[No public or meaningful name is available]

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

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in Section 13 of the dossier.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Materials and methods

Test guideline

Guideline:

other: Not specified

Principles of method if other than guideline:

Standard method

GLP compliance:

yes

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:

3a,4,7,7a-tetrahydro-1H-4,7-methanoindene

Constituent 2

Reference substance name:

dicyclopentadiene (DCPD)

IUPAC Name:

dicyclopentadiene (DCPD)

Details on test material:

- Name of test material (as cited in study report): DCPD
- Physical state: clear colourles liquid at room temperature
- Analytical purity: Analytical purity: >95% endo-DCPD,0.5% iso-DCPD and ~1% cyclopentadiene (CPD)

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 Breedign Laboratory, Portage, MI, USA
- Age at study initiation: 30-34 days
- Weight at study initiation: no data
- Fasting period before study: 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 (70-79°F during exposure)
- Humidity: 40-60% (39-68% during exposure)
- 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

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: not applicable

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel rectangular (2m x 2m x1m) exposure chamber with glass windows and door in front wall (total volume 4350L).
- 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, humidity, pressure in air chamber:
- 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

Details on analytical verification of doses or concentrations:

Actual concentrations: 0, 1.0, 5.1 and 51 ppm

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:
other: Target concentrations

Doses / concentrations 2

Remarks:

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

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0, 5, 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 wks.
Nine mice/sex/dose were scheduled for sacrifice after 2, 6, and 13 wks of exposure and 4 and 13 wks post-exposure.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mice were observed for clinical signs before and after each exposure, and daily during the recovery period. During exposure mice were observed several times trough the chamber window.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Body wt was recorded at initiation, weekly during both the exposure period and the first 5 wks of recovery, and then every 2 wks. Animals were also weighed before termination.

FOOD CONSUMPTION: no

FOOD EFFICIENCY: No data

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 wk exposure and 4 and 13 wk 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 wk exposure and 4 and 13 wk 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 (gastrocnemeous), 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 wks 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

Description (incidence and severity):

- No significant clinical signs or body wt 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.
- Mild conjunctivitis was seen in one male mouse at 51ppm.

Mortality:

mortality observed, treatment-related

Description (incidence):

Ten males and 9 female mice exposed to 51 ppm DCPD died during the study; whereas no more than 2 mice died at any other level.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males and females in the 51 ppm group showed significant elevation in body wt gain that returned to control values during recovery.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

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

Effect levels

1

Key result

Dose descriptor:

NOAEC

Effect level:

5.1 ppm (analytical)

Sex:

male/female

Basis for effect level:

other: 27.6 mg/m3. No systemic toxicity.

2

Key result

Dose descriptor:

LOAEC

Effect level:

51 ppm (analytical)

Sex:

male/female

Basis for effect level:

other: 276 mg/m3. Based on mortality

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Although there were no overt signs of toxicity, exposure to 51 ppm DCPD vapour resulted in the deaths of approximately 20% of mice (males and females), primarily due to pulmonary congestion. 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 h per day, 5 days/week, for 13 weeks (64 exposures) to DCPD vapour at concentrations of 0 (air control), 1, 5.1 or 51 ppm (analysed controls). 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, bodyweights, blood clinical chemistry and haematology, ophthalmology, organ weights and histopathology evaluations were made during the study. There were no overt signs of toxicity but approximately 20% of the mice (both sexes) of the 51 ppm exposure group died during the exposure period, primarily due to pulmonary congestion. Similar lung lesions were not seen in animals sacrificed throughout the study. A significant body weight gain was observed, only in female mice, at 51 ppm in the last weeks of the study. No other biologically significant effects were observed.

The NOAEC is therefore concluded to be 5.1 ppm (27.6 mg/m³).