5-methylhexan-2-one

Acute Toxicity: inhalation

Administrative data

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.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting 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. Gross pathology performed at study termination.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Five groups of four male mice each were administered a single dose of the test material at dose levels of 200, 400, 800, 1600, or 3200 mg/kg bw by oral gavage and observed for a period of two weeks. Clinical observations and mortality were noted during the study. Body weights were recorded prior to dosing and at termination of the observation period.

GLP compliance:

no

Test type:

other: Study conducted according to an internal Eastman Kodak Company laboratory method.

Limit test:

no

Species:

mouse

Strain:

not specified

Sex:

male

Details on test animals or test system 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:

200, 400, 800, 1600, or 3200 mg/kg bw

No. of animals per sex per dose:

4 male animals/dose

Control animals:

no

Details on study design:

Four male mice were assigned to each dose group (age and weights not provided). Mice were administered a single dose of the test material by oral gavage at dose levels of 200, 400, 800, 1600, or 3200 mg/kg bw. The mice were observed for a 14-day period for adverse clinical signs and mortality. Body weights were collected prior to dosing and at termination of the observation period.

Statistics:

no data

Sex:

male

Dose descriptor:

LD50

Effect level:

> 3 200 mg/kg bw

Remarks on result:

other: The highest dose level (3200 mg/kg bw) used in this study was higher than that used for a limit dose in present-day guideline studies.

Mortality:

None

Clinical signs:

At dose levels up to 800 mg/kg bw, animals appeared normal or slight weakness was noted on the day of dosing. On the day following dosing and thereafter, all animals in these dose groups appeared normal. Clinical signs of toxicity noted at the 1600 mg/kg bw dose level were limited to observations of excitement, vasodilatation, weakness, and slight tremors on the day of dosing only. Signs of toxicity in the 3200 mg/kg dose group included restlessness, vasodilatation, weakness, and prostration on the day of dosing. Weakness noted in this dose group persisted to Day 3 of the study. No other clinical abnormalities were reported during the study.

Body weight:

Not reported (the testing laboratory only commented on body weight losses).

Gross pathology:

No effects reported.

Interpretation of results:

other:

Remarks:

EU-GHS criteria not met

Conclusions:

Under conditions used in this study, methyl isoamyl ketone was not acutely toxic by the oral route in male mice. The oral LD50 in male mice was > 3200 mg/kg bw.

Based on an acute oral LD50 value greater than 3200 mg/kg bw in male mice, methyl isoamyl ketone does not need to be classified for acute lethality by the oral route according to EU-GHS. This result is supported by similar clinical signs and a reported oral LD50 value of greater than 3200 mg/kg bw in a study conducted in male rats by the same test laboratory during the same time period.

Executive summary:

In an acute oral toxicity study, five groups of four mice each were administered a single dose of methyl isoamyl ketone by gavage at dose levels of 200, 400, 800, 1600, or 3200 mg/kg bw and observed for mortality and adverse clinical signs for a period of 14 days. No mortality was noted during the study. At dose levels up to 800 mg/kg bw, animals appeared normal or slight weakness was noted on the day of dosing. On the day following dosing and thereafter, all animals in these dose groups appeared normal. At the 1600 mg/kg bw dose level, clinical signs were limited to observations of excitement, vasodilatation, weakness, and slight tremors on the day of dosing. Signs of toxicity in the 3200 mg/kg dose group included restlessness, vasodilatation, weakness, and prostration on the day of dosing. Weakness noted in this dose group persisted to Day 3 of the study. No other clinical signs were reported during the study. No signs of body weight loss were recorded. The oral LD50 in male mice is considered to be greater than 3200 mg/kg bw. Ingestion of large amounts may cause effects on the central nervous system. According to EU-GHS no classification is warranted for 5 -methylhexan-2 -one for acute oral toxicity.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting 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.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Initially, five groups of four male rats each were administered a single dose of the test material at dose levels of 200, 400, 800, 1600, or 3200 mg/kg bw by oral gavage and observed for a period of two weeks. Based on mortality attributed to possible aspiration of the test substance during the gavage procedure in the 1600 and 3200 mg/kg bw dose groups, two additional groups of four male rats were added to the study and administered doses of 1600 or 3200 mg/kg bw by oral gavage and observed for two weeks. Clinical observations and mortality were noted during the study. Body weights were recorded 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 or test system 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:

