4-methylpentan-2-one

Endpoint summary

Description of key information

A skin irritation study on methyl iso butyl ketone in rabbits performed according to test guidelines has demonstrated that the compound is not a skin irritant.  Similarly, 3 reliable eye irritation studies on methyl iso butyl ketone had demonstrated that the compound is at most slightly irritating.  

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented, according to accepted guidelines.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

- room temperature was 16 to 22 °C, relative humidity was 40 to 80%, and artificial lighting was 14 hr.

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd., Margate.
- Age at study initiation: 13 to 17 weeks.
- Weight at study initiation: 2.5 to 3.13 kg.
- Housing: Housed individually in floor-pens.
- Diet (e.g. ad libitum): SQC TRB Rabbit Diet 9603 (pelleted) from Harlan Teklad, Bicester, ad libitum.
- Water (e.g. ad libitum):Mains water, ad libitum.
- Acclimation period: At least 7 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 22 °C.
- Humidity (%): 40 to 80 %.
- Air changes (per hr): At least 10.
- Photoperiod (hrs dark / hrs light): 10 hrs dark / 14 hrs light.

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL.
- Concentration (if solution): Undiluted test substance.

Duration of treatment / exposure:

4 hour, single exposure.

Observation period:

72 hours.

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: Dorsum
- % coverage: Percentage not reported; covered by a dense gauze patch of 30 x 20 mm and this in turn was covered by a larger gauze patch (40 x 40 mm).
- Type of wrap if used: An open weave, elasticated adhesive bandage "Steroban" from Steroplast Ltd., Bredbury.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin was swabbed with moist cotton wool after patch removal.
- Time after start of exposure: 4 hours after start of exposure.


SCORING SYSTEM: Inflammatory skin reactions were graded according to the following scheme:

Erythema and eschar formation: Grade
No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate erythema: 3
Severe erythema (beet redness) or eschar formation preventing grading of erythema: 4

Oedema: Grade
No oedema: 0
Very slight oedema (barely perceptible): 1
Slight oedema (edges of are well-defined by definite raising): 2
Moderate oedema (edges raised approximately 1 mm): 3
Severe oedema (raised more than 1 mm and extending beyond the area of exposure): 4

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Max. score:

4

Reversibility:

other: no reaction observed

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No dermal response to treatment was observed in any animals throughout the observation period. See Attached File 1 Table 1 for individual data. See Attached File 1 Table 2 for group mean values for dermal reactions.

Other effects:

There were no signs of toxicity or ill health in any rabbits during the observation period.

Interpretation of results:

not irritating

Remarks:

Not classified. Criteria used for interpretation of results: other: CLP (EC 1272/2008)

Conclusions:

No irritation reactions or other dermal changes were observed following a single semi-occluded application of methyl iso butyl ketone to intact rabbit skin for 4 hours.

Executive summary:

A skin irritation study on methyl iso butyl ketone has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 404 and in compliance with GLP (Gardner, 1996).  In this study, 3 New Zealand White rabbits were exposed to 0.5 mL of undiluted methyl iso butyl ketone on the shaved dorsal region under semi-occlusive conditions.  Animals were exposed to the test compound for 4 hours and observations were recorded at 1, 24, 48, and 72 hours after removal of the patch and residual test substance.  Skin reactions were scored according to a prescribed numerical system.  No dermal response to treatment was observed in any animals throughout the observation period. In addition, no signs of toxicity or ill health were observed in any rabbit during the observational period.  Based on the results of this study, methyl iso butyl ketone elicited no dermal irritation to intact rabbit skin. Methyl iso butyl ketone is not classified as a skin irritant according to CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented, according to accepted guidelines

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

- room temperature was 16 to 22 °C, relative humidity was 40 to 80%, and artificial lighting was 14 hr.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

1992

Deviations:

not specified

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd., Margate.
- Age at study initiation: 13 to 16 weeks old.
- Weight at study initiation: 2.5 to 3.29 kg.
- Housing: Housed in floor-pens, each accomodating one animal.
- Diet (e.g. ad libitum): SQC TRB Rabbit Diet 9603 (pelleted) from Harlan Teklad, Bicester, ad libitum.
- Water (e.g. ad libitum): Mains water, ad libitum.
- Acclimation period: At least 3 weeks.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 22.
- Humidity (%): 40 to 80.
- Air changes (per hr): at least 10.
- Photoperiod (hrs dark / hrs light): 10 hrs dark / 14 hrs light.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL.
- Concentration (if solution): Undiluted.

Duration of treatment / exposure:

Single exposure.

Observation period (in vivo):

Up to 72 hours.

Number of animals or in vitro replicates:

3

Details on study design:

One dose consisting of 0.1 mL (after instillation, the eyelids were held closed for a few seconds to prevent loss of the dose). Ocular changes were assessed and recorded immediately, one half-hour, 1 and 4 hours after treatment on Day 1, and 24, 48, and 72 hours after instillation.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No.


