Isovaleraldehyde

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting 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:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Plasma samples were taken after sarifice of test animals fed with various diets and 3-methylbutanal levels were analyzed using a capillary column GC-FID method. In addition, the effect of neomycin on plasma 3-methylbutanal levels and the influence of 3-methylbutanal on central nervous system function and neurotransmitter metabolism was investigated.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Isovaleraldehyde

EC Number:

209-691-5

EC Name:

Isovaleraldehyde

Cas Number:

590-86-3

Molecular formula:

C5H10O

IUPAC Name:

3-methylbutanal

Details on test material:

- Name of test material (as cited in study report): 3-methylbutanal (obtained from Aldrich Chemicals Co Inc., Milwaukee, WI, USA)
- Analytical purity: no data
- no further information on test substance

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Canadian Breeding Laboratories, Montreal,Quebec, Canada
- Age at study initiation: young and adult rats
- Weight at study initiation: young rats: 205 ± 0.5 g (n=10); adult rats: 416 ± 5.6 g (n=8)
- Fasting period before study: no data
- Housing: individually in wire meshed galvanized cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): prior to feeding experiment: Purina rat chow, Ralston Purtina of Canada, Woodstock, Ontario, Canada, ad libitum;
experimental diet: purified test diet containing 20% casein supplemented with either 5% leucine and/or 0.1% neomycin, ad libitum
- Water (e.g. ad libitum): fresh water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 23°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12 (8:00 - 20:00 light)

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

unchanged (no vehicle)

Details on exposure:

Four different sets of experiments were performed. In all studies, plasma levels of 3-methylbutanal were analyzed.
1. injection study; young rats (n=8)
2. feeding study; young rats (205 g, n=10)
a) casein control diet
b) high leucine diet (5% leucine)
3. feeding study; adult rats (416 g, n=8)
a) casein control diet
b) high leucine diet (5% leucine)
4. feeding study (diet +/- Neomycin); young rats (209 g, n=8)
a) Casein control diet
Casein control + Neomycin diet
b) high leucine diet
high leucine + Neomycin diet

Duration and frequency of treatment / exposure:

Injection study: single ip injection; sacrifice after 9 min
Feeding studies: Diet and additional leucine but no test substance were administered; exposure period: young rats: 1 week, adult rats: 2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
Injection study: 30, 60, and 160 mg/kg bw
feeding study: no 3-methylbutanal administered

No. of animals per sex per dose / concentration:

injection study: 8
feeding studies: 8 - 10

Control animals:

no

Details on dosing and sampling:

METABOLIC/PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: at the end of each experiment
- Method type(s) for identification: GC-FID

Statistics:

Correlation analysis and Student's t-test were conducted as appropriate. A multiple comparison test, with an estimate of the pooled variance was also used to analyze the data.

Results and discussion

Any other information on results incl. tables

Plasma 3-methylbutanal (isovaleraldehyde) and leucine levels

 

Method	Diet / Injected dose [mg/kg bw]	3-Methylbutanal [mg/L]	Leucine [µmol/L]
feeding study; young rats (exposure period 1 week)	casein control diet	0.293 ± 0.050	294*
	high-leucine diet	1.377 ± 0.343**	430*
feeding study; adult rats (exposure period 2 weeks)	casein control diet	0.346 ± 2.60	189 ± 11
	high- leucine diet	0.711 ± 0.097**	289 ± 28**
feeding study (-/+ neomycin); young rats	casein control diet	0.464 ± 0.097	264 ± 41
	casein control diet + Neomycine	0.500 ± 0.137	262*
	high-leucine diet	1.142 ± 0.251**	372 ± 26
	high-leucine diet+ Neomycine	0.436 ± 0.068	360*
injection study (sampling 9 min after injection)	0	0.090	-
	30	0.877	-
	60	1.260	-
	120	2.160	-

 

* pooled analyses ** significantly greater than controls (P< 0.05)

 

3-Methylbutanal (isovaleraldehyde) is present in the plasma of normal rats indicating that it originates naturally from metabolic processes. The mean isovaleraldehyde level in normal rat plasma (0.46 ± 0.1 mg/L, 5.3 ± 1.2 µmol/L) corresponds to levels found in normal man (0.58 ± 0.22 mg/L (6.7 ± 2.6 µmol/L); Goldberg et al, 1979, Model Simulations 10, 167-173).

The increased isovaleraldehyde plasma levels observed with high-leucine diets and their correlation with plasma leucine levels suggest that plasma isovaleraldehyde is derived from leucine. But there is no information if leucine is the only source of isovaleraldehyde in plasma.

Reduction of plasma isovaleraldehyde levels after administration of high-leucine diet and Neomycine indicates that gut bacteria are at least partly involved in the formation of isovaleraldehyde. Again further evidence is lacking if isovaleraldehyde is in addition produced endogenously by mammalian tissues or if it is formed entirely from gut bacteria.

Applicant's summary and conclusion

Conclusions:

Isovaleraldehyde is naturally present in the plasma of rats and humans at levels of ca. 0.5 to 0.6 mg/L (6 to 7 µmol/L). It is formed at least partly from leucine by gut bacteria. Further information is not available if there are other sources and if isovaleraldehyde is additionally produced endogenously by mammalian cells/tissues.