Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

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other: Non GLP, non guideline, animal experimental study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1976
Report Date:
1976

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Rates of absorption, tissue distribution, metabolism and rate of excretion of 14C labelled dicyclopentadiene
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dicyclopentadiene (DCPD -14C)
- Physical state: uniformly labelled with 14C
- Analytical purity of stock: 97%
- Lot/batch No.: 895-157
- Radiochemical purity (if radiolabelling): 99%
- Specific activity (if radiolabelling): 3.02 µCi/mM
- Other: Total quantity of 53 mg dicyclopentadiene-14C was diluted with 600 mg nonradioactive dicyclopentadiene to form stock used for all pharmacokinetic and metabolism studies.
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: not reported
- Age at study initiation:
- Weight at study initiation: 180-280 g
- Fasting period before study: 18 h
- Housing: individually in Roth metabolism cages
- Individual metabolism cages: yes
- Diet :.Purina Rat chow (ad libitum)
- Water: ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS: Not reported

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- 53 mg DCPD-14C diluted with 600 mg non-radioactive dicyclopentadiene to form stock.
- dosing solution prepared in corm oil and contained 20 mg dicyclopentadiene-14C (specific activity 0.20 µCi/mg) per mL corn oil.

Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw.
No. of animals per sex per dose:
12
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, urine, faeces, expired carbon dioxide , spleen, lungs, heart, liver, kidneys, testes, brain, abdominal muscle, fat, urinary bladder, adrenals, eyes, femur, skin, gall bladder, small intestine, large intestine, caecum and stomach.,
- Time and frequency of sampling: urine, faeces and expired carbon dioxide collected for 24 h and then every 24 h thereafter until all were killed.
Blood samples collected from aorta from 2 rats/time period, killed at 2, 4, 6, 24, 48 and 72 hours after dosing with dicyclopentadiene-14C.
- Other: Expired carbon dioxide was absorbed by a mixture containing ethanolamine:methyl cellusolve:toluene (1:8:10v/v)

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine
- Time and frequency of sampling: 0 - 24 h
- From how many animals: 2 per time point (samples pooled)
- Method type(s) for identification: TLC
- Other: Radioactive spots on the TLC plates were localised by scanning with a radiochromatogram scanner.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption was rapid, Cpmax was 23.28 µg/ml at 6 h. Concentrations were greater in plasma than blood. Elimination from plasma was biphasic, the terminal half life was 27h.
Details on distribution in tissues:
Radioactivity was widely distributed, Cmax at 2-6 hours, highest concentrations were in the fat, adrenals and urinary bladder. Radioactivity was still detectable in all tissues at 72 hours.
Details on excretion:
The primary route of excretion of 14C was via urine. 94% of radioactivity was recovered within 72 h with approximately 75% in urine.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Urine contained 7 radioactive components; the major polar component accounted for 41% of the total radioactivity. No DCPD was detected. Conjugates were present.

Any other information on results incl. tables

Average plasma and whole blood levels (µg/ml) of 14 C radioactivity in rats after a single oral dose of dicyclopentadiene-14C

Time point (post dose)

15 m

30 m

1 h

2 h

4 h

6 h

24 h

48 h

72 h

Blood

-

-

-

10.65

11.92

19.76

14.09

1.93

0.47

Plasma

-

-

-

11.51

14.44

23.28

15.47

2.13

0.36

Key: m = minutes, h = hour

Applicant's summary and conclusion

Conclusions:
Dicyclopentadiene was rapidly absorbed, radioactivity was widely distributed into tissues. The terminal elimination half life from plasma was 27 hours. Excretion was primarily in urine; a total of 94% of radioactivity was recovered within 72 h with approximately 75% in urine. 7 radiolabelled components were separated in the 0-24h urine collection; these included conjugates but no dicyclopentadiene.