Acetone

Endpoint summary

Description of key information

13 week oral drinking water, rat male : LOAEL 20,000 ppm corresponding to a dose of 1,700 mg/kg bw/d 
                                                                   (target organs: testis, kidneys, and hematopoetic system); 
                                                                   NOAEL  10,000 ppm or 900 mg/kg bw/d
                                             rat, female:  NOAEL 50,000 ppm or 3,100 mg/kg bw/d                          
                                          mouse, male:  NOAEL 20,000 ppm or 4,858 mg/kg bw/d 
                                       mouse, female:  LOAEL 50,000 ppm or 11,298 mg/kg bw/d (target organ: liver)
                                                                   NOAEL 20,000 ppm or 5,945 mg/kg bw/d                                  
8-week inhalation, 5 d/wk, 3 hr/d, rat: 3-hr NOAEC 19,000 ppm acetone (45,000 mg/m3), 
                                                                    extrapolated to 6-hr NOAEC 9,500 ppm (22,500 mg/m3)     

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

900 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

22 500 mg/m³

Additional information

Oral toxicity

The assessment of repeated dose oral toxicity of acetone is possible based on a key study (Dietz et al., 1991; NTP, 1991):

In a 13-week drinking water study, groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were exposed to acetone. Concentrations were 2,500, 5,000, 10,000, 20,000, and 50,000 ppm for rats and female mice, and 1,250, 2,500, 5,000, 10,000, and 20,000 ppm for male mice. The test protocol was similar to OECD Guideline 408, without investigation of biochemical parameters and without functional observations, but with additional investigation of sperm parameters and vaginal cytology.

In rats, at 50,000 ppm final mean body weight gains of males and females were 27.5 % and 13.5 % lower than controls. Reduced water consumption in 50,000 ppm males and 20,000 and 50,000 ppm females resulted in effective dosages of 200, 400, 900, 1,700, 3,400 mg/kg bw/d in male rats and of 300, 600, 1,200, 1,600, 3,100 mg/kg bw/d in female rats.

Increased relative organ weights of liver and kidney at 20,000 ppm, and of lung and testis at 50,000 ppm were associated with decreases of terminal body weights. Correlating histopathological changes were only found in the kidneys of male rats showing increased incidence and severity of nephropathy at >= 20,000 ppm considered to be the most prominent chemically related finding. Increased liver weights may be associated with the ability of acetone to induce hepatic microsomal cytochrome P450. At 50,000 ppm a mild toxic effect on spermatogenesis was indicated by significant depressions of sperm motility, cauda epidydimal weight, and epididymal weight and a significantly increased incidence of abnormal sperm together with a 5 % decrease of absolute testis weight. Overall, changes of haematological parameters were small and partly without dose-relationship. Only in male rats, haematological changes indicated a mild macrocytic normochromic anemia with a depressed regenerative response (depression of reticulocytes) with an overall LOAEL of 20,000 ppm for mild leukocytosis and depression of erythrocytes. This finding was consistent with hemosiderosis in spleen.

For male rats the minimal toxic concentration (LOAEL) was 20,000 ppm corresponding to a dose of 1,700 mg/kg bw/d, and the NOAEL was 10,000 ppm or 900 mg/kg bw/d with the testis, kidneys, and hematopoetic system as target organs. No relevant toxicological findings were observed in female rats up to the highest dose leading to a NOAEL of 50,000 ppm or 3,100 mg/kg bw/d.

For male mice dosages were 380, 611, 1,353, 2,258, and 4,858 mg/kg bw/d, and for female mice dosages were 892, 2,007, 4,156, 5,945, and 11,298 mg/kg bw/d. Final mean body weights were similar to that of controls. Haematological analyses did not show any biologically significant effects. There were no changes of reproductive parameters.

In male mice no effects were observed up to the high dose group (20,000 ppm).

