3a,4,7,7a-tetrahydro-4,7-methanoindene

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: animal experimental study, also published in peer-reviewed literature, minor restrictions in design and reporting but otherwise acceptable for assessment.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Reference 2

Reference Type:

publication

Title:

Results of a 90-day inhalation study of dicyclopentadiene in B6C3F1 mice.

Author:

Kransler, K. M.

Year:

2014

Bibliographic source:

Toxicology and Industrial Health, 30:459–466

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

not specified

GLP compliance:

no

Remarks:

Klimisch Cat 2

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3a,4,7,7a-tetrahydro-4,7-methanoindene

EC Number:

201-052-9

EC Name:

3a,4,7,7a-tetrahydro-4,7-methanoindene

Cas Number:

77-73-6

Molecular formula:

C10H12

IUPAC Name:

tricyclo[5.2.1.0^{2,6}]deca-3,8-diene

Constituent 2

Reference substance name:

dicyclopentadiene

IUPAC Name:

dicyclopentadiene

Details on test material:

- Name of test material (as cited in study report): dicyclopentadiene (DCPD)
- Source: Exxon Chemical Company, Baton Rouge, LA, USA
- Sample reference: BRRC 43-156
- Physical state: clear, colourless liquid
- Analytical purity: =95% endo-DCPD, 0.5% exo-DCPD
- Impurities (identity and concentrations): several impurities of which only cyclopentadiene. and isoprene were present at =0.5%
- Stability under test conditions: The composition remained stable throughout the study

Test animals

Species:

mouse

Strain:

other: B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Portage, MI, USA
- Age on receipt: 30-34 days
- Health assessment: confirmed following arrival
- Weight at study initiation: no data
- Housing: individually in stainless steel wire mesh suspended cages
- Diet: powdered NIH-07 diet ad libitum except during exposure
- Water: ad libitum except during exposure
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 68-72°F non-exposure period
- Humidity: 40-60% non-exposure period
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: July 1981 - January 1981

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air

Remarks on MMAD:

MMAD / GSD: Not applicable

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel rectangular (2mx2mx1m) exposure chamber with glass windows and door in front wall (total volume 4350 L).
- Method of holding animals in test chamber: individually in suspended stainless steel wire mesh cage with stainless steel pans between each layer of cages to prevent contamination. Cage positions were rotated routinely.
- System of generating particulates/aerosols: DCPD vapour was generated by heating the liquid in a Pyrex tube using a minimum amount of heat to prevent decomposition and formation of CPD. Filtered air was used to dilute the vapour prior to introduction into the chamber.
- Temperature and humidity in air chamber: 70-79°F, 39-68%
- Air flow rate: 2000 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: Chamber concentrations were analysed at hourly intervals by gas chromatography/flame ionization detection.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 wks

Frequency of treatment:

6 hr/day, 5 days/wk

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 1, 5, 50 ppm
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1, 5.1, 51 ppm
Basis:
analytical conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0, 5.4, 27.6, 276 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

45

Control animals:

yes

Details on study design:

Post-exposure observation periods of 4 and 13 weeks.
9 mice/sex/dose were scheduled for sacrifice after 2, 6 and 13 weeks of exposure and 4 and 13 weeks post-exposure.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- During exposure mice were observed several times through the chamber window.

DETAILED CLINICAL OBSERVATIONS: Yes
- Mice were observed for clinical signs before and after each exposure and daily during the recovery period.

BODY WEIGHT: Yes
- Recorded at study initiation, weekly during both the exposure period and the first 5 weeks of the recovery period, and then every 2 weeks. Animals were also weighed before termination.

FOOD CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- High dose mice received ophthalmoscopic examination before sacrifice

HAEMATOLOGY: Yes
- Haematology analyses were performed on all mice prior to sacrifice after 2, 6 and 13 week exposure and 4 and 13 week post-exposure with blood from the orbital sinus. Erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin and concentration, and total/differential white blood cell counts were determined.

