γ-butyrolactone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only short study description; summary report

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Objective of study:

distribution

metabolism

Principles of method if other than guideline:

NTP-internal standard

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Butane-1,4-diol

EC Number:

203-786-5

EC Name:

Butane-1,4-diol

Cas Number:

110-63-4

Molecular formula:

C4H10O2

IUPAC Name:

Butane-1,4-diol

Details on test material:

- Name of test material (as cited in study report): 1,4-Butanediol
- Lot/batch No.: CFQ.5344
- Radiochemical purity (if radiolabelling): 97%
- Specific activity (if radiolabelling):20 µci
- Locations of the label (if radiolabelling): C-1 and C-4 carbons labeled

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: Roth-type glass metabolism chambers (Jencons Scientific, Ltd)
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled

Details on exposure:

no further details

Duration and frequency of treatment / exposure:

72 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
4, 40, 120, or 400 mg/kg. Each dose formulation was formulated to contain 20 microcuries of radiolabeled 1,4-butanediol with an appropriate amount of unlabeled 1,4-butanediol and distilled water to provide for a single dose of 5 mL/kg test animal body weight.

No. of animals per sex per dose / concentration:

4

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: breath, urine, feces, blood, adipose, muscle, skin, liver, and brain.
- Time and frequency of sampling:
- urine and feces: 8, 24, 48, and 72 hours after dosing
- breath: 2, 4, 8, 12, 24, 32, 48, 56, and 72 hours after dosing
- tissue: at the end of the experiement (72 hours)

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Rapid by the oral route as evidenced by approximately 50% of administered dose excreted within 2 hours of dosing.

Main ADME results 2

Type:

distribution

Results:

Persistence in tissues 72 hours after oral administration is low, accounting for approximately only 2% of the administered dose.

Main ADME results 3

Type:

excretion

Results:

Approximately 85% of oral dose excreted as carbon dioxide in exhaled breath within 72 hours of dosing. Excretion in urine after 72 hours accounted for 3 to 6% of administered dose, and 0.04 to 0.6% in feces.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

gamma-hydroxybutyric acid, succinic acid, and carbon dioxide.

Any other information on results incl. tables

Within the first 2 hours after administration of 4, 40, or 120 mg/kg, approximately 50% of the administered radiolabel was eliminated as ¹⁴CO2. After 4 hours, approximately 80% of the administered radiolabel had been eliminated as ¹⁴CO2 , and at the end of the 72-hour recording period a total of 85% to 86% of the administered dose had been eliminated as ¹⁴CO2. ¹⁴CO2 accounted for 94% of the radiolabel recovered in excreta. Approximately 4% of the administered radioactivity was excreted in the urine and 0.6% in the feces over the 72-hour collection period, with the majority of material excreted within the first 4 hours after administration. At 400 mg/kg, slight saturation of elimination was apparent at the early time points, as evidenced by somewhat slower formation of ¹⁴CO2; however, at later time points, the total production of ¹⁴CO2 was close to that observed at the lower doses.

The distribution of radioactivity was also studied. Seventy-two hours after administration, a total of 2.28% of the dose remained in the carcass, with the largest amounts present in liver, muscle, and skin. The greatest concentration of test article per gram of tissue was in liver and skin. There was no evidence of bioaccumulation in any tissue. The results indicate that 1,4-butanediol is rapidly metabolized and excreted, primarily as CO2, clearly showing that conversion to gamma-hydroxybutyric acid and succinic acid and processing through the tricarboxylic acid cycle is the major route of degradation.

According to NTP (NTP, 1996), the current literature documents that both 1,4-butanediol and gamma-butyrolactone are rapidly metabolized to gamma-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to gamma-hydroxybutyric acid.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results rapidly metabolized and excreted as carbon dioxide
This summary report presents a review of the current literature, and presents the results of NTP's own study of absorption and excretion, and documents that both 1,4-butanediol and gamma-butyrolactone are rapidly metabolized to gamma-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to gamma-hydroxybutyric acid.

Executive summary:

1,4 -butanediol is rapidly metabolized and excreted as carbon dioxide.