In high-dose females (50,000 ppm), water consumption was notably lower. A significant increase of absolute and relative liver weight was associated with centrilobular hepatocellular hypertrophy of minimal severity in 2/10 females. These liver changes are probably related to the ability of acetone to induce hepatic cytochrome P450. The absolute spleen weight and the spleen weight to body weight ratios were significantly decreased.

For female mice, the minimal toxic dose (LOAEL) was the highest tested dose of 50,000 ppm or 11,298 mg/kg bw/d with the liver as the target organ, the NOAEL was 20,000 ppm or 5,945 mg/kg bw/d. No toxicologically relevant effect or compound-related lesions were found in male mice up to 20,000 ppm with a NOAEL of 4,858 mg/kg bw/d.

In the preceeding 14-day range finding toxicity study, the liver was also identified as the target organ in mice. Liver weights were increased weights at >= 5,000 ppm (965 mg/kg bw/d) in males and >= 20,000 ppm (5,481 mg/kg bw/d) in females and centrilobular hepatocellular hypertrophy was found at >=20,000 ppm in males and at >=50,000 ppm in females. As these liver changes did not persist in the 13 -week study, a possible development of tolerance to acetone-induced liver effects is indicated (Supporting information: Dietz et al., 1991; NTP, 1991).

Dermal toxicity

Acetone has been applied as solvent in several dermal carcinogenicity studies with different strains of mice. Consequently, there is experience with up to lifetime dermal exposure to low doses of acetone with test volumes of 0.025 to 0.2 ml corresponding to doses of ca. 20 to 160 mg acetone/mouse with 2 or 3 treatments per week for up to lifetime (up to 573 days). In these studies no noticeable effects on survival or incidence of skin neoplasms was described for the acetone-treated solvent control groups.No other endpoints were examined. Principally, these data point in the direction that the low acute dermal toxicity of acetone would be confirmed upon chronic administration. Additionally, due to the volatility of acetone, standard conditions of dermal application will result in considerable evaporation from the skin surface so that the effective dose for dermal uptake will be reduced. Consequently, a dermal repeated dose toxicity study does not seem to be scientifically justified.

Inhalation toxicity

There is no standard inhalation repeated dose toxicity study available. The only existing study with a limited number of endpoints examined and with a single test concentration can be used for a weight of evidence approach together with information from other routes (see above):

Groups of male rats (N=9) were exposed to a single concentration of 19,000 ppm acetone (45,000 mg/m³) for 2,4 or 8 weeks, 5 days/week and 3 hours/daily. Under the conditions of this exposure there were no indications of an adverse toxic effect from the investigated endpoints being body weight gain, organ weights (liver, kidney, brain, lung; N=5), histopathology of liver, kidney, brain, lung, and heart (N=4) and serum clinical chemistry parameters (SGOT, LDH and BUN; N=5). Slight significant decreases of weights of brain (at 4 and 8 w of exposure) and of kidney (only at 4 w of exposure) correlated with a depression of body weight gain (not significant) and were without a histological correlate. Based on the investigated endpoints the NOAEC is 19,000 ppm acetone or 45,000 mg/m³ and no specific organ toxicity was indicated (Bruckner and Peterson, 1981).

Based on the daily exposure time of 3 hrs the following extrapolation to an exposure time of 6 hrs, as demanded in EC regulation 1272/2008 can be made. The dose resulting from a 3-hr exposure to 19,000 ppm would be equivalent to the dose resulting from a 6-hr exposure to 9,500 ppm or 22,500 mg/m³. This concentration is distinctly higher than the limit of 1,000 mg/m³ which would result in classification for specific organ toxicity.

Justification for classification or non-classification

Oral toxicity: no classification as LOAEL of 1,700 mg/kg bw/d for 90 day exposure of rats is distinctly higher than the limit of 100 mg/kg bw/d according to EC regulation 1272/2008

Inhalation toxicity: no classification as NOAEC of 22,500 mg/m³ for 8 week exposure is distinctly higher than the limit of 1,000 mg/m³ according to EC regulation 1272/2008