SCORING SYSTEM:
The “initial sting” response was assessed and recorded immediately after instillation of the test article. The response was graded according to the following scheme:

Response of animal: Grade: Sting response
No response: 0: None
A few blinks only, normal within two minutes: 1: practically none
Rabbit blinks and attempts to open eye but reflex closes it: 2: Slight
Rabbit keeps eye shut and puts pressure on it, may rub eye: 3: Moderate
Rabbit holds eye tightly shut, may struggle or squeal: 4: Marked

Ocular opacity- degree of density (area most dense taken for reading): Grade

No ulceration or opacity: 0
Scattered or diffused areas of opacity other than slight dulling of normal lustre, details of iris clearly visible: 1
Easily discernible translucent areas, details of iris slightly obscured: 2
Nacreous areas, no details of iris visible, but size of pupil barely discernible: 3
Opaque cornea, iris not discernible through the opacity: 4

Cornea: area of corneal opacity: Grade

Total area of opacity amounts to <25% of corneal area: 1
Area of opacity amounts to 25 - <50% of corneal area: 2
Area of opacity amounts to 50 - <75% of corneal area: 3
Area of opacity amounts to 75% or more of corneal area: 4

Iris: Grade

No reaction: 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of these or combination of any thereof, iris still reacting to light: 1
No iridial reflex to light, haemorrhage, gross destruction (any or all of these): 2

Conjunctivae Redness (refers to the most severe reading of palpebral and bulbar conjunctivae, as compared to the right, control eye): Grade

Blood vessels normal: 0
Some blood vessel definitely hyperaemic (injected): 1
Diffuse, crimson colour, individual vessels not easily discernible: 2
Diffuse beefy red appearance: 3

Chemosis (assessments included nictating membranes): Grade

No swelling: 0
Any swelling above normal: 1
Obvious swelling with partial eversion of lids: 2
Swelling with lids about half-closed: 3
Swelling with lids more than half-closed: 4

Conjunctivae- discharge: Grade

No discharge: 0
Any discharge greater than normal, not including the small amount normally present in the inner canthus: 1
Discharge with moistening of eyelids and hairs just adjacent to the eye: 2
Discharge with moistening of eyelids and hair for a considerable area around the eye: 3



TOOL USED TO ASSESS SCORE: Any ocular changes (e.g., vascularisation, pannus formation) excluded from this standard grading scheme were recorded in detail. The treated eyes were examined visually or with the aid of a pencil-beam torch or other device to illuminate or magnify the eye during examination. At examinations carried out 24 hours after treatment and on any subsequent examination at the discretion of the observer the cornea was subject to application of 2% aqueous fluorescein solution followed by irrigation with water for irrigation. The corneal surface was then illuminated by an ultraviolet source and inspected for areas of absorption of the fluorescing dye that indicate epithelial disruption.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Remarks:

- Redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Remarks:

- Redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Remarks:

- Redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritant / corrosive response data:

Instillation of methyl iso butyl ketone caused slight or practically no initial sting responses.

Conjunctival irritation reactions not exceeding a crimson appearance, slight chemosis and an ocular discharge were apparent in all rabbits during the four hour period following instillation of the test article. All conjunctival reactions had resolved 24 hours after treatment. The iris remained overtly unaffected by the test article.

No corneal opacities developed in any rabbit. A small part of the cornea of one rabbit was permeable to applied fluorescein 24 hours after instillation of the test article. This was taken to indicate minor disruption of the corneal epithelium. The cornea proved to be impermeable to applied fluorescein on the following day. See Table 1 (Attached) for individual data and Table 2 (Attached) for Group mean values.

Other effects:

No observations indicative of systemic toxicity or ill health were noted for any rabbits during the course of the study.

Interpretation of results:

slightly irritating

Remarks:

Migrated information not classified Criteria used for interpretation of results: other: CLP (EC 1272/2008)

Conclusions:

A single instillation of methyl iso butyl ketone into the conjunctival sac of three rabbits caused changes of the conjunctivae that resolved within 24 hours and minor disturbance of the corneal epithelium that resolved within 48 hours.

Executive summary:

An eye irritation study on methyl iso butyl ketone has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 405 and in compliance with GLP (Gardner, 1996).  In this study, 0.1 mL of undiluted methyl iso butyl ketone was instilled into one conjunctival sac of each of 3 New Zealand White rabbits.  Ocular changes were assessed 0.5, 1, 4, 24, 48, 72 hours after treatment, and scoring was performed according to guideline methods.  No clinical signs of systemic toxicity or ill health were observed in any rabbit during the course of the study.  Instillation of methyl iso butyl ketone caused slight or practically no initial sting response.  All rabbits developed conjunctival irritation (not exceeding a crimson appearance), slight chemosis, and an occular discharge during the 4-hour period following instillation of the test substance.  All conjunctival reactions were resolved 24 hours after treatment. The iris remained overtly unaffected by the test substance. No corneal opacities developed in any rabbit. A small part of the cornea of one rabbit was permeable to applied fluorescein 24 hours after instillation of the test article, indicative of a minor disruption of the corneal epithelium; however, the cornea was proved to be impermeable to applied fluorescein on the following day. All individual mean scores over 24, 48 and 72 h were 0. Under the conditions of this study, methyl iso butyl ketone was considered to be slightly irritating to rabbit eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