200, 400, 800, 1600, or 3200 mg/kg bw

No. of animals per sex per dose:

4 males at the 200, 400, and 800 mg/kg bw dose levels
8 males at the 1600 and 3200 mg/kg bw dose levels

Control animals:

no

Details on study design:

Initially, four male rats were assigned to each dose group (age and weights not provided). Rats were administered a single dose of the test material by oral gavage at dose levels of 200, 400, 800, 1600 or 3200 mg/kg bw. Based on mortality attributed to possible aspiration of the test substance during the gavage procedure in the 1600 and 3200 mg/kg bw dose groups, two additional groups of four male rats were added to the study and administered doses of 1600 or 3200 mg/kg bw by oral gavage and observed for two weeks. All rats were observed for a 14-day period for adverse clinical signs and mortality. Body weights were collected prior to dosing and at termination of the observation period.

Statistics:

no data

Sex:

male

Dose descriptor:

LD50

Effect level:

> 3 200 mg/kg bw

Remarks on result:

other: The highest dose level (3200 mg/kg bw) used in this study was higher than that used for a limit dose in present-day guideline studies.

Mortality:

No mortality was noted in the 200, 400, or 800 mg/kg dose groups. Possibly due to aspiration of the test material, one of four rats in the initial 1600 mg/kg bw dose group and two of four rats in the initial 3200 mg/kg bw dose group died. The remaining rats in these two dose groups survived to termination of the study. When the study was repeated at 1600 and 3200 mg/kg bw using the same study design, no mortality was observed.

Clinical signs:

At dose levels up to 800 mg/kg bw, animals appeared slight to quite weak on the day of dosing. On the day following dosing and thereafter, all animals in these dose groups appeared normal. Clinical signs of toxicity noted for the three surviving rats in the initial 1600 mg/kg bw dose group were limited to ataxia and weakness on the day of dosing but all animals were normal thereafter. Signs of toxicity for the two surviving rats in the initial 3200 mg/kg dose group were limited to weakness. In the repeat 1600 and 3200 mg/kg dose group study, all animals appeared weak and had rough hair coats. No other clinical abnormalities were reported during the study.

Body weight:

Not reported (the testing laboratory only commented on body weight losses).

Gross pathology:

No effects reported.

Interpretation of results:

other:

Remarks:

EU-GHS criteria not met

Conclusions:

Under conditions used in this study, methyl isoamyl ketone was not acutely toxic by the oral route in rats. The oral LD50 in male rats was considered to be > 3200 mg/kg bw.

Based on an acute oral LD50 value greater than 3200 mg/kg bw in male rats, methyl isoamyl ketone does not have to be classified for acute lethality by the oral route according to EU-GHS. This result is supported by similar clinical signs and a reported oral LD50 value of greater than 3200 mg/kg bw in a study conducted in male mice by the same test laboratory during the same time period.

Executive summary:

In an acute oral toxicity study, five groups of four rats each were administered a single dose of methyl isoamyl ketone by gavage at dose levels of 200, 400, 800, 1600, or 3200 mg/kg bw and observed for mortality and adverse clinical signs for a period of 14 days. No mortality was noted in the 200, 400, or 800 mg/kg bw dose groups during the study. At dose levels up to 800 mg/kg bw, animals appeared slightly to quite weak on the day of dosing, but normal thereafter. In the 1600 and 3200 mg/kg bw dose groups, deaths were attributed to possible aspiration of the test material. Surviving animals showed signs of weakness and/or ataxia on the day of dosing, but were normal thereafter. When a second group of male rats was administered 1600 and 3200 mg/kg bw of the test material using the same study protocol, clinical signs were limited to weakness and rough hair coats. No mortality was noted in the second 1600 and 3200 mg/kg bw dose groups. No other clinical signs were reported during the study. No signs of body weight loss were recorded. The oral LD50 in male rats is considered to be greater than 3200 mg/kg bw. Ingestion of large amounts may cause effects on the central nervous system. According to EU-GHS no classification is warranted for 5 -methylhexan-2 -one for acute oral toxicity.

