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Administrative data

Description of key information

Based on a high quality, guideline study in rats, the subchronic inhalation NOAEC for systemic toxicity of ethyl acetate is considered to be 350 ppm (1.28 mg/L), based on sedation during exposure, reduced food consumption and reduced body weight gain.  Nasal irritation was observed in this study at all exposure concentrations, therefore, the LOAEC for respiratory irritant effects in rats is considered to be 350 ppm (1.28 mg/L).

A subchronic oral NOAEL of 900 mg/kg bw/day was reported in a 90-day oral study in rats cited in the EPA IRIS database (US EPA, 1988), based on depressed food consumption, suppressed body weight gain and clinical signs observed at 3,600 mg/kg/day.

Repeated dose dermal studies of ethyl acetate have not been reported.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
900 mg/kg bw/day

Additional information

In a recent well conducted study (Christoph, 1998), rats exposed to concentrations of 350, 750, or 1500 ppm (1.28, 2.75, 5.49 mg/L) 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, and lower levels of serum triglycerides. No other changes were seen. As this is a modern study conducted to GLP for which the full report and supporting raw data is available, it is regarded as the most robust study for this end point. This study did produce some evidence of nasal mucosa degeneration at 350 ppm. This is a common lesion in rats exposed by inhalation to acetate esters of short-chain alcohols due to the liberation of acetic acid in these cells from the hydrolysis of the ester linkage. Since rats are obligate nose breathers, the delivered dose to this portion of the nose might be higher in rats than in humans and it is not clear what dose could result in lesions in humans. However, it is possible that the air concentration alone could be the most significant contributor to the effect. The NOAEC for systemic toxicity in this study is considered to be 350 ppm or 1.28 mg/L and the LOAEC 750ppm or 2.75 mg/L); the LOAEC for respiratory irritant effects (nasal toxicity) is 350 ppm (1.28 mg/L).

In a separate 100-day study designed to evaluate neurotoxicity by the same laboratory (Christoph, 2003) and conducted at the same exposure levels, decreased food consumption and decreased body weight gain were also noted at 350 ppm.

Other inhalation studies in various laboratory species have failed to show consistent substance-related pathology or toxicity (Blina, 1938; Seth, 1974; Smyth and Smyth, 1928; Sommer, 1957). As many are old and either reported in limited detail, of short duration or carried out using unverified protocols, less weight is put on their findings.

In a 90-day oral study in rats cited in the EPA IRIS database (US EPA, 1988), 900 mg/kg bw/day was established as an oral NOAEL based on depressed food consumption, suppressed body weight gain and clinical signs. Rats in this study received daily gavage doses of 0, 300, 900 or 3600 mg ethyl acetate/kg bw/day.

As mentioned earlier in the metabolism discussion, ethyl acetate is rapidly hydrolyzedin vivoto acetate and ethanol. Since exposure to either ethyl acetate or ethanol results in systemic exposure to ethanol, data from studies that administer ethanol directly are considered useful in identifying hazards associated with ethyl acetate exposure. A 90 day GLP study carried out to assess urethane toxicity used water and 5% ethanol in water as the vehicle. Data from this study showed effects at an approximate dose level of 6000 mg/kg ethanol in female mice. Male rats show minor changes to organ weights and hematology/biochemistry (2800mg/kg), female rats showed minor biochemistry changes and length of oestrus cycle along with liver nodules (2300 mg/kg), male mice showed increased organ weights (some fatty changes to liver) and a decrease in sperm concentration (8000 mg/kg) (NTP, 1996).

 

Justification for classification or non-classification

The substance neither meets the criteria for classification for repeat dose effects under directive 67/548 nor for specific organ effects following repeated exposures under regulation 1272/2008.