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Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

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Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
single dose followed by 14-day observation period
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted prior to introduction of Good Laboratory Practices; data from a summary report; number of animals similar to that used in current guideline studies; actual test report not available for review but raw data were reviewed for this entry. Study was conducted by an internal Eastman Kodak Company method developed prior to established guidelines. The results of this study are valid for classification insofar as the conditions of exposure are at least as stringent as modern guidelines. Dose range sufficient to determine actual LD50 value for classification purposes.
Qualifier:
no guideline available
Principles of method if other than guideline:
Four groups of four male rats (age and weights not provided) were administered a single dose of the test material at dose levels of 1000, 2000, 4000, or 8000 mg/kg bw by oral gavage and observed for a period of two weeks. The rats were observed for adverse clinical signs and mortality. Body weights were collected prior to dosing and at termination of the observation period. Gross pathology was performed at study termination.
GLP compliance:
no
Test type:
other: Study conducted according to an internal Eastman Kodak Company laboratory method.
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Each animal received a single dose of the test material by oral gavage.
Doses:
1000, 2000, 4000, or 8000 mg/kg bw
No. of animals per sex per dose:
4 males/dose level
Control animals:
no
Details on study design:
Four groups of four male rats (age and weights not provided) were administered a single dose of the test material at dose levels of 1000, 2000, 4000, or 8000 mg/kg bw by oral gavage and observed for a period of two weeks. The rats were observed for adverse clinical signs and mortality. Body weights were collected prior to dosing and at termination of the observation period.
Statistics:
The LD50 estimate was determined by the geometric mean of the top two dose levels.
Sex:
male
Dose descriptor:
LD50
Effect level:
5 657 mg/kg bw
Remarks on result:
other: The two highest dose levels (4000 and 8000 mg/kg bw) used in this study were higher than that used for a limit dose in present-day guideline studies.
Mortality:
No mortality was noted in the 1000, 2000, or 4000 mg/kg bw dose groups. All rats assigned to the 8000 mg/kg bw dose group died within one day of dosing.
Clinical signs:
No abnormal clinical signs were evident in the 1000 and 2000 mg/kg bw dose groups. At the 4000 and/or 8000 mg/kg bw dose levels, clinical signs of toxicity included weakness, ataxia, tremors, and prostration. All rats assigned to the 4000 mg/kg bw dose level recovered and survived to study termination. No other clinical abnormalities were reported during the study.
Body weight:
All surviving rats gained weight during the 14-day observation period.
Gross pathology:
Not reported
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Under conditions used in this study, methyl isoamyl ketone was not acutely toxic by the oral route in male rats. The oral LD50 in male rats was 5657 mg/kg bw.

Based on an acute oral LD50 value between 4000 and 8000 mg/kg bw (geometric mean of 5657 mg/kg bw) in male rats, methyl isoamyl ketone is not classified for acute lethality by the oral route under GHS.
Executive summary:

In an acute oral toxicity study, four groups of four male rats were administered a single dose of methyl isoamyl ketone by gavage at dose levels of 1000, 2000, 4000, or 8000 mg/kg bw and observed for mortality and adverse clinical signs for a period of 14 days. No mortality was noted in the 1000, 2000, or 4000 mg/kg bw dose groups. All rats assigned to the 8000 mg/kg bw dose group died within one day of dosing. No abnormal clinical signs were evident in the 1000 and 2000 mg/kg bw dose groups. At the 4000 and/or 8000 mg/kg bw dose levels, clinical signs of toxicity included weakness, ataxia, tremors, and prostration. All rats assigned to the 4000 mg/kg bw dose level recovered. All surviving rats gained weight during the 14-day observation period. The oral LD50 in male rats administered methyl isoamyl ketone is considered to between 4000 and 8000 mg/kg bw, with a geometric mean of 5657 mg/kg bw. Ingestion of large amounts may cause effects on the central nervous system.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
5 657 mg/kg bw