 

Cross-reference 3

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin irritation: in vivo

Remarks:

other: Study conducted according to an internal Eastman Kodak Company laboratory method.

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 introduction of Good Laboratory Practices; no information on number of animals used; data from a summary report; actual test data 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 are at least as stringent as modern guidelines.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Method is an in vivo study using guinea pigs. Following depilation of the abdomen of each animal, a single dose of the undiluted test material was applied under an occlusive cuff. Animals were exposed to test material for 24 hours, then 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 recorded.

GLP compliance:

no

Species:

guinea pig

Strain:

Hartley

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

occlusive

Preparation of test site:

other: The abdomen of each animal was depilated.

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

no data

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

no data

Details on study design:

Following depilation of the abdomen of each animal, a single dose of the undiluted test material (doses not reported) 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. Animals were observed following removal of the cuff, and on Days 7 and 14. Observations for mortality and dermal reactions were recorded.

Irritation parameter:

other: overall irritation

Time point:

other: 24 hours / 7 d / 14 d

Remarks on result:

other: Nummerical grades of irritation (erythmea and edema) were not provided in the study report. The report only specifies the following:

Remarks:

The test material was consideerd to cause slight irritation with some signs of desquamation.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

total number of animals not given

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to result presented above: overall irritation

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

total number of animals not given

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to result presented above: overall irritation

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

total number of animals not given

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to result presented above: overall irritation

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

total number of animals not given

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to result presented above: overall irritation

Numerical grades of irritation (erythema and edema) were not provided in the study report. Overall irritation was reported as slight on a scale of slight to strong.

The test material was considered to cause slight irritation with some signs of desquamation.

Signs of skin absorption were not evident.

Interpretation of results:

other:

Remarks:

EU-GHs criteria not met

Conclusions:

Following 24-hour occlusive exposure of the test material to the depilated abdominal skin of the guinea pig, methyl isoamyl ketone was slightly irritating, but not corrosive. Methyl isoamyl ketone is not a primary skin irritant. Only minimal irritation and some signs of desquamation were noted during the study. Skin absorption was not evident. The conditions of exposure in this non-guideline study were significantly more stringent than those used in present day guideline skin irritation studies, i.e., 24-hr exposure versus 4-hr exposure currently used. Based on the results of this study, the degree of irritation was insufficient to classify methyl isoamyl ketone as a skin irritant according to GHS guidelines.

Executive summary:

In a primary dermal irritation study, guinea pigs were exposed to methyl isoamyl ketone under an occlusive wrap for 24 hours. Animals were then observed for signs of irritation. Signs of irritation were scored as slight, moderate, or severe. Methyl isoamyl ketone caused minimal irritation with some signs of desquamation, but no signs of corrosion. Signs of skin absorption were not evident. Methyl isoamyl ketone is not considered a dermal irritant under conditions used in this study.

Cross-reference 4

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin irritation: in vivo

Remarks:

other: Study conducted according to an internal Eastman Kodak Company laboratory method.

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

7 daily applications over a 10-day period

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted prior to introduction of Good Laboratory Practices; data from a summary report; actual test data not available for review. Study was conducted by an internal Eastman Kodak Company method, developed prior to established guidelines.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Method is an in vivo study using five guinea pigs. Following clipping of the back of each animal, the undiluted test material was applied to the application site daily for 7 days over a 10-day period. The application sites were observed and dermal reactions recorded to see if repeated application of the test material exacerbated the slight dermal response observed following a single 24-hr occluded application.

GLP compliance:

no

Species:

guinea pig

Strain:

Hartley

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

open

Preparation of test site:

other: The hair on the back of each animal was clipped.

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

no data

Duration of treatment / exposure:

The undiluted test material was applied to the application site daily for 7 days over a 10-day period.

