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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:
supporting study
Study period:
no data
Reliability:
4 (not assignable)
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1962
Report Date:
1962

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
Determination of the degree of breakdown under in vitro digestion conditions using intestinal fluid
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Gamma-Undecalactone CP; so called Aldehyde C-14
- Laboratory reference sample: B-7095
- Source: Givaudan
- Physical state: no data
- Analytical purity: 97.0 % (as determined by alkali consumption)
- Stability under test conditions: no data
- Storage condition of test material: no data
Radiolabelling:
no

Test animals

Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
15, 30, 45, 60, 240 minutes
Doses / concentrations
Dose / conc.:
1 other: mM
No. of animals per sex per dose:
Not applicable
Positive control:
None
Details on study design:
1 mM of gamma-undecalactone was incubated and shaken at 37 °C, with 50 mL portions of simulated intestinal fluid for 15, 30, 45, 60 and 240 minutes. The simulated fluid is that described in the United States Pharmacopeia and consists of an aqueous mixture of monoblastic potassium phosphate, sodium hydroxide, and pancreatin adjusted to pH 7.5.
Details on dosing and sampling:
Following incubation, the solutions were extracted with ether and the unconverted gamma-undecalactone determined by adding standard alkali, heating, and back titrating the unconsumed base with standard acid. Results were calculated with respect to the known quantity of gamma-undecalactone present in the analytical sample, as determined by duplicate purity measurements. These were carried out by addition of one gram of each lactone to 25 mL of 0.5 N alcoholic potassium hydroxide. The solution was refluxed for one hour on a steam bath and then back-titrated with 0.1 N hydrochloric acid.
Statistics:
None

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

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

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not applicable

Any other information on results incl. tables

Partial conversion by the intestinal fluid was observed (See Table 7.1.1/1). Increased time (240 minutes) and/or doubling volume of intestinal fluid does bring about further ring opening although still not complete. It appears that pH is a rather critical factor in these experiments, and that the 7.5 value at the onset of the exposure constitutes the borderline of a "go-no-go" reaction for gamma-undecalactone. The small decrease brought about during the first minutes of exposure, as a result of alkali consumption for ring opening, sufficiently lowers the pH to virtually a non-reactive condition. Increased quantities of base available from the doubled volume exposures, permits a greater degree of reaction in a shorter period of time. Increased time (to four hours) with a single volume of intestinal fluid allows the gamma-undecalactone to proceed further.

Table 7.1.1/1: Lactone opening in intestinal fluid

Sample

Purity (%)

Degree of lactone opening with time (%)

15 min

30 min

45 min

60 min

60* min

240 min

240* min

Gamma-undecalactone

97.0

24

19

22

19

68

58

62

* using twice the quantity (100 mL) of intestinal fluid per millimole.

A 1-h incubation of 1 mmol 4,4-dibutyl-Ɣ-butyrolactone and omega-6-hexadecenlactone with 50 mL of simulated intestinal fluid resulted in 92% and 96% hydrolysis, respectively, yielding the ring-opened hydroxycarboxylic acids. Ninety-two percent of the omega-6-hexadecenlactone was hydrolysed within the first 15 min of incubation. Incubation of 1 mmol ofƔ-valerolactone and Ɣ-undecalactone with 50 mL of simulated intestinal fluid resulted in 32% and 58% hydrolysis within 4 h, respectively. Doubling the volume of intestinal fluid resulted in a 50% and 62% hydrolysis of Ɣ-valerolactone andƔ-undecalactone, respectively, within the same period of time

Applicant's summary and conclusion

Conclusions:
Only partial conversion of γ-Undecalactone by the intestinal fluid was observed.
Executive summary:

The degree of breakdown of γ-Undecalactone and γ-Nonalactone under in vitro digestion was determined using intestinal fluid.

Incubation of γ-Nonalactone and γ-Undecalactone with rat liver homogenate in buffer solution at pH 7.5 resulted in 62–94% and 26–40% hydrolysis within 1 h, respectively. After 1 h, 81–88% and 45–70% hydrolysis of γ-Nonalactone andγ-Undecalactone, respectively, occurred at pH 8.0.

Only partial conversion of γ-Undecalactone by the intestinal fluid was observed. Increased time (240 minutes) and/or doubling volume of intestinal fluid does bring about further ring opening although still not complete. It appears that pH is a rather critical factor in these experiments, and that the 7.5 value at the onset of the exposure constitutes the borderline of a "go-no-go" reaction for γ-Undecalactone.

The small decrease brought about during the first minutes of exposure, as a result of alkali consumption for ring opening, sufficiently lowers the pH to virtually a non-reactive condition. Increased quantities of base available from the doubled volume exposures, permits a greater degree of reaction in a shorter period of time. Increased time (to four hours) with a single volume of intestinal fluid allows the γ-Undecalactone to proceed further.