4,4'-methylenedicyclohexyl diisocyanate

Respiratory sensitisation

Administrative data

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sept - Oct 1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Principles of method if other than guideline:

Lung sensitization study following intradermal induction. For inhalation challenge the criteria specified in OECD TG 403 were fulfilled in so far as these are applicable to this study.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-methylenedicyclohexyl diisocyanate

EC Number:

225-863-2

EC Name:

4,4'-methylenedicyclohexyl diisocyanate

Cas Number:

5124-30-1

Molecular formula:

C15H22N2O2

IUPAC Name:

1,1'-methylenebis(4-isocyanatocyclohexane)

Test animals

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Dunkin-Hartley Pirbright-White (Crl: (HA)BR)
- Source: Charles River, Sulzbach, Germany
- Age at study initiation: approx. 2 months
- Weight at study initiation: at study start the variation of individual weights did not exceed +/- 10 % of the mean
- Housing: in groups of 4 in Makrolon Type IV cages (according to Spiegel & Goennert, Zschr. Versuchstierkunde 1, 38, 1961 and Meister, Zschr. Versuchstierkunde 7, 144-153, 1965)
- Diet and Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): approx. 50 %
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Route of induction exposure:

intradermal

Route of challenge exposure:

inhalation

Vehicle:

other: for intradermal induction: olive oil; for aerosol inhalation: air

Concentration:

intradermal induction: 100 µl / 0.13 % solution in olive oil
challenge: 68 ± 3.6 mg/m³ (mean concentration)

No. of animals per dose:

8 test animals / 8 controls

Details on study design:

ADMINISTRATION:
Groups of eight female guinea-pigs were intradermally induced once on Day 0 (injection volume: 100 µl / 0.13 % solution in olive oil). Eight female controls received vehicle alone under otherwise identical conditions. Following a recovery period of approximately four weeks (starting on Day 28) a test material-hapten challenge was performed at 68 ± 3.6 mg/m³ (mean concentration; challenge duration: 30 min). The aerosolized test material was proven to be of adequate respirability.

EXAMINATIONS:
During and after challenge exposures with the hapten, immediate-onset respiratory reactions were evaluated by measurement of respiratory rate, tidal volume, respiratory minute volume, inspiratory and expiratory times, and peak expiratory flow rate. Additional parameters were derived mathematically. During sacrifice the trachea, lung, and lung associated lymph nodes were fixed and subjected to histological evaluation.

Results and discussion

Results:

Following induction, slight skin reactions at the injection sites occurred. During or following test material-challenges, the incidence of immediate-onset respiratory reactions was roughly the same in vehicle controls and test substance-induced animals. No deaths or anaphylactic reactions were observed during challenge, and no clinical signs or specific abnormalities were observed at necropsy. The histopathological evaluation of lungs revealed a marked influx of eosinophils in test material-sensitized guinea-pigs, a characteristic feature of asthma and airway hypersensitivity.
The study provides evidence that the test substance is a weak respiratory sensitizer in guinea pigs.

Any other information on results incl. tables

Data from IUCLID4

RS-Freetext:
Following induction, slight skin reactions at the injection sites occurred. During or following test material-challenges, the incidence of  immediate-onset respiratory reactions was roughly the same in vehicle controls and test substance-induced animals. No deaths or anaphylactic reactions were observed during challenge, and no clinical signs or specific abnormalities were observed at necropsy. The histopathological evaluation of lungs revealed a marked influx of eosinophils in test  material-sensitized guinea-pigs, a characteristic feature of asthma and airway hypersensitivity.
The study provides evidence that the testsubtance is weak respiratory sensitizer in guinea pigs.

Applicant's summary and conclusion

Executive summary:

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.

Cited from SIAR of SIAM 20 (Paris, April 19 -22, 2005): In the study "sensitization of 8 guinea pigs with a single intradermal injection of 4,4´-methylenedicyclohexyl diisocyanate (100 μl, 0.13% solution in olive oil) followed after four weeks by inhalation challenge with the 4,4´-methylenedicyclohexyl diisocyanate hapten (30 min, 68 ± 3.6 mg/m³) was examined. No immediate-onset responses were observed. Gross pathological examinations showed roughly the same incidence of lung changes in all Guinea pigs of this study. The histopathological assessment of the degree of eosinophilia revealed an increased influx of eosinophilic granulocytes in animals sensitized with 4,4´-methylenedicyclohexyl diisocyanate. Because eosinophils are known to play a critical role in pathogenesis of asthma and of other hyperresponsive airway diseases the study provided evidence that 4,4´-methylenedicyclohexyl diisocyanate is a weak respiratory sensitizer in guinea pigs."