Number of animals:

5

Details on study design:

Method is an in vivo study using five guinea pigs. Following clipping of the back of each animal, the undiluted test material (dose not reported) was applied to the application site daily for 7 days over a 10-day period. The application sites were observed and dermal reactions recorded on Day 1, 4, and 10 to see if repeated application of the test material exacerbated the slight initial dermal response observed following a single 24-hr occluded application.

Irritation parameter:

other: dermal reaction

Remarks:

(Check if dermal reactions exacerbated the slight dermal response observed following a single 24-hr occluded application)

Time point:

other: daily

Remarks on result:

other: Repeated uncovered application to guinea pig skin slighlty exacerbated the dermal reaction observed following a single 24 -hours occluded application. Effects were insufficient to classify methyl isoamyl ketone for dermal irritation/corrosion.

Remarks:

The undiluted test material was applied to the application site daily for 7 days over a 10-day period. The initial dermal reaction after a single dose was slight irritation in two of the animals while repeated application caused slight to moderate irritation in 2 of 5 animals by the end of the 10-day exposure period.

Interpretation of results:

other: Repeated application of the test material for 10 days slightly exacerbated the initial dermal reaction observed following a single 24-hr occluded application of the test material.

Remarks:

Criteria used for interpretation of results: expert judgment

Conclusions:

Following a single 24-hour application to the clipped backs of guinea pigs under occluded contact, methyl isoamyl ketone caused slight skin irritation (slight erythema) in two of five animals. The application sites of the remaining three animals appeared normal. After seven daily exposures over a 10-day period, methyl isoamyl ketone caused slight or moderate erythema in two of five animals and dry skin and cracked eschars in all animals. Based on the results of this study, the degree of irritation noted after the single occluded and repeated uncovered applications was insufficient to classify methyl isoamyl ketone as a skin irritant. The initial irritant response following a single occluded application was slightly exacerbated after multiple exposures and therefore, methyl isoamyl ketone may present a slight irritation hazard following repeated skin contact.

Present-day dermal irritation studies use an exposure period of 4 hours. Both the single and repeated application studies used conditions that were significantly more stringent than current guideline protocols. Based on the results of the single and repeated exposure studies, methyl isoamyl ketone is not classified for “Skin irritation/corrosion" according to GHS guidelines.

Executive summary:

In a repeated dermal application study, five guinea pigs were exposed to seven daily applications of methyl isoamyl ketone over a ten day period. Animals were observed for signs of irritation on Days 1, 4, and 10. Signs of irritation were evaluated to see if the slight dermal reaction observed following a single occluded exposure was exacerbated with repeated daily exposures over a 10-day period. The initial dermal reaction after a single dose was slight irritation in two of the animals while repeated application caused slight to moderate irritation in 2 of 5 animals by the end of the 10-day exposure period. Repeated uncovered application of metyl isoamyl ketone to guinea pig skin slighlty exacerbated the dermal reaction observed following a single 24 -hours occluded application. Effects were insufficient to classify methyl isoamyl ketone for dermal irritation/corrosion.

Cross-reference 5

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

eye irritation: in vivo

Remarks:

other: Study conducted according to an internal Eastman Kodak Company laboratory method.

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Single ocular exposure followed by a 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; actual test data 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 are at least as stringent as modern guidelines.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Method is an in vivo study using six rabbits. One drop of the test substance was administered into the conjunctival sac of one eye of each of the rabbits. Three of the treated eyes were immediately washed with running distilled water; the other three eyes were not irrigated. The treated eyes of the rabbits were examined for signs of irritation. Over a 14-day observation period, ocular reactions and signs of irritation were recorded and graded.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

1 drop administered to one eye

Duration of treatment / exposure:

single application

Observation period (in vivo):

14 days

Number of animals or in vitro replicates:

6

Details on study design:

Method is an in vivo study using rabbits. One drop of undiluted methyl isoamyl ketone was administered into the conjunctival sac of one eye of each of six rabbits. After instillation, the lids were held together briefly to insure adequate distribution of the test material. The untreated eye of each rabbit served as a control. Three of the treated eyes were immediately washed with running distilled water; the other three eyes were not irrigated. The treated eyes of the rabbits were examined for signs of irritation immediately after test material administration, at 24 hours post dose, and at termination of the study. In addition, the treated eyes of all rabbits were examined with sodium fluorescein at 24 hours post-dose. Additional examinations of the eye, if any, were not defined in the study report. Ocular reactions were recorded at each examination and graded as slight, moderate, or strong. The general health of the rabbits was monitored at each observation time.

