Isopropyl acetate

Endpoint summary

Description of key information

Adequate studies of the repeated dose toxicity of isopropyl acetate were not found.  The repeated dose toxicity of the in vivo hydrolysis product, isopropanol, has been studied by inhalation in rats and mice.  The NOAEL of 500 ppm isopropanol seen in the rat and mouse corresponds to 394 ppm (1.675 mg/L) isopropyl acetate and a LOAEL of 1500 ppm isopropyl alcohol corresponds to 1181 ppm (4.9 mg/L) isopropyl acetate after correcting for differences in total respiratory bioavailability.

Exposure to high concentrations of isopropyl acetate or the in vivo hydrolysis product isopropanol have been reported to produce narcosis in exposed rats.  No presistent neurotoxicity was seen in subchronic studies of isopropanol. Data on ethyl acetate can be used to predict the potential for local effects through hydrolysis in the URT. Based on this available data, the BMDL10 for isopropyl acetate is predicted to be in the region 272 -523mg/m3

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 650 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

BMCL10

272 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is no reliable repeat dose toxicity data available on isopropyl acetate. For the purposes of this end point, read across to the hydrolysis products isopropyl acetate and acetic acid (using ethyl acetate as a proxy) are used to predict systemic and local toxicity.

In a sub-chronic repeated dose inhalation study performed to a US national guideline, CD-1 mice were exposed to isopropanol vapour concentrations of 100, 500, 1500 and 5000ppm for a period of 90 days. No mortalities were seen. The narcotic effects of isopropanol were noted at the two higher exposures, producing ataxia, narcosis and a lack of startle reflex in some animals. These symptoms disappeared after exposure. Significant adverse effects were limited to the 5000ppm females, and included increased body weight and body weight gain, increased food consumption, changes to haematology and increased relative liver weight. A 10% increase in the latter was also noted in the 1500ppm females. Based on the clinical changes due to narcosis and the marginal liver weight changes seen at 1500ppm in females (which could be adaptive changes) a NOEL of 500ppm was established.

In a sub-chronic repeated dose inhalation study performed to a US national guideline, F-344 rats were exposed to isopropanol vapour concentrations of 100, 500, 1500 and 5000ppm for a period of 90 days (Burleigh-Flayer, 1994).  No mortalities were seen.  In addition, a satellite group of animals exposed to the three higher doses were subjected to functional observation battery (FOB) assessment. The two higher doses caused depressed central nervous system function (e.g. narcosis, hypoactivity) during exposure. Some adverse clinical signs persisted in the high dose animals. Exposure of female rats to 5000 ppm (12.25 mg/L) also increased motor activity during nine and 13 weeks of the study but no persistent neurotoxicity was noted in any dose groups. Increases in body weight and/or body weight gain were noted in the two highest dose groups. Changes in clinical pathology and relative liver weight changes were noted in the high dose animals. Hylaine droplets were seen within the kidneys of male rats, including controls. There did seem to be a trend towards increased severity, but this was not clearly concentration related. Such lesions are known to affect rats but not humans so their relevance to human risk assessment is highly questionable. The NOAEL in the 13-week rat study was determined to be 500 ppm (1.23 mg/L) based on decreases in red blood cell parameters in the male and female rats and the during-exposure clinical signs noted in the 1500 and 5000 ppm (3.68 and 12.23 mg/L) groups. In the FOB part of this study there were signs of narcosis in the first 2 weeks of exposure to isopropanol vapour at the top vapour concentration. Thereafter there was evidence of adaptation (tolerance) and in the absence of histological neuropathology the effects are not considered to be adverse. The NOAEL for neurotoxic effects by inhalation exposure is 5000 ppm.

In a guideline and GLP study, rats exposed to concentrations of 350, 750, or 1500 ppm (1.28, 2.75, 5.49 mg/L) of ethyl acetate in air for 94 days showed no significant toxic effects. Diminished response to delivery of an alerting stimuli was noted during exposure at the 750 and 1500 ppm levels. This transient diminished response was confined to the exposure period and was attributed to acute sedative properties of ethyl acetate. Other findings at the 750 and 1500 ppm levels were limited to reduced food consumption and body weight gain (both primarily in females at 750ppm), and lower levels of serum triglycerides. No other changes were seen. Some evidence of nasal mucosa degeneration was seen at 350 ppm.

 The NOAEL for systemic toxicity in this study was considered to be 350 ppm (1.28 mg/L) and the LOAEL 750ppm (2.75 mg/L). The LOAEL for respiratory irritant effects (nasal toxicity) was considered to be 350 ppm (1.28 mg/L).

From the results of these studies, it can be considered that local effects are the critical effects rather than effects resulting from systemic exposure. The ethyl acetate study is therefore used to derive the critical parameter for inhalation exposure.

Justification for classification or non-classification

Classification for repeat dose target organ effects become relevant when effects are seen at doses resulting from inhalation exposure of less than 250ppm. There is no evidence of possible systemic toxicity resulting from exposures at such concentrations – the NOAEL for isopropanol is 500ppm. For local effects, the only consideration is the nasal olfactory lesions for which a LOAEL of 350ppm is seen in the ethyl acetate study and for which a BMDL10 of 64-123ppm is calculated based on local tissue concentrations of the metabolite acetic acid. However, it should be noted that the lesions seen at this concentration in 60% of the animals were rated as only mild and, more importantly, that the predicted human equivalent concentration for such effects is at least 6x higher based on the same metric. Based on the source substances and considering the human relevance of the findings in animals, there is no evidence that isopropyl acetate would exhibits any specific repeat dose toxicity that would warrant classification according to the CLP criteria.