γ-valerolactone

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Data published in 1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Comparison of CNS activity of different lactones in mice.
- Short description of test conditions: In a study in mice, the CNS activity of five different lactones was investigated. Groups of six mice, three males and three females weighting 17-27 g, were injected intraperitoneally with an aqueous solution of the test item. Signs of CNS activity or other changes were observed continuously for 2 hours and then at regular intervals for 2 days.
- Parameters analysed / observed: Cage side observations, neurological parameters (righting reflex, paralysis of the hind legs).

GLP compliance:

no

Specific details on test material used for the study:

Not specified

Radiolabelling:

no

Species:

mouse

Strain:

not specified

Details on species / strain selection:

Not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 17-27 g

Route of administration:

intraperitoneal

Vehicle:

water

Details on exposure:

Not specified

Duration and frequency of treatment / exposure:

Single treatment

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

3 males and 3 females

Control animals:

not specified

Positive control reference chemical:

Not specified

Details on study design:

Not specified

Details on dosing and sampling:

Not specified

Statistics:

Not specified

Type:

metabolism

Results:

The test item in alkaline medium showed no appreciable hydrolysis by liver ersterase preparations that were reactive toward methyl butyrate.

Type:

distribution

Results:

- decreased CNS depressant activity of lactones when a methyl group is attached to the α or γ position
- no loss of righting reflex at 2000 mg/kg bw after treatment with the test item
- potential local anesthetic activity on the peripheral nervous system

Details on absorption:

Not specified

Details on distribution in tissues:

Partial paralysis of the hind legs was observed at 1000 mg/kg bw, indicating local anesthetic activity on the peripheral nervous system. Mild sedation at 1000 mg/kg bw, indicating a decreased CNS activity compared to γ-butyrolactone, although the lipophilic character is increased.

Metabolites identified:

not specified

Details on metabolites:

Not specified

Enzymatic activity measured:

Not specified

Bioaccessibility (or Bioavailability) testing results:

Not specified

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Adequacy of study:

weight of evidence

Study period:

Data published in 1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Short summary of results from a data collection. The effect of pH on lactone ring hydrolysis of γ-valerolactone was studied in vitro by incubating the material with simulated intestinal fluid.
- Short description of test conditions: 1 mM of γ-valerolactone (purity 98.7%) was incubated with 50 mL of simulated intestinal fluid for 15, 30, 45, 60, and 240 min; an additional 1mM was incubated with 100 mL of intestinal fluid for 60 and 240 min. All samples were maintained at 37 °C and pH 7.5.
- Parameters analysed / observed: The degrees of opening of the lactone ring at 15, 30, 45, 60, and 240 min following incubation with 50 mL of intestinal fluid and after 60 and 240 min following incubation with 100 mL intestinal fluid

Original data from RIFM, 1962 / NTRL, 1985

GLP compliance:

not specified

Specific details on test material used for the study:

Purity: 98.7%

Radiolabelling:

no

Type:

metabolism

Results:

32%, 34%, 31%, 35%, and 32% opening of the lactone ring at 15, 30, 45, 60, and 240 min (50 mL intestinal fluid) and 48% and 50% after 160 and 240 min (100 mL intestinal fluid)

The degrees of opening of the lactone ring at 15, 30, 45, 60, and 240 min following incubation with 50 mL of intestinal fluid resulted in 32%, 34%, 31%, 35%, and 32%, respectively; whereas incubation with 100 mL for 60 and 240 min resulted in 48% and 50%, respectively. The results indicated that there was only a partial breakdown of the lactone ring at intestinal pH levels.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Data published in 1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Short summary of results from a data collection. The metabolism of γ-valerolactone was studied in vitro by incubation with rat liver homogenate and measurement of the degree of lactone ring opening.
- Short description of test conditions: 2 g of rat liver homogenate was incubated for 1 hour with the test item (purity 98.6%) at concentrations of 0, 0.5, 1, and 2 mM in 50 mL of phosphate buffer (pH 7.5) at 37 °C.
- Parameters analysed / observed: The degrees of opening of the lactone ring at 0.50, 1, and 2mM were measured as 93%, 92%, and 93%, respectively.