Irritation parameter:

other: ocular reaction of the

Remarks:

unwashed eyes

Time point:

other: 24 hours / 14 days

Remarks on result:

other: signs of irritation were reported as, at most, slight. Flourescein staining of the adnexa was evident for two of the three unwashed eyes.

Remarks:

No numerical scores were reported in the study report. Ocular reactions were graded as slight, moderate, or strong.

Irritation parameter:

other: ocular reaction of the

Remarks:

washed eye

Time point:

other: 24 hours / 14 days

Reversibility:

not reversible

Remarks on result:

other: signs of irritation noted during the observation were described as, at most, slight. No fluorescein staining was evident for the washed eyes.

Remarks:

No numerical scores were reported in the study report. Ocular reactions were graded as slight, moderate, or strong.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

cornea opacity score

Basis:

animal #4

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

cornea opacity score

Basis:

animal #5

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

cornea opacity score

Basis:

animal #6

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #4

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #5

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

iris score

Basis:

animal #6

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #4

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #5

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

conjunctivae score

Basis:

animal #6

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

unwashed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #4

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #5

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Irritation parameter:

chemosis score

Basis:

animal #6

Remarks:

washed eyes

Time point:

24/48/72 h

Reversibility:

not specified

Remarks on result:

other: not reported

Remarks:

please refer to results presented above: ocular reaction of the unwashed and washed eye

Ocular reactions were graded as slight, moderate, or strong. No numerical scores were reported in the study report.

For unwashed eyes, signs of irritation were reported as, at most, slight. Fluorescein staining of the adnexa was evident for two of the three unwashed eyes.

For washed eyes, signs of irritation noted during the observation were described as, at most, slight. No fluorescein staining was evident for the washed eyes.

Based on the lack of staining in washed eyes, irrigation of the eyes was palliative.

Note that no irritation scores were used in this study. The values of 1000 were used only as a placeholder, as numerical values are required to pass the completeness check.

Interpretation of results:

other:

Remarks:

EU-GHS criteria not met

Conclusions:

Methyl isoamyl ketone was, at most, a slight irritant by the ocular route under conditions used in this study. Prompt washing of the eyes was palliative. This is consistent with minimal effects observed following single and repeated application to the clipped skin of guinea pigs. Based on minimal signs of eye irritation with no signs of corrosion, methyl isoamyl ketone is not classified for eye irritation/corrosion under EU-GHS.

Executive summary:

In a primary eye irritation study, one drop of undiluted methyl isoamyl ketone was instilled into the conjunctival sac of one eye of each of 6 New Zealand albino rabbits. Of these, three had their eyes washed immediately after treatment and three were unwashed. Animals were then observed for 14 days. Ocular reactions were recorded and descriptors (slight, moderate, strong, severe) were assigned for grading severity of ocular lesions. The eyes of all rabbits were examined with fluorescein dye at 24 hours. Methyl isoamyl ketone was reported to cause, at most, slight irritation in unwashed and washed eyes. Immediate washing of the eyes was palliative. Based on the results of this study, methyl isoamyl ketone is, at most, a slight ocular irritant.

Cross-reference 6

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

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; insufficient experimental detail; actual test report not available for review. Study was conducted by an internal Eastman Kodak Company method, developed prior to established guidelines.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Deviations:

not specified

Principles of method if other than guideline:

Not specified; method used is most like the Open Epicutaneous Test in which the test substance is repeatedly applied topically, and subsequently evaluated for any increase in the dermal reaction elicited.

