3-methylbutanone

Endpoint summary

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation

  

The potential for methyl isopropyl ketone to cause skin corrosion/irritation is well understood. Although a study conducted according to current regulatory guidelines for a skin irritation study was not identified, two skin irritation studies, conducted according to accepted scientific principles of the times, were available for review. In addition, data from a key acute dermal toxicity study were considered in the overall evaluation. In the key skin irritation study, male guinea pigs were administered a single dose of 0.5 mL of methyl isopropyl ketone on depilated skin under occluded wrap.  Exposure was for 24 hours, a condition much more stringent than that used in current skin irritation protocols. Signs of irritation were limited to slight erythema at the site of application and all animals appeared clinically normal by 72 hours after termination of exposure. In a supporting skin irritation study, doses of 0.5 mL of methyl isopropyl ketone were repeatedly applied to the uncovered clipped backs of guinea pigs for nine daily applications over an eleven day period. There were no signs of systemic toxicity, all animals gained weight normally, and there were no observable signs of erythema or edema. In a key dermal toxicity study conducted by a method similar to OECD Guideline 402, but using a single limit dose of 20 mL/kg bw (equivalent to 16 g/kg bw) of the test material, there were no signs of irritation or treatment-related changes observed at necropsy in the nine of ten exposed rats that survived to study termination. Moderate necrosis of the skin was observed in a single animal that died less than 4 hours after dose administration. The dose levels used in the dermal toxicity study were significantly higher than the 0.5 mL dose specified in the current OECD 404 guideline for skin irritation. Based on the observations made in these three studies, methyl isopropyl ketone is not classified as a primary skin irritant.

  

Eye irritation

  

The potential for methyl isopropyl ketone to cause eye burns/irritation has been evaluated based on an absence of corrosivity or irritation following 24-hour occluded contact with intact skin and the results of an eye irritation study in which methyl isopropyl ketone was instilled into the eyes of rabbits. In the key eye irritation study, methyl isopropyl ketone was instilled into the conjunctival sac of the left eyes of 6 albino rabbits, followed by immediate flushing of the eyes of 3 rabbits with water. Eyes were then evaluated for up to 14 days. No numerical scores were provided in the study report but irritation, described as moderate, was observed in unwashed eyes at the 24-hr examination; irritation in washed eyes was described as slight. By 48 hours post-exposure, irritation was classified as slight in the unwashed eyes and 2 of 3 washed eyes were normal. At the 72-hour examination, all washed and 1/3 unwashed eyes were normal. Irritation in the remaining unwashed eyes was limited to slight irritation of the conjunctiva and nictitating membrane and all signs of irritation were fully reversible by 7 days. Although some subjective irritant responses were observed when methyl isopropyl ketone was placed in the eyes of New Zealand White rabbits under the conditions used in this study, the criteria for classifying the substance as corrosive or an ocular irritant under GHS were not met. Concentration-dependent lacrimation was observed at all exposure concentrations in both acute and repeat inhalation toxicity studies. In a repeat-exposure study in which animals were exposed 6 hr/day, 5 days/wk, excess lacrimation was minimal at 750 ppm and minor at 1500 and 3000 ppm with all clinical signs resolving before the next exposure. In an acute inhalation study in which animals received a single exposure to target concentrations of 4000, 6000 or 9000 ppm methyl isopropyl ketone, minimal to severe lacrimation was observed during or immediately following exposure but these effects resolved in most animals by the day following exposure. These results suggest that exposure to high airborne concentrations of methyl isopropyl ketone may cause transient eye irritation.

  

Respiratory tract irritation

  

The potential for methyl isopropyl ketone to cause respiratory tract irritation is well understood. In an acute inhalation study conducted according to OECD Guideline 403, in which groups of male and female rats were exposed to up to 9000 ppm for 6 hours, no clinical signs suggestive of respiratory tract irritation were observed and there were no gross or microscopic changes in the trachea or lungs at necropsy. In a repeat exposure study conducted by a method similar to OECD Guideline 412 in which groups of rats of each sex were exposed to up to 3000 ppm methyl isopropyl ketone for 6 hr/day, 5 days/wk for 4 weeks, no clinical signs of respiratory tract irritation were reported and there were no gross or microscopic effects suggestive of irritation when the nasal passages, trachea and lungs were examined at necropsy. Based on the results of these two studies, methyl isopropyl ketone is not expected to be a respiratory tract irritant.

 

Justification for classification or non-classification

Although no primary dermal irritation/corrosion study conducted according to current regulatory guidelines was available for review, the test conditions in a dermal irritation study and an acute dermal toxicity study used in the evaluation were significantly more stringent than current guideline specifications for skin irritation studies, i.e. 24-hour exposure rather than 4-hour exposure and, in the case of the dermal toxicity study, significantly higher dose levels. Signs of skin irritation in both studies were limited to slight erythema at the site of application. In addition, there was no exacerbation of the irritant response in guinea pigs receiving nine daily application of 0.5 mL of the test material over an eleven day period. Based on a weight-of-the-evidence assessment, methyl isopropyl ketone may cause slight, transient skin irritation but is not classified for “Skin irritation/corrosion” according to GHS.

  

In an eye irritation study conducted according to accepted scientific standards of the time, moderate irritation was observed at the 24-hour examination in unwashed eyes when the undiluted material was instilled into the conjunctival sacs of rabbit eyes. Immediate washing was palliative. By the 48-hour examination, all irritant responses in unwashed eyes were graded as slight and 2/3 washed eyes were normal. At the 72-hour examination, all washed eyes and 1/3 unwashed eyes were normal and by Day 7, all treated eyes were normal. Methyl isopropyl ketone is not classified under GHS for either skin corrosivity or irritation following 24-hours occluded contact with depilated guinea pig skin. While excessive lacrimation was observed following exposure to high vapor concentrations for prolonged periods of time, the effects were transient. Based on a weight-of-the-evidence assessment, methyl isopropyl ketone is not classified for “Serious Eye Damage/ Eye Irritation” under GHS.

  

There were no clinical signs indicative of respiratory tract irritation in rats following single or repeated inhalation exposures to up to 9000 ppm methyl isopropyl ketone. In addition, the test material is not classified as a skin irritant according to GHS. Based on a weight-of-the-evidence assessment, methyl isopropyl ketone is not classified under GHS for “Specific Target Organ Toxicity – Single Exposure” for respiratory tract irritation.