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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-04-07 to 1994-05-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other:
Remarks:
Comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995
Reference Type:
publication
Title:
Modeling of residual variability in toxicokinetic studies with sparse sampling: the case of tetrahydronaphthalene
Author:
Meineke I, Eisele J, Certa H and Gundert-Remy UM
Year:
1998
Bibliographic source:
Arch. Toxicol. 72, 807-810

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Directive 84/449/EEC, B.7 (1992), modified
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
tetrahydronaphthalene of Hüls AG, produced 02 February 1993
Purity 98.5 %
Sample No. 0099 (internal)
Sample ID 3633/81495

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS
- Strain: Wistar (Hsd/Win:WU)
- Source: Harlan Winkelmann, Borchen (Germany)
- Age: 6 - 8 weeks
- Weight at study initiation:    
range of group mean weights, males: 190-200 g   
range of group mean weights, females: 146-155 g
- Number of animals: total 30 males, 30 females

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
ADMINISTRATION / EXPOSURE 
- Vehicle: corn oil
- Total volume applied: 2 ml/kg bw
Duration and frequency of treatment / exposure:
28 day(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: vehicle; 15; 50; 150 mg/kg bw d; 150 mg/kg bw d reversal group
Females: vehicle; 15; 50; 150 mg/kg bw d; 150 mg/kg bw d reversal group
No. of animals per sex per dose:
Males: 5 Females: 5
Control animals:
yes, concurrent vehicle
Positive control:
no
Details on study design:
SATELLITE GROUPS AND REASONS THEY WERE ADDED: additional 150 mg/kg bw d  and control group for recovery study
Details on dosing and sampling:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: twice daily (weekends: once daily); detailed once a week
- Mortality: twice daily (weekends: once daily)
- Body weight: before first treatment, weekly thereafter until day of  necropsy
- Food consumption: weekly for each cage (5 rats/cage)
- Water consumption: daily for each cage
- Ophthalmoscopic examination: control and high dose groups during  acclimatization and prior to terminal bleeding
- Haematology: all animals once (terminal) for serum chemical and  haematological investigations plus twice for toxicokinetics during study  
(high dose group days 1 and 16; medium and low dose groups days 3 and 18  of treatment); detailed sampling times (approximately): sampling 0.5;   1.5; 3.0; 6.0; 23.0 hours after treatment on days 1 and 16 from one  animal per sex and group each; sampling on days 2 and 17 from control  
groups sampling 0.5; 1.5; 6.0 hours after treatment on days 3 and 18 from  2; 2; 1 animals per sex and group additional sampling from two animals   each of the high dose groups at five different times during the 14 day  reversal period (first sampling was from non-reversal animals before  their 
sacrifice); 200-500 ul/sample
- Urinalysis: end of study; non-satellite groups additionally on days 3  (males) and 4 (females)
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Macroscopic:    weights of adrenals, kidneys, liver, spleen, testes   adrenals, aorta (thoracic), anus, brain, caecum, coagulation gland,  colon, 
concha (tattooed), duodenum, epididymides, eyes, exorbital  lacrimal glands, gross lesions, heart, ileum, jaw (upper), jejunum,  kidneys, larynx, 
liver, lungs, lymph nodes (skin, cervical & mesenteric),  mammary gland, muscle (skeletal), ovaries, oesophagus, pancreas,  pituitary, prostate, 
rectum, salivary glands, sciatic nerve, seminal  vesicles, skin, spinal cord (cervical), spleen, stomach, testes, thymus,  thyroid / parathyroid, tongue,
 trachea, urinary bladder, uterus, vagina   bone marrow smears -
- Microscopic: eyes, kidney, liver, lung, lymph nodes, oesophagus,  Peyer's patches, spleen, uterus
OTHER EXAMINATIONS: toxicokinetics: see separate report and entry DEVIATIONS FROM PROTOCOL: No fixation of tibia during necropsy
Statistics:
STATISTICAL METHODS: 
- Kruskal Wallis non parametric analysis of variance, in case of  significance followed by Wilcoxon, Mann, and Whitney U tests: body  weights, body
 weight changes, organ weights, differential blood count,  urine analysis data - one way analysis of variance (ANOVA) incorporating Bartlett's test 
for  homogeneity of variance and if indicated followed by Kruskal Wallis or  Scheffe Test: haematological data (except differential blood count) and  
serum clinical chemistry data
- Median (geometric mean), minimum, maximum: differential blood count

