Butyl 2,3-epoxypropyl ether

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in 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

Data source

Reference

Reference Type:

publication

Title:

Metabolism and Disposition of n-Butyl Glycidyl Ether in F344 Rats and B6C3F1 Mice

Author:

Chen L.-J, Lebetkin E.H., Nwakpuda E.I., and Burka L.T.

Year:

2007

Bibliographic source:

Drug Metabolism And Disposition Vol. 35, No. 12

Materials and methods

Objective of study:

distribution

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

The disposition of [14C]-labeled n-butyl glycidyl ether (BGE) was studied in rats and mice.
Male and female rats and mice were dosed by gavage. Urine and faeces were collected 24 hours after dosing. Excretion of the substance in urine and faeces was measured and also in expired air for male rats and male and female mice. Tissue distribution was assessed, based on radioactivity and metabolites were identified in urine.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butyl 2,3-epoxypropyl ether

EC Number:

219-376-4

EC Name:

Butyl 2,3-epoxypropyl ether

Cas Number:

2426-08-6

Molecular formula:

C7H14O2

IUPAC Name:

2-(butoxymethyl)oxirane

Test material form:

liquid

Specific details on test material used for the study:

[n-Butyl-1'-14C]-BGE (specific activity, 55 mCi/mmol; radiochemical purity, 99.7%)

Radiolabelling:

yes

Test animals

Species:

other: Rats and Mice

Strain:

other: Fischer 344 and B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Rats:
- Source: Charles River Laboratories (Kingston, NY)
- Age at study initiation: Males 11.5–12.5 weeks old, and females 13 weeks old
- Weight at study initiation: Males 233–276 g, and females 179–196 g
- Housing: individually in metabolism cages allowing for the collection of urine, feces, and expired air
- Diet:National Institutes of Health #31, ad libitum
- Water: ad libitum

Mice:
- Source: Charles River Laboratories (Raleigh, NC)
- Age at study initiation: Males 8 weeks old, and females 7-9 weeks old
- Weight at study initiation: Males 24–27 g, and females 19–22 g
- Housing: individually in metabolism cages allowing for the collection of urine, feces, and expired air
- Diet:National Institutes of Health #31, ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Dose volume: rats 5 mL/kg; mice 10 mL/kg

Duration and frequency of treatment / exposure:

single administration

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 mg/kg bw/day (actual dose received)

Remarks:

Male rats and female mice

Doses / concentrations 2

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Remarks:

Male rats and female mice

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Remarks:

Male rats and female mice

Doses / concentrations 4

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Remarks:

Female rats and male mice

No. of animals per sex per dose / concentration:

4 or 5

Details on dosing and sampling:

Urine and feces were collected 24 h following dosing. The metabolism cages were rinsed with distilled water at the end of each study to increase urine recovery. Urine aliquots were counted for 14C in a liquid scintillation counter and the remainder was stored at -20 °C. Feces were air-dried, weighed, and ground to a powder using a ceramic mortar and pestle. The amount of BGE-derived radioactivity in expired air was determined for male rats receiving a single 20-mg/kg p.o. dose and in both male and female mice.
After the animals were euthanized by CO2 asphyxiation, blood was drawn by cardiac puncture, and the following tissues were collected: liver, kidney, lung, pancreas, thyroid, thymus, adrenal glands, abdominal muscle, skin (ear pinna), fat (abdominal), brain, testes or uterus, forestomach, glandular stomach, small intestine, and large intestine. All the tissue weights were determined gravimetrically, except blood, fat, skin, and muscle, which were estimated to be 8, 11, 16, and 50% of total body weight, respectively.
Tissue and feces aliquots (triplicate 50–100-mg samples from rats,up to 100 mg from mice) were oxidized and counted in the liquid scintillation counter for determination of total 14C.
Urine collected 24 h post-dosing from male rats dosed p.o. with BGE (200 mg/kg) was analyzed by the HPLC with radiochemical detection to reveal 13 radio-labeled peaks. The metabolites were not observed by UV detection, so the isolation of these urinary metabolites was accomplished by collection of HPLC fractions at 1-min intervals between 8 and 28 min and the metabolites were characterized by MS and 1H NMR.

Results and discussion

Main ADME results

Type:

excretion

Results:

Excretion, rats: urine 84–92% within 24 h, feces: 2.6 –7.7%, expired air (0.1% volatiles and 1.5% CO2, 20 mg/kg), remained in the tissues (1.8–4.4%). Excretion, mice: urine 64-73%, feces 5.3-12%, expired air 10-18% as CO2.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

The BGE-derived radioactivity remaining in tissues 24 h after dosing with 2 to 200 mg/kg accounted for less than 5% of the dose. The concentration of BGE-derived radioactivity in glandular and forestomach is high in mice. Tissue distribution data were obtained for 2 and 20 mg/kg doses for male rats and female mice. The distribution is generally dose-proportional, and with the exception of forestomach, the data for the 200-mg/kg dose adequately describe the distribution of lower doses. Forestomach concentration after a p.o. dose of 2, 20, and 200 mg/kg was 42, 530, and 1770 nmol/g in female mice and 9.6, 90, and 323 nmol/g in male rats.

Details on excretion:

Most of the dose (2–200 mg/kg) administered to male and female rats was excreted in urine (84–92%) within 24 h. The rest of the dose was excreted in feces (2.6 –7.7%), expired air (0.1% volatiles and 1.5% CO2, 20 mg/kg), or remained in the tissues (1.8–4.4%). There is no obvious dose effect on disposition among the range of doses (2–200 mg/kg) in male rats. Female rats have less of the dose remaining in tissues compared with males. Most of the dose given to male and female mice was also excreted in urine (64–73%). Mice appeared to excrete a larger percentage of the dose in feces (5.3–12%), but separation of urine and feces in mouse metabolism cages was not complete, and contamination of urine with feces occurred in some experiments. Mice excreted a larger percentage of the p.o. dose in expired air as 14CO2 (10–18%) and had less remaining in the tissues (1.5–1.7%) than rats within 24 h. Mice that received a 200-mg/kg dose excreted more 14CO2 than the lower dose treatment (2 and 20 mg/kg). The total recovery was 93 to 98% for rats and 88 to 97% for mice.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

No parent BGE was detected in rat or mouse urine. Fifteen urinary metabolites were identified, including 3-butoxy-2-hydroxy-1-propanol and its monosulfate or monoglucuronide conjugates, 3-butoxy-2-hydroxypropionic acid, O-butyl-N-acetylserine, butoxyacetic acid, 2-butoxyethanol, and 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol, the mercapturic acid metabolite derived from conjugation of glutathione (GSH) with BGE at the C-1 position. Some of these metabolites underwent further ω-1 oxidation to form a 3'-hydroxybutoxy substitution. One urinary metabolite was from ω-oxidation of 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol to yield the corresponding carboxylic acid. Oxidative deamination of 3-butoxy-1-(cystein-S-yl)-2-propanol gave the corresponding α-keto acid and α-hydroxy acid metabolites that were present in mouse urine but not in rat urine. An in vitro incubation of BGE with GSH showed that the conjugation occurred only at the C-1 position with or without the addition of GSH S-transferase.