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other: Non GLP, non guideline, animal experimental study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment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

Constituent 1
Reference substance name:
Reference substance 001
Cas Number:
77-73-6
Molecular formula:
C10H12
Details on test material:
- Name of test material (as cited in study report): Dicyclopentadiene (DCPD)
- Physical state: waxy solid, liquefied on slight warning
- Analytical purity: 98-99% pure DCPD
- Impurities (identity and concentrations): Trace - one may be the cis-form
- Lot/batch No.: LBI No. 763A
- Analysis by UC-W98 column. Retention time was 1.9 minutes (trace impurities noted at approximately 1.5 and 2.1 minutes)
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system 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 / concentration:
2
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.
Executive summary:

This study reports the rates of absorption, tissue distribution, metabolism and rate of excretion of 14C labelled dicyclopentadiene. DCPD was rapidly absorbed after oral administration to rats. Peak plasma levels of 23.28ug/ml occurred in 6 hours. Concentrations were greater in plasma than blood. Elimination from plasma was biphasic, with a terminal half-life of 27h. The test substance was widely distributed in other organs at 1 to 2 hours (Cmax at 2-6 hours) with the highest levels in the fat, adrenals and urinary bladder. Radioactivity was still detectable in all tissues at 72 hours. Excretion appeared to be primarily via the urine. About 85% of the administered radioactivity was accounted for in urine and faeces within 24 hours, with 94% of radioactivity recovered within 72 hours. Urine contained 7 radioactive components; the major polar component accounted for 41% of the total radioactivity. No DCPD was detected. Conjugates were present.

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