Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
Value:
1 500 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
Value:
17 600 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute Oral Toxicity

 

The acute oral toxicity of methyl n-amyl ketone was evaluated in one key and one supporting study conducted by methods that predate Good Laboratory Practices and regulatory guidelines but were conducted according to acceptable scientific methodology in effect at the time of the study. In the key study, five groups of two rats/group received a single dose of approximately 200, 400, 800, 1600 or 3200 mg/kg bw of the undiluted test material administered by oral gavage. Both animals in the high-dose group and one of two animals in the 1600 mg/kg bw dose group died 5 hours to 1 day after dose administration. Abnormal clinical signs indicating adverse effects on the central nervous system included weakness, vasodilatation, ataxia, prostration and labored respiration. Labored respiration occurred at doses of 800 mg/kg bw and above. All survivors gained weight over the 14-day observation period and no gross pathological changes were found at necropsy. The oral LD50 was approximately 1600 mg/kg bw in the key study. In the supporting study, three groups of two mice/group received a single dose of approximately 400, 800 or 1600 mg/kg bw of the undiluted test material by oral gavage. All animals survived to study termination. Weakness was reported across all dose groups and all animals gained weight. The oral LD50 was > 1600 mg/kg bw in mice administered a single dose of methyl n-amyl ketone.

 

Acute Dermal Toxicity

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following:

•OECD Guidelines for the Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987)

•Method 83 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008

A group of ten animals (five males and five females) was given a single, 24-hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight evelopment were monitored during the study. All animals were subjected to gross necropsy. There were no deaths. Staining aroung the snout was noted in three males and two females two and four hours after dosing. No other signs of systemic toxicity were noted. Small superficial scattered scabs were noted at the test sites of two females. There were no other signs of dermal irritation noted. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

 

In a second supporting study, the acute dermal toxicity of methyl n-amyl ketone was evaluated in a key study conducted by a method that predates Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. In this study, a single dose of 5, 10 or 20 mL/kg bw of the undiluted liquid was held in contact with the depilated abdomens of guinea pigs under occluded contact for 24 hours. No animals died and the dermal LD50 of methyl n-amyl ketone was considered to be > 20 mL/kg bw (equivalent to > 16 g/kg bw based on a density of 0.81 g/cm^3). No clinical signs suggestive of dermal absorption or systemic toxicity were observed during the study and all animals gained weight over the 14-day observation period. Signs of irritation were evident at the application site. Edema and up to Grade 3 erythema were present following 24-hour application, with scattered eschars observed at the 1 week observation, and eschars with scarring and sparse hair present at the final observation.

 

Acute Inhalation Toxicity

A study was performed to assess the acute inhalation toxicity of the test item. The method used was compatible with that described in the OECD Guidelines for Testing of Chemicals (2009) No. 403 "Acute Inhalation Toxicity" and was designed to be compatible with Method 82 (Inhalation) of Commission Regulation (EC) No. 440/2008. A group of ten Hsd:Han(TM) : WIST strain rats (five males and five females) was exposed to a vapour atmosphere. The animals were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean maximum attainable atmosphere concentration was 17.6 mg/l. 1/5 Male and 2/5 female rats died during the exposure. Common abnormalities noted during the study included decreased respiratory rate, increased respiratory rate, laboured respiration, prostration, hunched posture, pilo-erection and wet fur. Surviving animals recovered to appear normal from Days 5 to 6 post-exposure. All surviving animals exhibited a slight bodyweight loss or exhibited no bodyweight gain on Day 1 post-exposure, no bodyweight gain was noted for a female animal during Days 1 to 3, this animal also hadn't shown a bodyweight gain on Day 1. Bodyweight gains were noted for all other animals during the remainder of the recovery period. With the exception of one instance of dark patches on the lungs, no macroscopic abnormalities were detected amongst animals at necropsy that survived until Day 14. The following macroscopic abnormalities were detected amongst animals at necropsy that died during the course of the study: Lungs - haemorrhagic or abnormally dark; Liver - patchy pallor. It is considered that due to the observations noted in surviving animals on removal from the exposure chamber that the deaths noted may have been attributable to systemic toxicity. Three deaths occurred in a group of ten rats exposed to a mean maximum attainable atmosphere concentration of 16.7 mg/L for four hours. It was therefor considered that the acute inhalation median lethal concentration (4 hr LC 50) of Methyl n­ Amyl Ketone, in the HsdHan ™ : WIST strain rat, was greater than 16.7 mg/L.