GLP compliance:

no

Type of study:

other: Study conducted according to an internal Eastman Kodak Company laboratory method, not used elsewhere.

Justification for non-LLNA method:

This in vivo the Open Epicutaneous Test - in which the test substance is repeatedly applied topically to Guinea pig skin, and the dermal reaction elicited was evaluated - was avaialbel before conduct of in vitro tests were judged to be the preferred method.

Species:

guinea pig

Strain:

Hartley

Sex:

not specified

Details on test animals and environmental conditions:

no data

Route:

other: Not specified; most likely open epicutaneous

Vehicle:

no data

Concentration / amount:

no data

Route:

other: Not specified; most likely open epicutaneous

Vehicle:

no data

Concentration / amount:

no data

No. of animals per dose:

5 animals in test group (sex not reported)

Details on study design:

no data

Challenge controls:

no data

Positive control substance(s):

not specified

Reading:

1st reading

Group:

test chemical

Dose level:

no data

No. with + reactions:

1

Total no. in group:

5

Clinical observations:

A weak allergic response was observed in one of five guinea pigs.

Remarks on result:

other: Reading: 1st reading. Group: test group. Dose level: no data. No with. + reactions: 1.0. Total no. in groups: 5.0. Clinical observations: A weak allergic response was observed in one of five guinea pigs..

Reading:

1st reading

Group:

negative control

Remarks on result:

other: not specified in detail

Remarks:

please refer to results for test groups given above

Reading:

1st reading

Group:

positive control

Remarks on result:

other: not specified in detail

Remarks:

please refer to results for test groups given above

Interpretation of results:

other:

Remarks:

EU-GHS criteria not met

Conclusions:

One of five guinea pigs displayed a weak allergic response following a presumed open epicutaneous exposure to methyl isoamyl ketone. No sensitization responses were observed in the four remaining animals. Based on the results of this study, methyl isoamyl ketone is not expected to be classified for sensitization by skin contact under EU-GHS.

Executive summary:

In a skin sensitization study using an Eastman Kodak Company study design, five guinea pigs were induced and challenged by presumed open epicutaneous exposure to methyl isoamyl ketone. Skin examinations after the challenge dose indicated no positive sensitization reactions were evident in four of the five animals. Only a weak allergic response was reported in the remaining animal after the challenge application. Based on results of this study, methyl isoamyl ketone is not considered to be a skin sensitizer in guinea pigs, and therefore, presents a low skin sensitization hazard upon skin contact under conditions of normal use.

Cross-reference 7

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted prior to introduction of Good Laboratory Practices; limited number of animals; data from a summary review; actual test data not available for review. Study was conducted according to an internal Eastman Kodak Company method developed prior to established guidelines but in accordance with acceptable scientific standards.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Groups of 5 rats (sex not reported) were exposed via inhalation to 0 or 400 ppm of methyl isoamyl ketone 6 hr/day, 5 days/week for a total of 12 exposures over a 16 day period. Controls were exposed to conditioned air only. Animals were evaluated for clinical signs, body weights, hematology, and serum clinical chemistries. At study termination, animals were necropsied and select organs were weighed and examined for gross and histopathologic changes.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

no data

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: fresh air

Details on inhalation exposure:

Groups of 5 animals were exposed via whole body inhalation to 0 or 400 ± 13 ppm methyl isoamyl ketone for 6 hr/day, 5 days/week for a total of 12 exposures over a 16 day period.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hr/day, 5 days/week

Frequency of treatment:

12 total exposures in 16 days

Dose / conc.:

400 ppm (analytical)

Remarks:

Doses / Concentrations: 400 ± 13 ppm

No. of animals per sex per dose:

5/dose (sex not reported)

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 5 animals were exposed via whole body inhalation to 0 or 400 ± 13 ppm methyl isoamyl ketone for 6 hr/day, 5 days/week for a total of 12 exposures over a 16 day period.

Observations and examinations performed and frequency:

Clinical observations:
Frequency was not reported.

Body weights:
Frequency of measurement was not reported.