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6-hour exposure followed by 14-day observation period
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted prior to introduction of Good Laboratory Practices; actual test report not available for review but sufficient data were provided to determine classification. Study was conducted by an internal Eastman Kodak Company method, developed prior to established guidelines. The results of this study are valid for classification insofar as the conditions of exposure are at least as stringent as modern guidelines.
Qualifier:
no guideline available
Principles of method if other than guideline:
Method is an in vivo study using groups of four male rats exposed (whole body) to an atmosphere containing the test material for a period of six hours. After termination of exposure, the animals were observed for mortality and adverse clinical signs for a period of 14 days. Body weights were measured prior to exposure and at termination of the 2-week observation period. No gross pathology was performed at study termination.
GLP compliance:
no
Test type:
other: Study conducted according to an internal Eastman Kodak Company laboratory method using a 6-hour inhalation exposure period.
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
Weight Range at Study Initiation: 181-233 grams
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
Rats were exposed (whole-body) to target vapor concentrations of 800, 1600, 3200, or 6400 ppm of the test material for 6 hours. The test material was vaporized, diluted with ambient (room temperature) air, then directed to a 20-liter glass bell jar for exposure, and monitored by infrared spectroscopy. Actual mean vapor concentrations achieved were 802, 1603, 3207, and 5878 ppm.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Atmosphere concentrations monitored by infrared spectroscopy.
Duration of exposure:
6 h
Concentrations:
Mean vapor concentrations achieved were 802, 1603, 3207, and 5878 ppm.
No. of animals per sex per dose:
4 males/dose concentration
Control animals:
not specified
Details on study design:
Groups of four male rats (strain not available) with a weight range of 181-233 grams were exposed (whole-body) to target vapor concentrations of 800, 1600, 3200, or 6400 ppm of the test material for 6 hours. The test material was vaporized, diluted with ambient (room temperature) air, then directed to a 20-liter glass bell jar for exposure, and monitored by infrared spectroscopy. Actual mean vapor concentrations achieved were 802, 1603, 3207, and 5878 ppm. During and subsequent to exposure, the animals were observed for mortality and adverse clinical signs for a period of 14 days. Body weights were measured prior to exposure and at termination of the 2-week observation period. No gross pathology was performed at study termination.
Sex:
male
Dose descriptor:
LC50
Effect level:
> 3 207 - < 5 875 ppm
95% CL:
> 1 903 - < 3 805
Exp. duration:
6 h
Remarks on result:
other: Based on mortality, the calculated LC50 (6-hr) was approximately 3813 ppm (17806 mg/m3).
Mortality:
All rats in the 5878 ppm concentration group died within 2.5 hours after the start of exposure. One of four rats in the 3207 ppm concentration group died just prior to termination of the 6-hour exposure.
Clinical signs:
other: At the 5878 ppm concentration level, eye irritation and narcosis were observed for all animals prior to death during the exposure period. Within 2 hours of the start of exposure, all animals exposed to a concentration of 3207 ppm displayed signs of eye ir
Body weight:
Although the three surviving rats in the 3207 ppm group lost weight (3-13 grams) between Day 0 and Day 3, subsequent weight gain was normal. All other rats gained weight normally over the 14-day study.
Gross pathology:
Not performed

An LC50 (6-hr) of 3813 ppm is equivalent to an LC50 (4-hr) of approximately 5000 ppm.

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
Under conditions used in this study, methyl isoamyl ketone was lethal by the inhalation route to all male rats exposed to a concentration of 5878 ppm for 2.5 hours. Since only one of four male rats died at a concentration of 3207 ppm, the LC50 (6-hr) in male rats was >3207 ppm but <5878 ppm. The calculated LC50 (6-hr) was approximately 3813 ppm which is equivalent to an LC50 (4-hr) of approximately 5000 ppm.

Based on a calculated inhalation LC50 (6-hr) value of 3813 ppm (equivalent to a 4-hr LC50 of approximately 5000 ppm), methyl isoamyl ketone is classified as Category IV for classification and labeling for acute lethality by the inhalation route under GHS.

Methyl isoamyl ketone currently carries an R20 Risk Phrase (Harmful if Inhaled) under Annex 1 of the European Union Dangerous Substances Directive.
Executive summary:

In an acute inhalation toxicity study, groups of four male rats were exposed (whole body) to methyl isoamyl ketone at vapor concentrations of 802, 1603, 3207, and 5878 ppm for a period of 6 hours. All rats in the 5878 ppm group and one of four rats in the 3207 ppm group died during the exposure period. At the 5878 ppm concentration level, eye irritation and narcosis were noted for all animals prior to death. Within 2 hours of exposure, all animals exposed to a concentration of 3207 ppm displayed signs of eye irritation, unresponsiveness, and impaired gait. By 4-5 hours of exposure, these rats were narcotized with depressed respiration. The three remaining rats at this concentration level recovered fully following cessation of exposure. At the 1603 ppm concentration level, abnormal signs were limited to sluggish responses after 6 hours of exposure. In the 802 ppm group, animals appeared alert during exposure, though immediately after exposure, animals appeared a bit sluggish. Although the three surviving rats in the 3207 ppm group lost weight (3-13 grams) between Day 0 and Day 3, subsequent weight gain was normal. All other rats gained weight normally over the 14-day study. The LC50 was calculated to be 3813 ppm for a 6-hour exposure. Methyl isoamyl ketone was toxic to rats at high airborne concentrations and caused reversible effects on the central nervous system.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
17 806 mg/m³

