(tert-butoxymethyl)oxirane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Study period:

1984-11-08

Justification for type of information:

Read-across

Data source

Reference

Reference Type:

publication

Title:

The metabolism of n-butyl glycidyl ether in the rat and rabbit

Author:

Eadsforth CV

Year:

1984

Bibliographic source:

Eadsforth, C. V., D. H. Hutson, C. J. Logan, and B. J. Morrison. "The metabolism of n-butyl glycidyl ether in the rat and rabbit." Xenobiotica 15, no. 7 (1985): 579-589.

Report Date:

1984

Materials and methods

Principles of method if other than guideline:

- Principle of test: Elimination of test item in rats and rabbits and the identification of major urinary metabolites, which may provide the basis of amethod for exposure monitoring
- Short description of test conditions: Animals given a single oral dose of test item, housed individually and fed with food and water ad libitum.
- Parameters analysed / observed: elimniation and retention of n-BGE.

GLP compliance:

no

Test material

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Fluorochem Ltd (Dinting Lane, Glossop, Derbyshire, UK); [1-14C]Butyl glycidyl ether supplied by ICI Radioisotope Section (Billingham, Cleveland, UK)
- Expiration date of the lot/batch: Not reported
- Purity test date: Not reported

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: >98%, as measured by radio g.l.c.
- Specific activity: 3.52 Ci/mol (total activity 2.4 mCi)
- Locations of the label: Not reported
- Expiration date of radiochemical substance: Not reported

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Stored under argon at 4°C
- Stability under test conditions: Not reported
- Solubility and stability of the test substance in the solvent/vehicle: Not reported

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: diluted in corn oil (Rats); double-gelatin capsule (Rabbit)
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel: 41 mg n-butyl glycidyl ether and 15 mg 14C-n-butyl glycidel ether made up to 2.5 mL corn oil (Rats); 160 ul 14C-n-butyl glycidyl ether and 63 mg n-butyl glycidyl ether dispensed into a double-gelatin capsule
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Dissolved in corn oil (Rat); Double-gelatin capsule (Rabbit)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Sittingbourne Research Centre, Rodent Breeding Unit
- Age at study initiation: Not reported
- Weight at study initiation: 250 g
- Housing: Housed individually in numbered plastic metabowls
- Diet (e.g. ad libitum): PRD pellets (Labsure Animal Diets LTd, Poole, Dorset, UK)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: starved overnight before dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Room temperature
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hour light/12 hour night

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
13C-nBGE (5.6 mg, equiv. to approx. 20 mg/kg body weight, 42.3 uCi) in corn oil (0.25) in a Hamilton 1000 ul gas-tight glass syringe

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Dose / conc.:

20 mg/kg bw (total dose)

No. of animals per sex per dose:

5

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces
- Time and frequency of sampling: collected during 24 hour periods for 3 days at room temperature

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces
- Time and frequency of sampling: collected during 24 hour periods for 3 days at room temperature
- From how many animals: (samples pooled or not) : pooled; 5 rats
- Method type(s) for identification: HPLC, hydrolysis, analytical thin-layer chromatography, liquid-scintillation, nuclear magnetic resonance spectroscopy, mass spectrometry

Results and discussion

Preliminary studies:

N.A.

Main ADME results

Main ADME results 1

Type:

excretion

Results:

87% excreted in urine within 24h

Main ADME results 2

Type:

excretion

Results:

92% excreted in urine within 96h

Toxicokinetic / pharmacokinetic studies

Details on absorption:

N.A.

Details on distribution in tissues:

N.A.

Details on excretion:

Further elimination of the administered radioactivity over the three days following 24 hours post-administration was minmal.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolite A (butyoxyacetic acid): 10% excreted, Rf value = 0.92
Metabolite D (p-bromphenacyl ester of 3-butoxy-2-acetylaminopropionic acid): 23% excreted, Rf value = 0.75
Metabolite E (p-bromophenacyl ester of 3 butoxy-2-hydroxypropionic acid): 9% excreted, Rf value = 0.68
Metabolite F (decomposed to amore polar metabolite and no further work was done to identify the compound): 19% excreted, Rf value = 0.57

Applicant's summary and conclusion

Conclusions:

[l-14C]Butyl glycidyl ether when administered to rats or rabbits as a single oral dose (20mg/kg) was rapidly absorbed and eliminated as a complex mixture of metabolites in the urine. The major urinary metabolites were identified as 3-butoxy2-hydroxypropionic acid, 3-butoxy-2-acetylaminopropionic acid and butoxyacetic acid. The structures of the identified products show that a major route of biotransformation of n-butyl glycidyl ether in rat was via hydrolytic opening of the epoxide ring followed by oxidation of the resulting diol to 3-butoxy-2-hydroxypropionic acid and subsequent oxidative decarboxylation to give butoxyacetic acid. Another major metabolite, 3-butoxy-2-acetylaminopropionic acid is novel, and the authors conclude that these reactions represent efficient detoxication of this molecule.

Executive summary:

[l-14C]Butyl glycidyl ether when administered to rats or rabbits as a single oral dose (20mg/kg) was rapidly absorbed and eliminated as a complex mixture of metabolites in the urine. This test item was used as read-across substance for tert-butyl glycidyl ether. The major urinary metabolites were identified as 3-butoxy2-hydroxypropionic acid, 3-butoxy-2-acetylaminopropionic acid and butoxyacetic acid. The structures of the identified products show that a major route of biotransformation of n-butyl glycidyl ether in rat was via hydrolytic opening of the epoxide ring followed by oxidation of the resulting diol to 3-butoxy-2-hydroxypropionic acid and subsequent oxidative decarboxylation to give butoxyacetic acid. Another major metabolite, 3-butoxy-2-acetylaminopropionic acid is novel, and the authors conclude that these reactions represent efficient detoxication of this molecule.