 

A skin irritation study on methyl iso butyl ketone has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 404 and in compliance with GLP (Gardner, 1996).  In this study, 3 New Zealand White rabbits were exposed to 0.5 mL of undiluted methyl iso butyl ketone on the shaved dorsal region under semi-occlusive conditions.  Animals were exposed to the test compound for 4 hours and observations were recorded at 1, 24, 48, and 72 hours after removal of the patch and residual test substance.  Skin reactions were scored according to the prescribed numerical system in the study guidelines.  No dermal response to treatment was observed in any animals throughout the observation period. In addition, no signs of toxicity or ill health were observed in any rabbit during the observational period.  All individual mean scores over 24, 48 and 72 h were 0. Based on the results of this study, methyl iso butyl ketone elicited no dermal irritation to intact rabbit skin.

 

Eye Irritation

 

Three eye irritation studies performed according to current guidelines have demonstrated that MIBK is at most slightly irritating for the eyes.

 

An eye irritation study on methyl iso butyl ketone has been performed in accordance with OECD Guidelines #405 and in compliance with GLP (Gardner, 1996).  In this study, 0.1 mL of undiluted methyl iso butyl ketone was instilled into one conjunctival sac of each of 3 New Zealand White rabbits.  Ocular changes were assessed 0.5, 1, 4, 24, 48, 72 hours after treatment, and scoring was performed according to guideline methods.  No clinical signs of systemic toxicity or ill health were observed in any rabbit during the course of the study.  Instillation of methyl iso butyl ketone caused slight or practically no initial sting response.  All rabbits developed conjunctival irritation (not exceeding a crimson appearance), slight chemosis, and an occular discharge during the 4-hour period following instillation of the test substance.  All conjunctival reactions were resolved 24 hours after treatment. The iris remained overtly unaffected by the test substance. No corneal opacities developed in any rabbit. A small part of the cornea of one rabbit was permeable to applied fluorescein 24 hours after instillation of the test article, indicative of a minor disruption of the corneal epithelium; however, the cornea was proved to be impermeable to applied fluorescein on the following day. All individual mean scores over 24, 48 and 72 h were 0. Under the conditions of this study, methyl iso butyl ketone was considered to be slightly irritating to rabbit eyes.

 

Individual raw data of a study performed in accordance with the OECD guideline #405 on 4 rabbits were reported by ECETOC (1992). The overall mean scores for MIBK were 0.08 for cornea opacity, 0 for iris lesion, 0.8 for redness of conjunctivae and 0.17 for chemosis. MIBK was slightly irritating.

 

In a test performed by the French Health National Laboratory of the Medicine Agency following OECD Guideline #405, 0.1 mL of undiluted MIBK was instilled into the eyes of 3 rabbits (Giroux, 1992). It was observed a slight conjunctival irritation, which cleared in 4 days and a slight corneal opacity which cleared in 2 days. The mean individual score over 24, 48 and 72 hours were 0.3, 0.3 and 0 for chemosis, 0.7, 0.7 and 1.0 for conjunctival redness, and 0 for iritis and corneal opacity.

 

Respiratory tract irritation

 

De Ceaurriz et al.(1981) measured the reflex decrease in respiratory rate in male Swiss OF1 mice as an index of sensory irritation.This model was based upon data that had shown that sensory irritation of the upper respiratory tract is accompanied by a reflex pause in the expiratory phase of the respiration. This phenomenon gave rise to a decrease in the respiratory rate. In this study, MIBK caused a concentration-dependent decrease in respiratory rate during a 5-min exposure, and a 50% decrease in respiratory rate (RD50) was seen at 13,100 mg/m3 (3195 ppm). It should be recognized that the reduction of the respiratory rate at concentration closed to the lethal or anesthetic concentrations may not be due to sensory irritation.

Justification for selection of skin irritation / corrosion endpoint:
Key study

Justification for selection of eye irritation endpoint:
Key study

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Skin irritation: The substance does not meet the criteria for classification and labelling for this endpoing, as set out in Regulation (EC) No. 1272/2008.

Eye irritation: Based on the data presented, the substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) No. 1272/2008, however, this substance has already been classified in CLP Annex VI as category II: causes serious eye irritation.

Respiratory irritation: According to CLP classification criteria, the substance does meet the criteria for classification and labelling for this endpoint (STOT single exposure category 3, H335 - May cause respiratory irritation), as set out in Regulation (EC) No. 1272/2008.