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24-hour application followed by 14-day observation period
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted prior to the introduction of Good Laboratory Practices; data from a summary report; limited number of animals; actual test report not available for review. Study was conducted by an internal Eastman Kodak Company method, developed prior to established guidelines. The results of this study are valid for classification insofar as the conditions of exposure (24 hours under an occlusive wrap) are at least as stringent as modern guidelines.
Qualifier:
no guideline available
Principles of method if other than guideline:
Method is an in vivo study using two guinea pigs. A single dose of 5 or 10 mL/kg bw of test material was held in contact with the depilated abdomens of the animals under an occlusive cuff for 24 hours. After termination of exposure, animals were observed for mortality, dermal reactions and weight changes for a total of 14 days.
GLP compliance:
no
Test type:
other: Study conducted according to an internal Eastman Kodak Company laboratory method.
Limit test:
no
Species:
guinea pig
Strain:
Hartley
Sex:
not specified
Details on test animals and environmental conditions:
no data
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Following depilation of the abdomen of each animal, a single dose of 5 or 10 mL/kg bw of the undiluted test material was applied under an occlusive wrap prepared from a pad of gauze held in place with an impervious cuff made of rubber dental dam. The cuff was wrapped securely around the torso and held in place using non-irritating tape. After an exposure period of 24 hours, the cuffs and wrappings were removed.
Duration of exposure:
24 hours
Doses:
One animal each was exposed to a single application of 5 or 10 mL/kg bw of the undiluted test material.
No. of animals per sex per dose:
1 animal/dose (sex not determined)
Control animals:
no
Details on study design:
Two guinea pigs (sex, age, and initial weights not provided) were used. Following depilation of the guinea pig abdomens, a single application of either 5 or 10 mL/kg bw of the undiluted test material was applied under an occlusive wrap prepared from a pad of gauze held in place with an impervious cuff made of rubber dental dam material. The cuff was wrapped securely around the torso of the guinea pig and held in place with non-irritating tape. Animals were exposed for 24 hours, and then the cuffs were removed. Animals were observed following removal of the cuff, and on Days 7 and 14. In addition to observations for mortality, dermal reactions were also noted. Guinea pigs were weighed prior to administration of the test substance and at termination of the 14-day observation period.

Based on the specific gravity of methyl isoamyl ketone (0.814), the administered doses in this study were approximately 4 and 8 g/kg bw.
Statistics:
no data
Sex:
not specified
Dose descriptor:
LDLo
Effect level:
> 10 mL/kg bw
Mortality:
None
Clinical signs:
No signs of test material absorption or systemic toxicity were noted during the study. Signs of irritation at the application site were limited to slight erythema after termination of exposure. No signs of edema were evident during the study.
Body weight:
Although one animal lost weight, the remaining animal gained weight over the 14-day observation period.
Gross pathology:
Not performed
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Methyl isoamyl ketone was not acutely toxic by the dermal route in guinea pigs under conditions used in this study. The dermal LDLo in guinea pigs for the undiluted substance was > 10 mL/kg bw, equivalent to approximately 8 g/kg bw.

Based on an acute dermal LDLo value of > 10 mL/kg bw in guinea pigs, methyl isoamyl ketone is not expected to be classified for Acute Toxicity by the dermal route under GHS. However, insufficient data were available in this study to provide a definitive value for dermal LD50. In the absence of signs of systemic toxicity and/or skin absorption, methyl isoamyl ketone is not classified under GHS for Specific Target Organ Toxicity – Single Exposure. Based on minimal signs of irritation after an extreme exposure period of 24 hours under an occlusive wrap to depilated abdominal skin of guinea pigs, methyl isoamyl ketone is not classifiable for Skin Irritation/Corrosion according to GHS.
Executive summary:

In an acute dermal toxicity study, two Hartley guinea pigs were exposed to either 5 or 10 mL/kg bw of undiluted methyl isoamyl ketone under occlusive contact for 24 hours. Under the conditions of this study, no deaths occurred and the dermal LDLo was considered to be > 10 mL/kg bw. No signs of skin absorption or systemic toxicity were evident during the study. At the application sites, signs of skin irritation were limited to slight erythema after termination of exposure. One animal lost weight and one animal gained weight over the 2-week observation period. Based on the results of this study, methyl isoamyl ketone presents a low toxicity hazard upon skin contact under conditions of normal use.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
16 000 mg/kg bw