Blood collection:
Time of collection was not reported

Hematology:
Blood was analyzed for hemoglobin concentration, hematocrit, white blood cell count, and differential white blood cell count.

Serum Clinical Chemistry:
Blood was analyzed for glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactic acid dehydrogenase, alkaline phosphatase, urea nitrogen, and glucose.

Sacrifice and pathology:

Gross Pathology and Organ Weights:
Liver and kidneys were examined and weighed.

Histopathology:
Liver and kidneys were examined microscopically.

Statistics:

No information

Clinical signs:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Mortality:

no mortality observed

Description (incidence):

No animals died.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

There were no adverse effects on any parameters examined in this study.
In animals exposed to methyl isoamyl ketone, there were no adverse effects on clinical signs, body weight gain, hematology, serum clinical chemistries, and liver and kidney weights. No compound-related gross or microscopic changes were detected in the liver or kidneys at necropsy.

Dose descriptor:

NOEC

Effect level:

> 400 ppm

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

In a subacute toxicity study, methyl isoamyl ketone was administered to groups of 5 rats (sex and strain not specified) via whole body inhalation at a concentration of 0 or 400 ppm for 6 hr/day, 5 days/week for a total of 12 exposures in 16 days. The NOEC was > 400 ppm since no adverse effects were observed in any of the parameters examined in this study, including clinical signs, body weight gain, hematology, serum clinical chemistries, liver and kidney weights, and gross and microscopic kidney and liver pathology.

Based on an absence of significant treatment-related effects in rats exposed to 400 ppm of the test substance for a total of 12 exposures in 16 days, methyl isoamyl ketone is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to the GHS guidelines.

Executive summary:

In a subacute toxicity study, methyl isoamyl ketone was administered via whole body inhalation to 5 rats per group at 0 or 400 ± 13 ppm for 12 exposures over a period of 16 days. No statistically significant effects were noted for clinical signs, body weight gains, hematology, serum clinical chemistries, organ weights, or gross or histo-pathology. Under the conditions of this study, the NOEC was > 400 ppm following exposure to methyl isoamyl ketone.

Data source

Reference

Reference Type:

other: Eastman Kodak Company Basic Toxicity Summary Report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

5-methyl-2-hexanone

IUPAC Name:

5-methyl-2-hexanone

Constituent 2

Reference substance name:

5-methylhexan-2-one

EC Number:

203-737-8

EC Name:

5-methylhexan-2-one

Cas Number:

110-12-3

Molecular formula:

C7H14O

IUPAC Name:

5-methylhexan-2-one

Constituent 3

Reference substance name:

MIAK; Isoamyl methyl ketone

IUPAC Name:

MIAK; Isoamyl methyl ketone

Details on test material:

-Name of test material as cited in study report: Methyl isoamyl ketone
-Appearance: liquid
-Melting Point: -74 °C
-Boiling Point: 145 °C at 760 mm Hg
-Solubility: 0.5% in water at 20 °C
-Storage conditions: room temperature and humidity

Test animals

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Weight Range at Study Initiation: 181-233 grams

Administration / exposure

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.

Results and discussion

Effect levels

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 5878 ppm, eye irritation & 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 3207 ppm displayed signs of eye irritation unresponsiveness, and impaired gait.

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

Any other information on results incl. tables

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.

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

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Criteria used for Classification: EU-GHS

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 EU-GHS. This is analog to the information given in the dangerous substances directive: Methyl isoamyl ketone carried an R20 Risk Phrase (Harmful if Inhaled) under Annex 1 of the European Union Dangerous Substances Directive. Now it is listed in Annex VI of the Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (the CLP Regulation) as Flam Liq. 3 (H226) and Acute Tox 4 (H332 - harmfull if inhaled).

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. 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 EU-GHS. This is analog to the information given in the dangerous substances directive: Methyl isoamyl ketone carried an R20 Risk Phrase (Harmful if Inhaled) under Annex 1 of the European Union Dangerous Substances Directive. Now it is listed in Annex VI of the Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (the CLP Regulation) as Flam Liq. 3 (H226) and Acute Tox 4 (H332 - harmfull if inhaled).