CLINICAL CHEMISTRY: Yes
- Serum chemistry analyses were performed on all mice prior to sacrifice after 2, 6 and 13 week exposure and 4 and 13 week post-exposure with blood from the orbital sinus. Serum was analyzed for creatinine, urea nitrogen, calcium, phosphrous, chloride, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, total bilirubin, alkaline phosphatase, glucose and osmolality.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Necropsies were conducted on all mice.
- Kidneys, lungs, liver and testes were weighed.
- Adrenals, bone and bone marrow (sternum), brain, epididymides, eyes, heart, kidneys, larynx, liver, lungs, lymph nodes (mediastinal), muscle (gastrocnemius), nasal turbinates, parathyroids, pituitary, sciatic nerve, spleen, testes, thymus, thyroids, trachea, urinary bladder and gross lesions were preserved for microscopic evaluation.

HISTOPATHOLOGY: Yes
- Organs were examined microscopically in control and high dose mice sacrificed after 13 weeks of exposure.

Statistics:

Analysis of variance, Bartlett’s test, Duncan’s multiple range test, F-test, Student’s t-test, Cochran t-test (applied when appropriate).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
- Ten males and 9 female mice exposed to 51 ppm DCPD died during the study; no more than 2 mice died at any other level.
- No significant clinical signs or body weight changes were noted prior to death. The likely cause of death appeared to be pulmonary congestion and possibly renal failure. These effects were not seen in mice sacrificed at the end of the study.
- During exposure, a few of the mice at 51 and 5.1 ppm showed coordination loss and/or decreased activity.

BODY WEIGHT AND WEIGHT GAIN
- Males and females in the 51 ppm group showed significant elevation in body wt gain that returned to parity with control values during recovery.

Effect levels

Dose descriptor:

NOAEC

Effect level:

5 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: 27.6 mg/m3. Mortality (20%) occurred in the high-dose mice during the study

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

A number of statistically significant alterations were noted in this study but the aetiology and association with dicyclopentadiene exposure are unclear. Approximately 20 percent of mice exposed to 51 ppm died during the exposure regimen. The cause of death was pulmonary congestion yet similar lung lesions were not found in animals terminated during the study. Also, female mice exposed to 51 ppm showed an increase in body weight during the last few weeks. A potential effect of dicyclopentadiene was seen in the female mice given 64 exposures to 51 or 5.1 ppm was a decrease in serum albumin indicative of slight liver dysfunction (7% difference from control); absolute and relative liver weights were also increased. No morphological changes were found to indicate any effect of dicyclopentadiene exposure. Thus any effect of dicyclopentadiene on the livers of female mice was considered to be minimal in severity.

Applicant's summary and conclusion

Conclusions:

Although there were no overt signs of toxicity due to dicylopentadiene, approximately 20% of mice died primarily as a result of pulmonary congestion. The aetiology and association with dicyclopentadiene exposure are unclear. The NOAEC is concluded to be 5.1 ppm (27.6 mg/m3).

Executive summary:

Groups of 45 male and 45 female B6C3F1 mice were exposed by inhalation, 6 hr/day, 5 days/week, for 13 weeks (64 exposures) to dicyclopentadiene vapour at concentrations of 0 (air control), 1, 5.1 or 51 ppm (analysed concentrations). Animals were sacrificed after 10, 30 and 64 inhalation exposures and post-exposure sacrifices were made at 29 and 92 days following the last exposure. Clinical observations, body weights, blood clinical chemistry and haematology, ophthalmology, organ weights and histopathology evaluations were made during the study. A number of statistically significant alterations were noted in this study but the aetiology and association with dicyclopentadiene exposure are unclear. There were no overt signs of toxicity although approximately 20% of the mice of the 51 ppm exposure group died during the exposure period, primarily due to pulmonary congestion. The NOAEC is concluded to be 5.1 ppm (27.6 mg/m3).