Additional information

Acute Oral Toxicity

The acute oral toxicity of methyl isoamyl ketone is well understood. Although no acute oral toxicity studies conducted according to present-day guidelines were identified, seven lesser non-guideline studies in rats (4) and mice (3) showed similar results for the calculated oral LD50 values and clinical signs observed. In six of the studies, animals were administered a single dose of undiluted test material and observed for two weeks. All animals receiving ≥ 6400 mg/kg bw of the test material died on the day of dosing. For a total of 14 animals receiving 3200 mg/kg bw, 1/7 rats died within 1 day of dosing while all 7 mice survived. The LD50s in these studies were reported as 3200, >3200 or >3200 but <6400 mg/kg bw. An additional study conducted with four groups of four rats used dose levels of 1000, 2000, 4000 and 8000 mg/kg bw. All 4000 mg/kg bw animals survived while all 8000 mg/kg bw animals died within 1 day of dosing. The LD50 for this group of animals was 5657 mg/kg bw. In all seven studies, clinical signs indicating reversible effects on the central nervous system included one or more of the following: weakness, ataxia, rough hair coats, excitement, vasodilatation, slight tremors, restlessness, and prostration. All surviving animals gained weight normally. Based on these seven studies, methyl isoamyl ketone is considered to be a low acute toxicity hazard following ingestion.

Acute Dermal Toxicity

The acute dermal toxicity of methyl isoamyl ketone is well understood. Although an acute dermal toxicity study conducted according to OECD Guideline 402 was not identified, two non-guideline studies were available for review. In these studies, doses of 5, 10 or 20 mL/kg bw (equivalent to 4, 8 and 16 g/kg bw) methyl isoamyl ketone were applied to the depilated abdomens of guinea pigs under occluded contact for 24-hours. There were no deaths observed in these studies. Except for weight loss at the two higher dose levels, there were no clinical signs indicating absorption or systemic toxicity. While a definitive dermal LD50 was not identified, the dermal LD50 is considered to be > 20 mL/kg bw (16 g/kg bw). Based on the results of these studies, methyl isoamyl ketone presents a low toxicity hazard for skin contact.

Acute Inhalation Toxicity

The acute inhalation toxicity of methyl isoamyl ketone is well understood. Although a study conducted according to OECD Guideline 403 was not identified, one non-guideline key study and 4 non-guideline lesser studies were available for review. In the key study, groups of 4 male rats were exposed via whole body inhalation to target concentrations of 800, 1600, 3200 or 6400 ppm methyl isoamyl ketone (actual achieved concentrations were 802, 1603, 3207 and 5878 ppm) for 6 hours. All rats at the highest exposure concentration died within 2.5 hours of the start of exposure. One of four rats at the 3207 ppm concentration died just prior to termination of exposure. The calculated LC50(6-hr) of 3813 ppm is equivalent to an LC50(4-hr) of approximately 5000 ppm. At the highest concentration tested, eye irritation and narcosis were observed in all animals prior to death. Reversible central nervous system effects were also observed in survivors at all exposure concentrations. Although surviving rats in the 3207 ppm group lost weight over the first 3 days, subsequent weight gain was normal and all other rats gained weight normally over the 14-day observation period. These data are supported by four lesser studies in which groups of 3 rats were exposed via whole body inhalation to 3.88 mg/L (948 ppm), 21 mg/L (4000 ppm), 29 mg/L (5500 ppm), or 31.57 mg/L (7718 ppm) for 6 or 7 hours. At 7718 ppm, all animals exhibited signs of central nervous system depression and died shortly after hour 4 of exposure. All animals survived exposure at 5500 ppm for 7 hours but exhibited central nervous system effects including loss of coordination, prostration, and labored breathing. One of three animals exposed to 4000 ppm died at 5 hours into the 6-hr exposure period. Reversible central nervous system effects were observed in survivors. No deaths or clinical signs were observed in the 948 ppm exposure group. Based on these data, methyl isoamyl ketone is considered to be harmful by the inhalation route. 

Justification for classification or non-classification

Based on a weight-of-the-evidence assessment, methyl isoamyl ketone is not classified for acute lethality by the oral or dermal routes according to GHS guidelines. Based on an estimated acute inhalation LC50(4-hr) of approximately 5000 ppm, methyl isoamyl ketone is classified as Category IV for acute lethality according to GHS guidelines. 

Methyl isoamyl ketone currently carries an R20 Risk Phrase (Harmful if Inhaled) under Annex 1 of the European Union Dangerous Substances Directive.