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Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4 787 mg/m³
Study duration:
chronic
Species:
monkey

Additional information

The potential for methyl n-amyl ketone to cause target organ toxicity following repeated exposure was evaluated based on several key studies conducted by methods that predate Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. In a key subchronic study, the NOEL was 20 mg/kg bw/day for both sexes when the test material was administered by oral gavage to groups of male and female rats at dose levels of 20, 100 or 500 mg/kg bw daily for 13 weeks. There were no statistically significant dose-related effects on mortality, appearance, behavior, body weight gains, food and water consumption, hematology, serum chemistries, urinary concentration and dilutions tests, or gross pathology or histopathology at any dose level tested. Although absolute and relative liver weights were increased in both sexes in the high-dose group, there were no corresponding changes in clinical chemistry parameters at any time period or gross or microscopic changes at necropsy indicative of a significant target organ effect. Increases in kidney weight were observed in male rats only. While an increase in the excretion of cells in the urine was observed in high-dose group males and females at 13 weeks and high-dose group males at 6 weeks, tests for glucose, bile salts and blood in the urine were negative for all time periods, function in concentrations tests was unimpaired, and there were no significant effects observed in kidney tissue upon microscopic examination. Tubular dilation and atrophy in the kidneys of high-dose group animals were similar in incidence and severity to that observed in control animals. The NOAEL for target organ damage when methyl n-amyl ketone was administered to rats by oral gavage for 13 weeks is considered to be 500 mg/kg bw/day based on an absence of significant functional changes in any organ system.

  

In a key chronic inhalation study when groups of 50 male rats and 8 male monkeys were exposed to 0, 131 or 1025 ppm methyl n-amyl ketone 6 hours/day, 5 days/week for 10 months, there were no statistically significant concentration-dependent effects on mortality, clinical signs or body weight gains. No gross or microscopic changes were reported in the organs and tissues examined at necropsy. Specialized studies conducted within the chronic studies showed that in rats, long term inhalation of methyl n-amyl ketone did not induce liver microsomal enzymes and that prior exposure to unlabeled methyl n-amyl ketone by the inhalation route for a period of 6 months did not affect the pattern of tissue distribution when rats were subsequently exposed to radiolabeled methyl n-amyl ketone by inhalation for a period of 6 hours. Clinical chemistry profiles examined in monkeys showed no dose-dependent significant differences from controls. There were also no adverse effects in monkeys on any parameters examined in pulmonary function testing or electrocardiographic examinations that could be attributed to methyl n-amyl ketone following six months of exposure. In supporting repeat inhalation exposure studies in which groups of 10 rats and 8 monkeys were exposed to 0, 131 or 1025 ppm methyl n-amyl ketone 6 hr/day, 5 days/week for 9 months, there were no statistically significant dose-dependent effects on mortality, clinical signs or body weights and no gross or microscopic changes were observed in organs and tissues examined at necropsy. Monthly neurological examination of maximum motor-nerve conduction velocity of the sciatic-tibial and ulnar nerves and amplitude of evoked muscle action potential of those two nerves showed no significant differences between exposure groups and controls for either species. In addition, visually evoked potentials and electroencephalograms in monkeys were similar to controls at each examination period.

 

Justification for classification or non-classification

There were no treatment-related deaths; no significant functional changes in any organ system; no significant effects on hematology or clinical chemistry parameters; and no significant gross or histopathological organ damage in male and female rats exposed to 500 mg/kg bw/day methyl n-amyl ketone by oral gavage for 13 weeks or in male rats and monkeys exposed by whole body inhalation to 1025 ppm methyl n-amyl ketone 6 hr/day, 5 days/week for up to 10 months. Methyl n-amyl ketone is not classified for Target Organ Toxicity according to Annex I of Directive 67/548/EEC. Based on the results of a 13-week oral gavage study in rats, 10-month inhalation studies in rats and monkeys, and 9-month neurotoxicity studies in rats and monkeys, methyl n-amyl ketone is not classified for Specific Target Organ Toxicity – Repeated Exposure 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).