3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type

Respiratory sensitisation

Administrative data

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1995-04-03 - 1995-05-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: exposure criteria of OECD 403 and EC Guideline 892/69/EEC (1992) were fullfilled

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: exposure criteria of OECD 403 and EC Guideline 892/69/EEC (1992) were fullfilled

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, oligomers

EC Number:

500-125-5

EC Name:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, oligomers

Cas Number:

53880-05-0

Molecular formula:

residual C12H18N2O2, otherwise C36H54N6O6 (trimer) and higher species

IUPAC Name:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer

Constituent 2

Reference substance name:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type

EC Number:

931-312-3

Cas Number:

53880-05-0

Molecular formula:

residual C12H18N2O2, otherwise C36H54N6O6 (trimer) and higher species

IUPAC Name:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type

Details on test material:

Test itemDistribution of molecular weights: IPDI-monomer: ca. 0.3%; IPDI-Trimer: 50-60%; IPDI-Polymer: 40-50%

Test animals

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Strain: DHPW (Dunkin-Hartley Pirbright-White) strain from the Charles River [Crl:(HA)BR]
- Sex: female
- Source: Sulzfeld, Germany
- Age: ca. 2 weeks
- Weight at study initiation:
- pre-experimental treatment of animals and animal housing: animals were acclimatized for at least 5 days before use;before start of experiment
health status of each animal was assessed; animals were assigned to exposure gruops at random; room temperature: 22 °C (+/- 2°C);
humidity: appr. 50%; dark/light: 12h/12h (14 watt/m2); air-exchange: appr. 10-fold/h; diet: Altromin 3022 (Altromin GmbH, Lage);
tap-water ad libitum

Test system

Route of induction exposure:

other: intradermal or inhalation

Route of challenge exposure:

other: nose only inhalation of aerosol

Vehicle:

other: intradermal: aceton; inhalation: unchanged (no vehicle)

Concentration:

see: "Details on study design"

No. of animals per dose:

8 treated (intradermal and inhalation)
8 vehicle (control

Details on study design:

STUDY DESIGN:
Groups of eight female guinea-pigs were intradermally induced once per day on days 0, 2, and 4 (injection volume: 50 µl; 5% solution in aceton) and
one additional group of animals was exposed for five consecutive days by inhalation (duration of exposure per day: 3 hrs/day) to 147 mg/m3
IPDI-homopolymer dust (solid aerosol). The aerosolized test item proved to be of adequate respirability (MMAD approximately 2.1 µm, GSD ca. 1.8;
relative mass of particle <= 3 µm approximately 75%). Eight female controls received the vehicle alone (acetone intradermally) under otherwise
identical conditions. During the recovery period (starting on day 21) a IPDI-challenge (mean concentration: 48 mg/m3 air) was performed (challenge duration: 30 min) which was followed (one day after hapten challenge) by an acetylcholine bronchoprovocation challenge (ramped
concentrations).
Following day 28 all guinea pigs were challenged again with the guinea pig serum albumin (GPSA) conjugate of the hapten (mean concentration:
49 mg/m3 air).
During and after challenge exposures 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.
One day thereafter, animals were sacrificed, the lungs, including trachea and lung associated lymph nodes, were examined histopathologically. The weight of the exised lungs was determined. At sacrifice blood was sampled for serological examinations.

Challenge controls:

Treatment: vehicle

Positive control substance(s):

trimellitic anhydride (TMA)

Negative control substance(s):

other: vehicle (acetone)

Results and discussion

Results:

Following induction, mild skin reactions occured which appeared to be related to the vehicle used (acetone). During or following hapten, ACh or conjungate-challenges, the incidence of immediate-onset respiratory reactions were roughly the same in all groups. No deaths or stereotypic anaphylactic reactions were observed during challenge, and no clinical signs, conclusive changes in body weight or specific abnormalities were observed at necropsy. The histopathological investigations were unobstructive, i.e., there was no evidence of a specific airway eosinophilia, a hallmark of allergic airway hyperresponsiveness. The serological investigations did not reveal merked differences in anti-IPDI-Homopolymer IgG1-antibody titres between the groups.

Positive control results:

In previous studies the known human respiratory sensitizer TMA was investigated with the current animal model using roughly the same induction
and challenge protocol. The TMA study demonstrated that the experimental approaches employed provide an adequate basis for a clear assessment of chemicals with a strong potential to cause respiratory hypersensitivity in guinea pigs. Upon challenge with TMA, the most of the guinea pigs
experienced a characteristic "waveform" breathing pattern which had not been observed in IPDI homopolymer challenged guinea pigs. This
stereotypic breathing response has not yet been observed in naive animals and therefore provides a solid basis for the classification of strong
respiratory tract sensitizers.

Negative control results:

no relevant reactions observed

Any other information on results incl. tables

no further remarks

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study the test item IPDI-homopolymer did not induce respiratory sensitization in guinea pigs.

Executive summary:

A lung sensitization study with IPDI-homopolymer was performed in accordance with the exposure criteria defined in OECD TG 403 using female guinea pigs . A standard approach was used that included three intradermal injections (one per day, 5%, 50 µl in acetone). In order to investigate wether the test substance has any potential to induce specific or non-specific airway hyperreactivity an additional group of female guinea pigs was induced by using a 5 x 3 hours inhalation (147 mg/m³) sensitization protocol followed by inhalation challenge with the hapten, acetylchloline and conjugate by inhalation.

Under the conditions of this study no conclusive immediate-onset responses were observed nor was there any indirect evidence of a lung sensitizing potential, i.e. eosinophilia of airways or production of specific antibody. Therefore, this study does not provide any evidence that IPDI-homopolymer is a respiratory sensitizer.