 

A second supporting study is available using methods that predate Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. Five groups of three rats/group were exposed (whole-body) to an atmosphere containing 3.88, 6.7, 9.4, 19.4 or 23.9 mg/L of the test substance for up to six hours. All animals in the two highest exposure groups died during exposure or within 1 hour of exposure termination. No mortality was observed in the lowest three exposure groups and all surviving animals gained weight over the observation period, although those in the higher exposure groups gained less weight on average. Treatment-related clinical signs noted shortly after the start of exposure and in surviving animals in one or more exposure groups included piloerection, vasodilatation with pink extremities, hyperpnea, lassitude, ataxia, and/or prostration. The acute inhalation 6-hr LC50 was considered to be > 9.4 but < 19.4 mg/L.  

 

Justification for classification or non-classification

Methyl n-amyl ketone is currently classified for acute lethality by the oral and inhalation routes according to Annex I of Directive 67/548/EEC which requires the risk phrases R22 "Harmful if swallowed" and R20 "Harmful by inhalation". Based on an acute oral LD50 of approximately 1600 mg/kg bw for rats in the key study and an acute inhalation 6-hr LC50 between 9.4 and 19.4 mg/L for rats, methyl n-amyl ketone would be classified as Category IV for acute lethality by the oral and inhalation routes of exposure according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. A harmonized classification exists in that regulation for methyl n-amyl ketone and the designations Acute Toxicity, Category IV, H-302 “Harmful if swallowed” and H-332 “Harmful if inhaled” appear in Table 3.1 of Annex VI of CLP. In addition, methyl n-amyl ketone meets the criteria for Acute Toxicity Category IV for oral and inhalation routes according to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Methyl n-amyl ketone is not currently classified for acute lethality by the dermal route according to Annex I of Directive 67/548/EEC.  Based on an acute dermal LD50 of > 20.0 mL/kg bw (> 16 g/kg bw) for guinea pigs, methyl n-amyl ketone is not classified for acute lethality by the dermal route of exposure according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

 

 

Methyl n-amyl ketone is not classified as an aspiration hazard according to Annex I of Directive 67/548/EEC. Methyl n-amyl ketone does not meet the criteria for a Category I Aspiration Hazard according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS), i.e., (a) a chemical known to be a human aspiration hazard, or (b) a hydrocarbon with a kinematic viscosity of 20.5 mm2/s measured at 40 ºC. Since there is no other classification for aspiration hazard in the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, methyl n-amyl ketone is not classified for aspiration according to that regulation. The UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) contains a second category for aspiration hazard which takes into account various physical properties including viscosity and surface tension. Methyl n-amyl ketone has a surface tension of 26.1 dynes/cm and a viscosity of 0.71 cP (equivalent to about 22 SUS). In a publication by Panson and Winek (1980) that investigated the potential aspiration hazard of ketones, the authors found that the surface tension in ketones that caused aspiration toxicity in rats was in the range 23-27 dynes/cm at 24 ºC and the viscosity was less than 32 SUS. In addition, some authorities include ketones containing no more than 13 carbon atoms for inclusion as aspiration hazards. Methyl n-amyl ketone contains 7 carbon atoms. Based on all available information, methyl n-amyl ketone should be considered a Category 2 Aspiration Hazard according to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

 

Reference:

Panson RD and Winek CL, 1980. Aspiration toxicity of ketones. Clinical Toxicology, 17:271-317.