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Description of key information

N-butyl acetate is readily absorbed after inhalation exposure or tracheal intubation. Dermal absorption is low. Absorption is followed by rapid systemic distribution throughout the body. Hydrolysis to metabolites n-butanol and acetic acid, a process mediated by esterases, is fast, with half life in blood being less than one minute. 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetics

For n-butyl acetate toxicokinetic data are available after intravenous application (Deisinger et al., 1997; Teeguarden et al., 2005) and inhalation/intratracheal intubation (Poet et al., 2002 corresponds to IUCLID study record ESR OPP/ACC,2002; Groth and Freundt, 1991; Essig et al., 1989). Additionally, data on hydrolysis (Dahl et al., 1987; Longland et al., 1977), on tissue/blood partition coefficients (Kaneko et al., 1994), and on skin permeability in vitro (Ursin et al., 1995; Rauma, 2009) were obtained.

The absorption of n-butyl acetate after inhalation exposure or tracheal intubation was investigated in three studies. Investigations with male Sprague Dawley rats using a whole body plethysmograph indicated that n-butyl acetate is readily absorbed after inhalation exposure. The respiratory bioavailability of n-butyl acetate was calculated to be 100% of alveolar ventilation (about 60% of minute ventilation). Maximum blood levels of n-butyl acetate (2.43 +/- 2.7 µg/ml) were reached about 10 minutes after start of exposure to n-butyl acetate (2000 ppm at start of exposure). Except for the first measurement after 5 minutes the n-butanol blood levels (maximum: 8.18 +/- 3.1 µg/ml, 20 minutes after start of exposure) were higher than the n-butyl acetate blood levels (Poet et al., 2002 corresponds to IUCLID study record ESR OPP/ACC,2002; Teeguarden et al., 2005).

Similar results were obtained with female Sprague Dawley rats which were exposed for 5 hours to 1000 ppm n-butyl acetate via tracheal intubation. Both, n-butyl acetate and its metabolite n-butanol were detectable in blood immediately after start of exposure, maximum levels were reached at about 30 minutes after start of exposure. The concentration of n-butyl acetate reached a nearly constant level (mean concentration: 24.6 +/- 3.8 µmol/L). The blood concentrations of n-butanol followed were about twice the levels of n-butyl acetate (mean concentration: 52.4 +/- 10.3 µmol/L; AUC: 260 +/- 29 µmol per Lxh) (Groth and Freundt, 1991).

These findings were supported by another investigation with Sprague Dawley rats, which were exposed for 1 hour to 7000 ppm n-butyl acetate via intratracheal intubation (Essig et al., 1989).

Absorption of n-butyl acetate after dermal application seems to be low as can be concluded from the permeability constant for n-butyl (1.6 +/- 0.1 g/m2*h or 1.8 +/- 0.1 cm3/m2*h), which was obtained in vitro using human skin (Ursin et al., 1995). Similar results were obtained in vitro using pig-skin (flux = 0.47 +/- 0.07 mg/cm2/h; Rauma, 2009). Based on the data on physico-chemical properties on n-butyl acetate a default assumption of 100% dermal absorption can be taken into account following the recommendations of the Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c (i.e. water soluble liquid with molecular mass below 500 and log Pow in the range of -1 to 4).

n-Butyl acetate is rapidly distributed throughout the body as can be seen from investigations with Sprague Dawley rats, which received radioactive labelled n-butyl acetate intravenously. Liquid scintillation analysis of whole blood and brain tissue of these rats

revealed rapid systemic distribution of radioactivity and very rapid elimination from both whole blood and brain tissue (Deisinger et al., 1997).

The metabolism of n-butyl acetate is characterised by the rapid hydrolysis of the parent compound to n-butanol and acetic acid, a process which is catalyzed by esterases found in several tissues and blood (Dahl et al., 1987, Longland et al., 1977). Metabolism studies with male Sprague Dawley rats using radioactive labelled n-butyl acetate indicated that n-butyl acetate was very rapidly eliminated from the blood (biphasic elimination; t1/2 = 0.41 min), and was detected in brain tissue only at low concentrations (mean maximum of 3.8 µg equivalents/g at 1.9 min) in the first 2.5 min following dosing. n-Butanol was found at higher concentrations in both blood (Cmax = 52 µg equivalents/g at Tmax 2.6 min)and brain (Cmax = 79 µg equivalents/g at Tmax 2.5 min), but this was also rapidly eliminated in both tissues (biphasic elimination; t1/2, of 1.0 - 1.2 min) and was undetectable beyond 20 min post dosing. n-Butyric acid was present at low concentrations in blood (mean maximum of 5.7 µg equivalents/g at 7.4 min) and declined slowly following dosing; it was largely undetected in brain tissue. Early eluting, polar metabolites, presumably Krebs cycle intermediates of [14C]n-butanol and glucuronide and sulfate conjugates of [14C]n-butanol, were detected in the whole blood (mean maximum of 12.2 µg equivalents/g at 4.2 min), but were seen only in trace amounts in brain tissue. The hydrolysis of n-butyl acetate in blood and brain is estimated to be 99% complete by 2.7 min at this dose level (Deisinger et al., 1997).

Parameter
(dimension)

n-Butanol in blood

n-Butanol in brain

A

24.365

48.050

alpha (min')

1.890

1.574

t1/2 alpha(min)

0.367

0.440

B

65.447

105.472

beta (min')

0.215

0.147

t1/2 beta (min)

3.228

4.714

Kelim (min-1)

0.669

0.594

t1/2 (min)

1.036

1.167

Cmax (µg/g)

52.2

79.2

Tmax (min)

2.6

2.5

The findings from Deisinger et al. (1997) were confirmed in further studies (Teeguarden et al., 2005; Essig et al., 1989).

There were no data on excretion identified. But the data on metabolism revealed that n-butyl acetate is rapidly hydrolyzed to n-butanol and acetate, which are further metabolized and finally enter the Krebs cycle.

The toxicokinetic data of n-butyl acetate obtained in several studies (see above) and information on partition between distilled water, olive oil, human blood and various rat tissues (blood, liver, kidney, brain, muscle, and fat) (Kaneko et al., 1994) were used for the establishing a PBPK-Model for n-butyl acetate and its metabolites (Barton et al., 2000; Teeguarden et al., 2005).