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st: 1.5 hours
Toxicokinetic parameters:
half-life 2nd: 4.7 hours
Toxicokinetic parameters:
half-life 3rd:

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

 

 

Maximum concentration

Area under the curve (AUC) (µg*h/mL)

Sex

First day

Second day

First sampling

Second sampling

Low dose

15 mg/kg bw

male

0.78 mg/L (36 min)

0.62 mg/l (34 min)

1.70

1.57

female

0.76 mg/L (30 min)

1.35 mg/l (29 min)

1.22

2.61

Mid dose

50 mg/kg bw

male

2.57 mg/L (99 min)

1.04 mg/l (90 min)

6.81

6.29

female

3.46 mg/L (43 min)

3.14 mg/l (84 min)

5.91

8.26

High Dose

150 mg/kg bw

male

19.01 mg/L (30 min)

5.54 mg/l (31 min)

72.32

51.23

female

9.64 mg/L (30 min)

12.02 mg/l (88 min)

71.89

81.81


  Maximum concentrations of first sampling males > females
  Maximum concentrations of second sampling females > males
=> The tetrahydronaphthalene blood concentration maximum was reached  

approximately 30 minutes after administration of the highest dose. 

  AUC of second sampling always lower with males, higher with females as  

compared to first sampling
=> The AUC of the high dose groups is more than proportional higher than  that 

of the lower dose groups indicating that elimination may be  saturated at this dose level. An accumulation of test substance after  

repeated oral administration of up to 150 mg/kg body weight was, however,  not observed.
FIRST ORDER HALF LIVES OF ELIMINATION (1 compartment model)
  high dose, male:     82.2 min
  reversal, male:      99.5 min
  high dose, female:   80.8 min
  reversal, female:    85.0 min
FIRST ORDER HALF LIFE OF ELIMINATION (2 compartments model)
  ca. 4.7 hours (males)
=> After 23 hrs, only traces of test substance were detectable in the  blood. The elimination half life was determined in the range 

of 30 to 100  minutes. In the low and mid dose groups, elimination was almost finished  after 6 hours.
OTHER / GENERAL OBSERVATIONS:
Dark coloured urine was observed in all treated animals.

Tox. behaviour: see chapter 5.4

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Resorption is rapid, but is probably decreased upon repeated dosing at high dose level. Excretion is rapid and complete.
Executive summary:

The present study describes the kinetics of tetrahydronaphthalene in male and female rats (five animals per dose per sex) at three dose levels (15, 50, and 150 mg/kg daily). Plasma concentration measurements were performed in the course of a subacute toxicity study of 28 days duration in an enriched study design. Two blood samples per animal were taken at different time points after application at day 1 and 16 (150 mg/kg daily) and at day 3 and 18 (15 and 50 mg/kg daily), respectively. Tetrahydronaphthalene was assayed by gas chromatography-mass spectrometry (GC-MS) after extraction. The data of plasma concentration time were analysed using non-linear mixed effects modelling as implemented in NONMEM. The structural model with the best fit employed one compartment kinetics with instantaneous drug input. Interindividual variability in both k and V was found to be very small [k, 0.201 h(-1), 0.013; V, 16.19 (kg), 1.77; population mean and SE]. No unequivocal evidence of dose dependence could be found. The kinetic parameter with the highest extent of variability was the extent of bioavailability which showed an coefficient of variation (CV) of 96%. Both gender and dose had no influence on the variability. The results of this study indicate that tetrahydronaphthalene is rapidly absorbed from the gastrointestinal tract and also rapidly excreted. Upon repeated application by gavage resorption was delayed at the highest dose level. There appears to be no induction of elimination upon repeated dosing. At higher dose level elimination is apparently saturated.

There was no accumulation upon repeated oral application of tetrahydronaphthalene up to 150 mg/kg bw.