3-methylbutanone

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

3 078 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

22 464 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

16 000 mg/kg bw

Additional information

Acute Oral Toxicity

  

The acute oral toxicity of methyl isopropyl ketone is well understood. A well-conducted key study in rats and three supporting studies in rats and mice were identified. All three studies were conducted according to OECD guideline/GLP or generally accepted standards of the time. In the key study in which groups of five rats of each sex received up to 5000 mg/kg bw methyl isopropyl ketone by oral gavage, the calculated oral LD50 was 3078 mg/kg bw. A similar LD50 value (~2600 - 3200 mg/kg bw) was observed in the supporting studies. All rats and mice dying prior to study termination died within 3 days of dose administration. In all four studies, clinical signs indicating reversible effects on the central nervous system (CNS) included ataxia and slight to moderate weakness. More severe signs of CNS depression, such as severe weakness and prostration, were observed at the highest dose groups in which animals died.

  

Based on a weight-of-the-evidence evaluation, the oral LD50 for methyl isopropyl ketone is estimated to be about 3100 mg/kg bw. Based on clinical signs indicating a dose-dependent increase in severity of CNS effects with increasing dose levels and the absence of significant gross or microscopic findings in animals administered up to 5000 mg/kg bw of test material, the CNS effects reported in all three studies were the likely cause of lethality.

 

  

Acute Dermal Toxicity

  

The acute dermal toxicity of methyl isopropyl ketone is well understood. Two acute dermal toxicity studies were identified for review. In the key acute dermal toxicity study conducted according to a method similar to OECD Guideline 402, a single limit dose of 20 mL/kg of methyl isopropyl ketone was administered to the clipped backs of 5 rats/sex under an occlusive cuff for 24 hours. This dose was equivalent to approximately 16 g/kg bw, significantly higher than the limit dose described in the regulatory guidelines. A single female died within four hours of dose administration. No cause of death was determined. Two to five hours after initial application, moderate weakness was observed in all animals, implying percutaneous absorption of the test substance. No other clinical observations were noted. All animals gained weight normally and no treatment-related changes were noted at necropsy in animals that survived to study termination. The only findings in the single female that died were moderate necrosis of the skin of the back and red discoloration of the inguinal hair. In a supporting non-guideline study in which guinea pigs were also administered up to 20 mL/kg bw of the test material under occluded contact for 24 hours, no deaths were observed. No signs of test material absorption or systemic toxicity were noted at any time during the study. Based on a weight-of-the-evidence evaluation, the dermal LD50 is considered to be > 20 mL/kg bw (>16 g/kg bw). Methyl isopropyl ketone is demonstrated to be a low order of acute toxicity following dermal contact.

  

Acute Inhalation Toxicity

  

The acute inhalation toxicity of methyl isopropyl ketone is well understood. In the key study, an acute inhalation study conducted according to OECD Guideline 403, nine of ten animals exposed to 9000 ppm of methyl isopropyl ketone for 6 hours died within 24 hours of exposure. In addition, 1 of 5 males and 2 of 5 females in the 6000 ppm exposure group died within 2 days of exposure. During exposure, all males and females exposed to methyl isopropyl ketone exhibited severe central nervous system depression and excessive lacrimation. Most clinical signs in animals that survived were seen either during or just after exposure but resolved within 48-72 hours. There was no adverse effect on terminal body weight and no organ damage sufficient to cause death was seen in rats dying prior to study termination. No test substance-related changes were observed during gross or microscopic examination in animals dying early or surviving to study termination. Under the conditions of this study, the LC50 was 6377 ppm/6 hours in male and female rats and methyl isopropyl ketone was considered to be harmful by the inhalation route.

 

Justification for classification or non-classification

Methyl isopropyl ketone is not classified for acute lethality by the oral or dermal routes of exposure. Based on an oral LD50 value of approximately 3100 mg/kg bw in acute studies in rats and mice, methyl isopropyl ketone would be classified as Category V for acute lethality according to the UN Globally Harmonized System of Classification and Labelling (GHS). However, there is no Category V in EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Therefore, methyl isopropyl ketone is not classified for acute lethality by the oral or dermal routes according to EU CLP GHS. Applying Haber’s Law to express the 6-hr LC50 value of 6377 ppm in terms of a 4-hour exposure, the LC50/4-hr would fall in the classification range 2500-20000 ppm. Therefore, methyl isopropyl ketone is classifiable as Category IV for classification and labeling for “Acute Toxicity” by the inhalation route under the UN GHS regulations and CLP Regulation (EC) No. 1272/2008. 

 

 

Methyl isopropyl ketone belongs to a class of chemicals associated with the potential for human aspiration hazard, i.e., ketones with a composition of no more than 13 carbon atoms. In addition, it has a predicted surface tension of 21.4 dyne/cm, a low water solubility, and a boiling point of 94 °C. Although a kinematic viscosity was not identified, methyl isopropyl ketone would seem to meet the criteria for a Category 2 Aspiration Hazard according to the guidelines outlined in UN GHS guidelines. While an evaluation for aspiration hazard is included, there is no Category 2 in CLP Regulation (EC) No. 1272/2008. Therefore, methyl isopropyl ketone is not classified as an aspiration hazard according to EU CLP GHS.