Nonane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic hydrocarbons in rat after repeated exposures

Author:

Zahlsen, K. et al.

Year:

1992

Bibliographic source:

Pharmacology & Toxicology 71: 144-149

Reference 2

Reference Type:

publication

Title:

Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4-trimethylbenzene) and naphtenic (1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation.

Author:

Zahlsen, K. et al.

Year:

1990

Bibliographic source:

Pharmacology & Toxicology 67: 436-440

Materials and methods

Objective of study:

distribution

toxicokinetics

Principles of method if other than guideline:

14 day toxicokinetic study in rats.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nonane

EC Number:

203-913-4

EC Name:

Nonane

Cas Number:

111-84-2

Molecular formula:

C9H20

IUPAC Name:

nonane

Details on test material:

- Name of test material (as cited in study report): n-Nonane
- Analytical purity: no data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Møllegaard A/S, L1, Skensved, Denmark
- Weight at study initiation: 150 - 200 g
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±1 during exposure
- Humidity (%): 70 ± 20 during exposure
- Photoperiod (hrs dark / hrs light): 10/14

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: conical 0.7 m³ inhalation chambers with a glass front door and walls, accommodating 4 cages each containing up to 6 rats each.
TYPE OF INHALATION EXPOSURE: whole body

Dynamic exposure of anomals was performed in conically shaped 0.7 m3 steel chambers with glass front door and walls as described elsewhere (Walseth & Nilsen 1984). The concentration of hydrocarbons in the inhalation chambers was monitored automatically by on-line gas chromatography, Concentrations were measured in 15 min intervals. The injected sample was separated at 200°C on a 2m x1/8'' stainless steel column packed with GP 10% SP-2100 on Supelcoport 100/120 mesh, with helium as carrier gas. The hydrocarbons were detected by flame ionization (FID) with injector and detector temperatures of 250°. The daily mean concentration was calculated from all measurements performed after the first hour of exposure. During this first hour the concentration exceeded 95% of the steady state concentration.

Duration and frequency of treatment / exposure:

1, 3, 7, 10 and 14 days, 12 hours/day

Doses / concentrations

Remarks:

Doses / Concentrations:
5.18 (day 1), 5.24 (day 3), 5.51 (day 7), 5.49 (day 10) and 5.46 (day 14) mg/L, respectively (corresponding to 987, 1000, 1051, 1047 and 1041 ppm, respectively)

No. of animals per sex per dose / concentration:

4 per exposure duration

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

The aimed concentration was 1000 ppm. All exposures were performed at daytime for 12 hr (8 a.m. - 8 p.m.). Measurements were done on days 1, 3, 7, 10, and 14 after 12 hr exposure. Animals were one by one removed, killed, and blood and organs obtained within 3 min after removal from exposure chamber.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, brain, perirenal fat
- Time and frequency of sampling: day 1, 3, 7, 10 and 14, within 3 min of removal from inhalation chamber

Statistics:

Student's t-test. Differences in mean concentrations between groups of unequal size were tested by Cochran t-test after comparison of variances by F-test. p<0.05 for statistical significance.

Results and discussion

Preliminary studies:

Not performed

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not addressed.

Details on distribution in tissues:

n-Nonane demonstrated the highest concentration in blood and brain tissue on day 1 after exposure with gradually decreasing levels thereafter. In perirenal fat, a different pattern was seen with concentrations increasing significantly from day 1 to day 3, thereafter decreasing rapidly from day 7 to 14. The brain/blood concentration ratio was 11.4 and the fat/blood ratio was 113 at day 14.

In comparison with the aromatic and naphthenic hydrocarbons with which it was tested, n-nonane showed the highest accumulation potential in the brain concurrent with a low concentration in the blood. The lower solubility and lower absorption efficiency may facilitate further transportation of alkanes to the brain resulting in transient CNS effects.

Transfer into organs

Key result

Test no.:

#1

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Details on excretion:

Not addressed.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Tissue values extrapolated from graphs:

Day	1	3	7	10	14
ppm	987	1000	1051	1047	1041
Blood (µmol/L)	174	140	125	95	94
Brain (µmol/kg)	1416	1200	1200	1050	1000
Fat (µmol/kg)	12500	15980	13500	10000	7500

Conclusion:

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.

In subsequent studies, Zahlsen et al. 1992 corroborated these observations for n-alkanes administered at lower concentration of 100 ppm for 12 hours for 3 days: low concentration in blood, relatively high concentration in brain and potential for accumulation in fat with repeated exposure up to day 3 termination.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: other: see conclusions below

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.

Executive summary:

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.