ppm (ca. 14,500 - 145,000 mg/m3) in a closed system showed that uptake from the gas phase reached equilibrium after 8 hrs independent of initial concentration. At 60,000 ppm, 90% of the uptake was completed within 2 hrs. Uptake accounted to ca. 12,000 µmol (700 mg) at the end of the equilibration period while the atmospheric concentration had declined to 2,410 ppm (5,800 mg/m3). Acetone is distributed mainly in the aqueous compartment of the body as Ostwald's distribution coefficients Keq of 330, 210 and 220 for urine/air, blood/air and total animal/air indicate. Actual distribution coefficients Kst(based on blood concentrations) decreased from ca. 230 to 170 as the actual concentration in the atmosphere declined from 4,550 to ca. 45 ppm. Exhalation of the compound is strictly monoexponential both after inhalative and oral uptake with a half-life of 2.1 hrs in breath. Consequently, the rat is not expected to accumulate acetone under conditions of intermittent daily exposure (8 hrs/d). The kinetics of metabolic elimination strictly follow Michaelis-Menten kinetics with saturation of metabolism at air concentrations > 20 ppm (ca. 50 mg/m3) (Supporting study: Hallier et al., 1981).

Throughout a 14-day, 6 hrs/d, daily inhalative exposure of non-pregnant and pregnant rats to 440, 2,200 and 11,000 ppm (1,060, 5,310 and 26,550 mg/m3), maximal plasma acetone levels measured at 30 min after termination of daily exposures were constant at ca. 40, 290 and 2000 mg/L throughout the 14-day exposure. Plasma levels of the metabolites acetoacetate and ß-hydroxybutyrate showed a dose- and time-dependent slight increase at 30 min after termination of daily exposures. Within 17 hrs after daily exposures, plasma levels of acetone and its metabolites dropped to control levels (< 1mg/L for acetone) at exposures up to 5,310 mg/m3. Although they were still elevated in the high dose group (174-348 mg/L for acetone), there was no indication of bioaccumulation from daily maximal plasma levels also for the high-dose group of 11,000 ppm (26,550 mg/m3) throughout 14 daily exposures (condition different from workplace exposure). There was no significant difference of plasma levels of acetone or metabolites between pregnant and non-pregnant rats (data only for low-dose group) (Key study: NTP, 1988 - Developmental toxicity study).

Comparison of different exposure modes

Blood half-lifes increased to values of 2.4, 4.9, and 7.2 hr after single oral application (gavage, vehicle water) to rats at doses of ca. 200, 800 and 2,000 mg/kg, respectively. Consequently, acetone elimination appeared to be saturated when the blood levels rise above 300-400 mg/L corresponding to an oral dose of about 200 mg/kg when applied as a single bolus by gavage. Maximal blood levels at a total dose of 1,200 mg/kg bw within 72 hrs were highly dependent on the mode of dosing either as a single bolus (800 mg/L blood) or as repeated gavage doses (145 mg/L blood after 100 mg/kg for 12 times every 6 hrs) (Plaa et al., 1982).Between 3 and 19 hrs after a single bolus application of doses of 20 or 80 mg/kg bw by gavage (vehicle water) to rats, blood acetone concentrations were increased to levels of up to15.26 mg/Lmeasured in rats after fasting for 48 hrs due to endogenous production of acetone (Supporting study: Miller and Yang, 1984). Consequently, comparable plasma levels will be reached at even higher dose levels during continuous oral uptake, e.g from drinking water.

After gavage application to rats, the use of corn oil as vehicle increases gastrointestinal absorption and maximum blood levels compared to water as vehicle, while the time course of elimination from blood was similar. Comparing inhalation exposure with oral uptake by gavage, similar maximum blood levels of about 300 mg/L were reached after 4-hr inhalation of 6,000 mg/m3 and an oral dose of 400 mg/kg bw, and levels of about 700 – 1,000 mg/L after 12,000 mg/m3 by inhalation and 800-1,200 mg/kg bw by gavage (Supporting studies: Charbonneau et al., 1986, 1991).

After a 7-day exposure of rats via drinking water in concentrations ranging from 0.5 to 5.0 % (ca. 50 to 500 mg/kg bw/d), plasma levels of acetone showed a concentration-dependent increase from 0.52 to 15.9 mM (29 to 920 mg/L) (32fold). In contrast, concentrations of the metabolites acetol and 1,2 -propanediol increased only slightly from 0.04 to 0.29 mM (7fold) and from 0.05 to 0.14 mM (3fold) as the dose increased from 100 to 500 mg/kg bw/d, indicating that metabolism is a minor path for elimination of acetone (supporting study: Skutches et al., 1990).

At comparable doses of ca. 400 mg/kg, the extrapolated maximal concentration at time t0corresponded to 146 mg/L after an 8-hr inhalation of 1,000 ppm while it was 332 mg/L after intraperitoneal injection. After a 3-day inhalation of 1,000 pppm or 2,400 mg/m3, plasma elimination of acetone was by first order kinetics, with a half-life of 4.5 hrs and an AUC of 960 µg x hr/mL. Toxicokinetic parameters for i.p. application were characterized by a half-life of 4.1 hrs, an AUC of 1,980 µg x hr/mL, a plasma clearance of 202 mL/hr x kg, and an apparent volume of distribution of 1.2 L/kg. During oral uptake in drinking water for 11 days, plasma concentrations were highly variable ranging from 315 to 1510 mg/L on the first and last day of exposure. On the average, the plasma concentration appeared to plateau after 4 days, around 1,200 mg/L. In summary, there were no indications of bioaccumulation (supporting study: Scholl and Iba, 1997).

Dermal absorption 

In human volunteers acetone (dose not specified) is rapidly absorbed during dermal application with peak blood levels occurring at the termination of each application (no quantitative data on absorption rates) (Weight of evidence: Fukabori et al., 1979).

In an in vitro skin absorption model, the recovery of14C-acetone in pig skin samples accounted to 40 % and 33 % of the applied dose after 2 and 120 min, respectively.14C-acetone was assumed to have penetrated at least to the stratum corneum (Weight of evidence: Williams et al., 1994).