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Toxicological information

Respiratory sensitisation

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Administrative data

respiratory sensitisation: in vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant respiratory sensitisation study
Reason / purpose:
reference to other study

Data source

Reference Type:
study report
Report Date:

Materials and methods

Principles of method if other than guideline:
No guideline is available for testing respiratory sensitisation. The method used was similar to the following: Karol et. al., Fundam. Appl. Toxicol. 5, 1985, 459; Karol et. al., Am. Ind. Hyg. Assoc. 39, 1978, 546; Mullin et. al., Toxicol. Appl. Parmacol. 71, 1983, 113; Deceaurriz et. al., Toxicology 43, 1987, 93; Barrow et. al., Archives of Environmental Health, 1977, 68; Botham et. al., Toxicology Letters 41, 1988, 159; technical exposure procedure according OECD TG 403.
GLP compliance:
yes (incl. certificate)

Test material


Test animals

guinea pig
other: Iva: PDH
Details on test animals and environmental conditions:
- Strain: Iva: PDH (Pirbright - White - Dunkin - Hartley)
- Source: Ivanovas, Kisslegg
- Age at study initiation: 1 - 2 months
- Weight at study initiation: 300 +/- 25 g
- Housing: in groups of five in conventional Makrolon Type IV cages
- Diet and water: ad libitum
- Acclimation period: at least 1 week

- Temperature (°C): 22 ± 2
- Humidity (%): ca. 50
- Air changes (per hr): approximately 10
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Route of induction exposure:
Route of challenge exposure:
other: 10% acetone for the substance; 0.9% aqueous NaCl-solution for substance-conjugate
For induction: analytical substance concentrations 0, 3, 16, 49, and 261 mg/m³
For first challenge: mean substance concentration 97 mg/m³ air
For second challenge: mean concentration of substance - guinea pig albumin conjugate 27 mg/m³ air
No. of animals per dose:
15 per dose group
Details on study design:
RANGE FINDING TESTS: see prestudy report no. 18393, Pauluhn, 1989.

- Day 1-5: inhalative exposure 3h daily on 5 consecutive days.

- Day 21-25: 1. test substance challenge 30 min.
– Day 30-38: 2. test substance-conjugate challenge 30 min.

Respirability of aerosol given: for induction - MMAD ~1.5 µm, GSD ~1.4; for 1st challenge MMAD ~1.5 µm, GSD ~1.5; for 2nd conjugate-challenge MMAD ~3.7 µm, GSD ~2.1;
Challenge controls:
No challenge control was done. Only vehicle control.

Results and discussion

All dose groups tolerated the substance exposure up to 261 mg/m³ air without observable toxicological effects. No effects on body weight or body weight gain observed.
Antibody determination: dose group 3 mg/m³ no increase, dose group 16 mg/m³ with marginal increase, dose groups 49 and 261 mg/m³ with noticeable concentration-related increase of specific antibody count. 2/7 animals of the 261 mg/m³ group had antibody counts > 2000.
Lung function tests: no evidence of a lung sensitizing potential with respirable aerosolized substance seen. No immediate hypersensitivity reactions. A moderate to heavy increase in respiratory rate observed at 1 animal of the highest challenge concentration group (200 mg/m³ nominal conc.) and 4 animals of the control group is regarded as an effect induced by pulmonary irritation. Some animals showed delayed increase in respiratory rate after substance-conjugate challenge, but non dose-correlated.
Only slight effects on lung weight in the 261 mg/m³ group. Histopathological investigations revealed in the 261 mg/m³ group inflammatory changes of the lung. No evidence of recruitment of eosinophilic granulocytes in the airway walls.

Any other information on results incl. tables

For respiratory sensitisation a read across to a substance with a similar chemical composition (HDI oligomerisation product, isocyanurate type, EC No. 931 -274 -8, CAS No 28182 -81 -2) is applied. The read across is based on physicochemical and toxicological similarity of the two substances. Especially a recent comparative pulmonary irritant potency study according to TRGS 430 (Technical Rule for Hazardous Substances 430; published by the German Federal Ministry of Labour and Social Affairs, 2009) confirmed for HDI oligomerisation product, allophanate-type the same toxicological mode of action (irritant portal of entry toxicity) with a similar potency (NOAEC for pulmonary irritation: 3.4 mg/m³ for HDI oligomerisation product, allophanate-type versus 3.3 mg/m³ for HDI oligomerisation product, isocyanurate type). For further justification of the grouping and read-across according to regulation (EC) No 1907/2006, Annex XI, 1.5 see document attached to chapter "Assessment Reports".

Applicant's summary and conclusion

Executive summary:

A lung sensitization study with respirable aerosolized substance for induction and challenge in head/nose only exposed guinea pigs was performed. For induction the animals were exposed to 4 different concentrations on 5 consecutive days for 3 hours daily. After a post-exposure period of 2 -3 weeks a first challenge experiment was conducted with 97 mg/m³ test item and after an additional week with 27 mg/m³ test item - protein conjugate. To correlate potential alterations of the lung function with the immunologic status, lung function tests were performed and specific antibody titer were determined.

Specific immediate or delayed effects indicating sensitization were not observed after the first and second challenge. Neither recruitment of eosinophilic granulocytes nor conclusive physiological response upon challenge were seen. Unspecific, non dose-correlated delayed effects after conjugate challenge were seen in the context of pulmonary irritation. An observed concentration-related increase of specific antibody count is thus not correlated with an immediate or delayed pulmonary sensitization. In conclusion the study result show with respect to the conditions of the test, that the substance has no lung sensitizing potential after repeated exposure to respiratory tract.