3-methoxybutyl acetate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

The rates of hydrolysis were determined for several carboxylic acid esters (acetic acid esters) using S-9 homogenates from various respiratory tract tissues and livers of rats, rabbits and Syrian hamsters

GLP compliance:

not specified

Radiolabelling:

no

Species:

other: rats, rabbits and hamster

Strain:

other: male F344/N rats; male New Zealand white rabbits; male Syrian hamsters

Sex:

male

The hydrolysis rate of n-butyl acetate in rat ethmoturbinate S-9 homogenate was determined to be 77 ± 2.13 nmol/mg S-9 protein /min (n = 3 to 5). Hydrolysis rates for other tissues are not reported.

 

As demonstrated with pentyl and phenyl acetate, liver S-9 homogenate had the highest catalytic activity of all rat tissues tested (nasal, trachea, lung tissues). S-9 mix from hamster tissues had higher activities than the respective rat tissue S-9 mixes and the S-9 mixes from hamster maxilloturbinates and ethmoturbinates had even higher activities than hamster liver S-9 mix. The values for rabbits were somewhere inbetween.

 

For saturated linear alkyl acetates (C1 to C6 and C8) hydrolysis rates were determined with rat ethmoturbinate preparations. Rates increased from 15 nmol/mg S-9 protein/min for methyl acetate up to a maximum of 94 nmol/mg S-9 protein/min for pentyl acetate. For the longer chain hexyl and octyl acetate decreasing hydrolysis rates were found (64 and 47 nmol/mg S-9 protein/min respectively):

Conclusions:

The study results revealed no bioaccumulation potential of the test substance.
n-Butyl acetate seems to be rapidly hydrolyzed by esterases of the respiratory tract.

Executive summary:

The hydrolysis rates of several acetic acid esters were determined in vitro using S-9 homogenate preparations from various tissues of rats, rabbits and hamsters. For each assay 50 µL of a 0.5 M solution of ester in ethanol were incubated at 37°C for 30 min with 2 - 5 mL S-9 homogenate in 0.01 M Tris buffer at pH 7.4 containing 0.7 to 2.5 mg protein. The amount of acetic acid/acetate resulting from hydrolysis was analyzed by ion chromatography.

The hydrolysis rate of n-butyl acetate in rat ethmoturbinate S-9 homogenate was determined to be 77 ± 2.13 nmol/mg S-9 protein /min.

As demonstrated with pentyl acetate and phenyl acetate, liver S-9 homogenate had the highest catalytic activity of all rat tissues tested (nasal, trachea, lung tissues). Higher activities were observed for hamster S-9 preparations.

For linear alkyl acetates (C1 to C6 and C8), hydrolysis rates with rat ethmoturbinate preparations increased with chain length up to a maximum for pentyl acetate (94 nmol/mg S-9 protein/min). Longer chain acetates (hexyl and octyl) showed again decreasing hydrolysis rates (Dahl et al., 1987).

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

year of publication: 1989

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Investigation of n-butyl acetate and n-butanol blood levels and blood clearance after inhalation exposure of rats via tracheal cannula to n-butyl acetate for 1 hour.
Determination of the half-life of the enzymatic hydrolysis reaction of n-butyl acetate in rat and human blood in vitro.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

no data

Route of administration:

intratracheal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: tracheal intubation of anesthetized (with nembutal) rats

Duration and frequency of treatment / exposure:

1 hour, single exposure

Dose / conc.:

7 000 ppm

No. of animals per sex per dose / concentration:

no data

Control animals:

no

Positive control reference chemical:

- none

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: arterial blood from a. carotis
- Time and frequency of sampling: no data reported

Metabolites identified:

yes

Details on metabolites:

The known metabolite n-butanol was measured in blood in order to determine clearance rates/half-lifes

n-Butyl acetate reached nearly constant blood levels (140 µmol/L; 16.3 mg/L) during the 1 hour inhalation exposure to 7000 ppm (33740 mg/m3) n-butyl acetate. The metabolite n-butanol amounted (to 480 µmol/L; 35.6 mg/L) in the blood within 40 min. After termination of exposure, n-butyl acetate disappeared completely from blood within 1 min. For n-butanol an elimination half-life of 5 min was determined. n-Butyl acetate could not be detected in the venous blood. 

The half-life of n-butyl acetate in rat blood in vitro was determined to be 4 min (hydrolytic cleavage of ester to n-butanol and acetic acid). In human blood, the half-life was somewhat longer (12 min).

Conclusions:

The study results revealed no bioaccumulation potential of the test substance.
Intratracheal intubation of rats to 7000 ppm n-butyl acetate for 1 hour resulted in nearly constant arterial blood levels of n-butyl acetate (140 µmol/L) within 1 minute. n-Butanol in blood reached a concentration of 480 µmol/L within 40 minutes. After termination of exposure, elimination of n-butyl acetate and n-butanol was fast. n-Butyl acetate disappeared completely from blood within 1 min and half-life for n-butanol was 5 min.

Executive summary:

Sprague Dawley rats were exposed to 7000 ppm (33740 mg/m³) n-butyl acetate for 1 hour via intratracheal intubation. Arterial blood concentrations of n-butyl acetate and n-butanol were measured. Exposure resulted in nearly constant arterial blood levels of n-butyl acetate (140 µmol/L) within 1 minute. n-Butanol in blood reached a concentration of 480 µmol/L within 40 minutes. After termination of exposure, elimination of n-butyl acetate and n-butanol was fast. n-Butyl acetate disappeared completely from blood within 1 min and half-life for n-butanol was 5 min. No n-butyl acetate was detectable in venous blood (Essig et al., 1989).

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Principles of method if other than guideline:

in vitro hydrolysis by artificial gastrointestinal juices and rat tissue preparations

GLP compliance:

no

Radiolabelling:

no

- butyl acetate was rapidly hydrolysed by artificial gastric and pancreatic juice as well as by rat liver and small intestine homogenates;

- esterase activity calculated were 14.4 and 69.3 mg ester hydrolysed/l/min for gastric juice and pancreatic juice, respectively

- esterase activity calculated were 0.56 and 2.54 mg ester hydrolysed/g wet tissue/min for rat liver and rat small intestine, respectively

Conclusions:

The study results revealed no bioaccumulation potential of the test substance.
The data indicate that n-butyl acetate is rapidly hydrolysed by esterases.

Executive summary:

In vitro investigations using artificial gastric and pancreatic juice as well as rat liver and small intestine homogenates revealed that n-butyl acetate is rapidly hydrolysed by esterases (Longland et al., 1977).

Description of key information

Absorption of n-butyl acetate 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

Additional information

n-Butyl acetate, isobutyl acetate and sec-butyl acetate may be readily hydrolysed to acetic acid and their respective alcohols in the blood, liver, small intestine, and respiratory tract, as has been shown in several in vitro experiments using homogenates from liver, small intestinal mucosa, and ethmoturbinates (Longland et al., 1977; Dahl et al., 1987). When added to blood samples from male volunteers or female rats, respective hydrolysis half-lives of n-butyl acetate were 4 and 12 min, while those of tert-butyl acetate were 300 and 270 min (Essig et al., 1989).

The full read-across assessment can be found in Section 13.2 ("Read across assessment"). In addition the following textbook entry should be noted. Generally, open chain aliphatic ethers undergo O-dealkylation to yield the corresponding aldehyde and alcohol, followed by complete oxidation to the fatty acid pathway and tricarboxylic acid/Krebs cycle (Krantz and Carr, 1969).