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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published peer reviewed evaluation; in vitro assessment of metabolism

Data source

Reference
Reference Type:
publication
Title:
Carboxylesterases in the respiratory tracts of rabbits, rats and Syrian hamsters
Author:
Dahl AR, Miller SC & Petridou-Fischer J
Year:
1986
Bibliographic source:
Toxicology Letters, 36 (1987) 129-136

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Investigation into acetate ester hydrolysis by liver respiratory tract enzymes, in vitro.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
acetic acid hexyl ester
IUPAC Name:
acetic acid hexyl ester
Constituent 2
Chemical structure
Reference substance name:
Hexyl acetate
EC Number:
205-572-7
EC Name:
Hexyl acetate
Cas Number:
142-92-7
Molecular formula:
C8H16O2
IUPAC Name:
hexyl acetate
Test material form:
not specified
Details on test material:
Acetate esters of methanol, ethanol, propanol, butanol, pentanol, hexanol, octanol, isobutyl alcohol, sec-butyl alcohol , tert-butyl alcohol and phenol;
ß-butyrolacetone and ß-propiolactone. All esters evaluated were obtained from Aldrich Chemical Co, including the two standards - acetic acid and 2-hydroxybutyric acid, at the highest purity available.
Radiolabelling:
no

Test animals

Species:
other: in vitro study

Administration / exposure

Route of administration:
other: in vitro
Vehicle:
not specified
Positive control reference chemical:
Not required for this type of study
Details on study design:
S9 fractions were prepared from samples of liver and respiratory tract tissues (turbinates, trachea, lung) from hamsters, rats and rabbits. The extent of hydrolyis of various esters was investigated in vitro. The esters tested were the acetates of methanol, ethanol, propanol, butanol, pentanol, hexanol, octanol, isobutyl alcohol, sec-butyl alcohol,tert-butylalcohol, and phenol; and ß-propiolactone and ß-butyro)actone. Pentyl acetate, phenylacetate, and ß-butyrolactone were selected for interspecies and intertissue comparisons.

Results and discussion

Preliminary studies:
None

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not investigated
Details on distribution in tissues:
Not investigated
Details on excretion:
Not investigated

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No data

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
No data

Any other information on results incl. tables

Pentyl acetate was the most readily hydrolyzed substrate among the straight chain aliphatic alcohol esters. Phenyl acetate was generally the most rapidly hydrolyzed of all the substrates. ß-Butyrolactone was essentially stable toward hydrolysis at pH 7.4 in the absence of S-9, whereas uncatalyzed hydrolysis of ß-propiolactone was extensive (t1/2 -20 min).  In rats, liver S-9 had the most catalytic activity toward all 3 test substrates, but in rabbits and hamsters the ethmoturbinates equalled or exceeded liver for all substrates except pentyl acetate with rabbit tissues. Lung S-9 consistently had less esterase activity than the other tissues, but trachea S-9 was usually nearly as active as nasal and liver tissues. The potential carcinogen ß-butyrolactone was a relatively poor substrate for rat and hamster S-9 enzymes but was comparable to pentyl acetate in the rabbit. An alcohol chain length of 5 atoms (pentyl acetate) with hydrophobicity constant 2.67 appeared to maximize rate of hydrolysis of acetate esters with the highly active ethmoturbinate-derived S-9. Straight chain alcohol esters were most rapidly hydrolyzed and tert-butyl alcohol had the slowest hydrolysis rate among 4-carbon alcohol acetates

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The results of this study indicate the rapid hydrolysis of esters including hexyl acetate, following inhalation exposure.
Executive summary:

Data support the hypothesis that the metabolism of inhaled xenobiotics may occur extensively in the respiratory tract. Using the rat as an example, it is calculated that hydrolytic enzymes in the nasal cavity can hydrolyze a major portion of acetate esters inhaled at commonly encountered air concentrations.  Calculations, based upon the experimental results, indicate that inhaled esters may be largely converted to hydrolysis products in the nasal cavity.