Original data from RIFM, 1963 / NTRL, 1985

GLP compliance:

not specified

Specific details on test material used for the study:

Not specified

Radiolabelling:

no

Type:

metabolism

Results:

93%, 92% and 93% opening of lactone rings at 0.5, 1 and 2 mM of the test item in rat liver homogenate

Metabolites identified:

yes

Details on metabolites:

Degrees of opened lactone rings

Enzymatic activity measured:

Not specified

The degrees of opening of the lactone ring at 0.50, 1, and 2mM were reported as 93%, 92%, and 93%, respectively.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Neurotoxicity study, γ-valerolactone was administered to male rats intraperitoneally at dose levels of 0 (vehicle) and 400 mg/kg/day and metabolites were measured in blood and brain.
- Short description of test conditions: Male rats were administered 400 mg/kg/day of γ-valerolactone
- Parameters analysed / observed: Detection of the metabolites in the blood and brain

GLP compliance:

not specified

Specific details on test material used for the study:

No details given

Radiolabelling:

not specified

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Not specified

Route of administration:

intraperitoneal

Vehicle:

not specified

Details on exposure:

Not specified

Duration and frequency of treatment / exposure:

Not specified

Dose / conc.:

400 mg/kg bw/day

Dose / conc.:

0 mg/kg bw/day

Remarks:

vehicle

No. of animals per sex per dose / concentration:

Not specified

Control animals:

not specified

Positive control reference chemical:

Not specified

Details on study design:

Not specified

Details on dosing and sampling:

Not specified

Statistics:

Not specified

Type:

metabolism

Results:

Metabolism to 4-methyl hydroxybutyrate, both 4-methyl hydroxybutyrate and γ-valerolactone were detected in the blood and brain.

Type:

distribution

Results:

4-methyl hydroxybutyrate (metabolite) and γ-valerolactone were detected in the blood and brain

Description of key information

The metabolism of γ-valerolactone was studied in two in vitro studies, revealing that the γ-valerolactone is metabolised up to 50% in intestinal fluid and up to 93% in rat liver homogenate. In an in vivo study, γ-valerolactone as well as a metabolite, 4-methyl-γ-hydroxybutyrate, was detected in blood and brain of male rats after intraperitoneal administration. In an in vivo study in mice, γ-valerolactone induced mild CNS depressant activity and local anesthetic activity on the peripheral nervous system at 1000 mg/kg bw, indicating that γ-valerolactone partially crosses the blood-brain-barrier and is distributed to the peripheral nervous system.

 

Conclusion: After oral uptake, γ-valerolactone may be partially broke down by intestinal fluid, absorbed and partially metabolised to its metabolite 4-methyl γ-hydroxybutyrate. It is presumably distributed to different organs, including the brain and the peripheral nervous system via the blood.

Additional information

Metabolism in vitro, RL2

The metabolism of γ-valerolactone was studied in vitro. 2 g of rat liver homogenate was incubated for 1 hour with the test item (purity 98.6%) at concentrations of 0, 0.5, 1, and 2 mM in 50 mL of phosphate buffer (pH 7.5) at 37 °C. The degrees of opening of the lactone ring at 0.50, 1, and 2 mM were measured as 93%, 92%, and 93%, respectively (Api et al., 2019 a, based on RIFM, 1963; NTRL, 1985).

 

Metabolism in vitro, RL2

The effect of pH on lactone ring hydrolysis of γ-valerolactone was studied in vitro by incubating the material with simulated intestinal fluid. 1 mM of γ-valerolactone (purity 98.7%) was incubated with 50 mL of simulated intestinal fluid for 15, 30, 45, 60, and 240 min; an additional 1 mM was incubated with 100 mL of intestinal fluid for 60 and 240 min. All samples were maintained at 37 °C and pH 7.5. The degrees of opening of the lactone ring at 15, 30, 45, 60, and 240 min following incubation with 50 mL of intestinal fluid resulted in 32%, 34%, 31%, 35%, and 32%, respectively; whereas incubation with 100 mL for 60 and 240 min resulted in 48% and 50%, respectively. The results indicated that there was only a partial breakdown of the lactone ring at intestinal pH levels (Api et. al 2019b, based on RIFM, 1962; NTRL, 1985).

 

Metabolism and distribution in vivo, RL2

In a neurotoxicity study (no details on GLP or guidelines used) conducted on male rats, γ-valerolactone was administered intraperitoneally at dose levels of 0 (vehicle) and 400 mg/kg/day. At the end of the study, 4-methyl hydroxybutyrate and γ-valerolactone were detected in the blood and brain. 4-Methyl γ-hydroxy butyrate was found in the blood and brains of all rats examined, which indicated that γ-valerolactone is metabolized to 4-methyl-γ-hydroxy butyrate and that it can cross the blood-brain barrier with a potential to cause locomotor dysfunction (Marinetti et al., 2012).

 

Distribution in vivo, RL2

In a study in mice, the CNS activity of five different lactones was investigated. Groups of six mice, three males and three females weighting 17-27 g, were injected intraperitoneally with an aqueous solution of the test item. Signs of CNS activity or other changes were observed continuously for 2 hours and then at regular intervals for 2 days. Mild sedation, but no loss of the righting reflex was observed at 1000 mg/kg bw of γ-valerolactone. At the same dose level, paralysis of the hind legs was observed, indicating local anesthetic acticity on the peripheral nervous system. The five investigated lactones decreased in CNS activity with additional alkyl groups and increasing lipophily (Lien et al., 1973).