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Toxicological information

Respiratory sensitisation

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Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-01-31 to 1994-03-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

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:
other: exposure criteria of OECD Guideline 403 (1981) and Directive 84/449/EEC, B.6 fulfilled
Deviations:
not applicable
Principles of method if other than guideline:
exposure criteria of OECD Guideline 403 (1981) and Directive 84/449/EEC, B.6 fulfilled
Pauluhn J and Eben A (1991). Validation of a non-invasive technique to  assess immediate- or delayed-onset of airway hyperreactivity in  guinea-pigs.
 J. Appl. Toxicol. 11, 423-431; Pauluhn J (1994). Validation of an improved nose-only exposure system for  rodents. J. Appl. Toxicol. 14, 55-62.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Isophorone diisocyanate of Bayer AG, Batch No. 1.5 / 3-20, purity > 99 %

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: 
- Strain: Hartley [Crl:(HA)BR]
- Sex: female
- Source: Charles River Wiga, Sulzbach (Germany)
- Age: ca. 2 months
- Weight at study initiation: 237-273 g; mean 256 g - 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:
intradermal
Route of challenge exposure:
other: nose only inhalation of aerosol
Vehicle:
other: corn oil
Concentration:
first day: 10.2 mg/m3 test substance 30 min nose-only   
second day: 0.05; 0.15; 0.5 % Acetylcholine for 15 min each   
last day: 35.5 mg/m3 conjugate of test substance with guinea pig serum  albumin
No. of animals per dose:
8 treated
8 vehicle (control)
Details on study design:
1st application: Induction 0.1 % intracutaneous
2nd application: Challenge other: nose only inhalation of aerosol
ADMINISTRATION/EXPOSURE 
- Induction schedule: days 0, 2, 4 (100 ul each)
- Challenge schedule: 4 subgroups, 4 animals each   
days 21/22/28 (control subgroup a)   
days 22/23/29 (treated subgroup a)   
days 23/24/30 (control subgroup b)   
days 24/25/31 (treated subgroup b)
- Concentrations used for challenge:    
first day: 10.2 mg/m3 test substance 30 min nose-only   
second day: 0.05; 0.15; 0.5 % Acetylcholine for 15 min each   
last day: 35.5 mg/m3 conjugate of test substance with guinea pig serum  albumin EXAMINATIONS - During sacrifice the trachea, lung and lung associated lymph nodes were  fixed and subjected to histopathological evaluation.  Lung weights were  also determined - Pilot study: assessment of the approximate irritant threshold  concentration
Challenge controls:
Validity of this animal model was assessed with the known human sensitizer Trimellitic Anhydride. Additional ACh challenge was performed to enhance identification of and distinction between specific as well as non specific airway hyperresponsiveness.
Positive control substance(s):
trimellitic anhydride (TMA)
Negative control substance(s):
other: vehicle (corn oil)

Results and discussion

Results:
RESULTS OF PILOT STUDY: see test concentration RESULTS OF TEST - Sensitization reaction: High titer IgG1 antibody observed proved that  successful sensitization had occurred. However, 
when challenged, the  incidence of immediate-onset respiratory reactions was roughly the same  in all groups. No delayed-onset 
reactions, deaths or anaphylactic  reactions were observed. Challenge with acetylcholine did not evoke group  specific respiratory 
responses. - Clinical signs: No clinical signs or specific abnormalities were  observed at necropsy.
Positive control results:
Severe reactions were observed with trimellitic anhydride (CAS RN  552-30-7) when investigated with the current animal model, 
using the same  induction and challenged.
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 did not induce respiratory sensitization in guinea-pigs.
Executive summary:

Respiratory tract sensitization of guinea pigs following intradermal induction (1%, 100 µl) was examined in this study in accordance with the exposure criteria defined in OECD TG 403. High titer IgG1 antibody observed proved that successful sensitization had occurred. However, when challenged by nose only inhalation of aerosol at varying concentrations, the incidence of immediate-onset respiratory reactions was roughly the same in all groups. No delayed-onset reactions, deaths or anaphylactic reactions were observed. Challenge with acetylcholine did not show specific respiratory responses indicating that the animals were hyperrespondive to cholinergic acetylcholine stimuli. Severe reactions were observed with trimellitic anhydride (CAS No. 552-30-7) when investigated with the current animal model, using the equivalent induction and challenge. Under the conditions of this study the test item did not induce respiratory sensitization in guinea-pigs.