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Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Stoffwechsel von mittelkettigen und langkettigen Triglyceriden in Mischemulsionen für die Infusionstherapie - Untersuchungen an Probanden und im Tierexperiment
Author:
Schulz, A.
Year:
2002
Bibliographic source:
Inaugural-Dissertation, Fachbereich Biochemie, Pharmazie und Lebensmittelchemie, Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany

Materials and methods

Type of study / information:
Study with human volunteers on the use of Medium and Long Chain Triglycerides for parenteral nutrition.
Endpoint addressed:
basic toxicokinetics
Principles of method if other than guideline:
Different types of lipid emulsions for parenteral nutrition were infused to male volunteers.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lipidol ½ MCT 20%
- Name of test material (as cited in study report): Lipidol ⅓ MCT 20%
For composition details see Tables 1 and 2.

Method

Ethical approval:
not specified
Details on exposure:
STUDY POPULATION
- Selection criteria: The volunteers were free of any metabolic diseases and were not treated with any pharmaceuticals.
- Total number of subjects participating in study: 80
- Sex/age: male/18-40

TYPE OF EXPOSURE: Infusion
Before intravenous exposure a 12 hour fasting period was kept.
During exposure no additional energy supply was allowed to avoid any influence on the lipid metabolism.

TYPES OF EXPERIMENTS:
1) Single bolus injection: 10 g triglycerides in 3 minutes, 10 subjects per tested lipid emulsion
2) Short time infusion: 50 g triglycerides in 30 minutes, 10 subjects per tested lipid emulsion
3) 12 h infusion: 0.1 g triglycerides/kg bw/h, 10 subjects per tested lipid emulsion
4) 8 h infusion: 0.25 g triglycerides/kg bw/h, 10 subjects per tested lipid emulsion

TYPE OF EXPOSURE MEASUREMENT: Biomonitoring blood
Analysed blood parameter: total triglyceride concentration, fatty acid composition, max. triglyceride concentrations, increase of ketone bodies.
Additionally a new GC-method was used to measure MCT concentrations.


Results and discussion

Results:
Intravenous application of triglycerides in human subjects at concentrations of 100 mg/kg bw/h were well tolerated resulting in a dynamic equilibrium.

Any other information on results incl. tables

Toxicokinetics Single bolus injection:

After single bolus injection of 10 g triglycerides, human serum triglyceride concentrations measured 1 minute after injections were increased to 373 % and 320 %, respectively (using two different lipid emulsions). Maximum measured serum triglyceride concentrations were 601 mg/dL (Lipidol ⅓ MCT 20%) and 630 mg/dL (Lipidol ½ MCT 20%) after initial values of 128 - 150 mg/dL. Elimination half-times were between 15.1 minutes (kel4.6 % per min) for Lipidol ½ MCT 20% and 27.9 minutes. (kel2.48 % per min) for Lipidol ⅓ MCT 20%.

 

Short time infusion - 50 g triglycerides in 30 minutes:

Maximum measured human serum triglyceride concentrations were 1992 mg/dL (Lipidol ⅓ MCT 20%) and 1964 mg/dL (Lipidol ½ MCT 20%) after initial values of 108 - 128 mg/dL. Elimination half-times were between 46.2 minutes (kel1.5 % per min) for Lipidol ½ MCT 20% and 54.6 minutes. (kel1.27 % per min) for Lipidol ⅓ MCT 20%.

 

After infusion of higher triglyceride concentrations a high increase of the elimination half-times was observed:

 

12 h infusion - 0.1 g triglycerides/kg bw/h:

Within 3-4 hours maximum measured human serum triglyceride concentrations were 236 mg/dL (Lipidol ⅓ MCT 20%) and 287 mg/dL (Lipidol ½ MCT 20%) after initial values of 100 - 120 mg/dL. With both lipid emulsions a dynamic equilibrium was observable with serum triglyceride concentrations of 200 - 250 mg/dL. After 9 hours a steady state concentration of 177-200 mg/dL serum triglycerides was measured.

 

8 h infusion - 0.25 g triglycerides/kg bw/h:

No dynamic equilibrium could be observed. The elimination capacity was exceeded. The maximum measured human serum triglyceride concentrations were 1449 mg/dL (Lipidol ⅓ MCT 20%) and 1305 mg/dL (Lipidol ½ MCT 20%) after initial values of 94.3 and 75.8 mg/dL. 4 hours after termination of infusion, the triglyceride concentrations were still 4-5 fold of the initial values, indicating a slow elimination.

Other observations:

After infusion of both lipid emulsions a significant increase of fatty acid concentrations was measured, indicating a rapid hydrolysis of Triglycerides after intravenous application. After infusion of high dose triglycerides a remarkable increase of caprylic acid and decanoic acid concentrations were measured, clearly exceeding physiologic reference values.

After high dose infusion some subjects stated sickness.

Measured ketone body concentrations were proportionally higher with higher MCT content in lipid emulsions.

 

Applicant's summary and conclusion

Conclusions:
Medium chain and long chain triglycerides are used in humans for parenteral nutrition.
Well tolerated intravenous concentrations during a 12 hour infusion were found to be 100 mg triglycerides/kg bw/h.