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Diss Factsheets

Toxicological information

Acute Toxicity: inhalation

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Administrative data

acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Klimisch reliability of study is 1 (GLP guideline study); according to ECHA Practical Guide 6 rel. 2 is selected from the pick-list as this should be the maximum score for read-across.
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
GLP compliance:
Test type:
standard acute method

Test material

Constituent 1
Reference substance name:
HDI oligomers, isocyanurate
HDI oligomers, isocyanurate

Test animals

Details on test animals or test system and environmental conditions:
- Strain: Wistar rats Bor: WISW (SPF-Cpb)
- Source: Winkelmann, Borchen, Germany.
- Age at study initiation: 10 to 12 weeks
- Weight at study initiation: approx. 160 - 220 g
- Housing: in groups of 5 in conventional Makrolon® Type III cages
- Diet and water: ad libitum
- Acclimation period: at least 5 days

- Temperature (°C): 19-25
- Humidity (%): 40-60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Details on inhalation exposure:
- Mode of exposure: Animals were head-nose exposed to the aerosolised test article.
- Generation of atmospheres: Atmospheres were generated under dynamic conditions using a piston pump and a binary nozzle.
- Generation of aerosol: The test substance was nebulized neat using conditioned (dry, oil-free) compressed air. The liquid containing parts were maintained at 80 °C, in order to decrease the viscosity of the test item. To increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the chamber a preseparator/ baffle system was used. The inhalation chamber had a volume of 40 L.
- Conditioning of compressed air: The air supply was approx. 15 L/min. Control devices were employed to control supply pressure. The ratio between the air supplied and exhausted was chosen so that approx. 80% of the supplied air was removed via the exhaust system. The achieved air exchange was 15- up to max. 30-times/hour.
- Exhaust air treatment: The exhaust air was purified via filter systems.
- Temperature measurements revealed a temperature range of 23-25 °C.

- Lower concentrations of the aerosol were characterised by using real-time laser-velocimeter (TSI APS 33).
- Samples taken from breathing zone: yes
- Brief description of analytical method used: gravimetric (analysis of glass-fibre-filter) and HPLC analysis (HPLC-method: Nitro-reagent-treated glass fibres were exposed to the test atmosphere. The content of isocyanate was analytically detected via HPLC.). Gravimetrically determined concentrations were essentially similar to concentrations determined by nitro-reagent derivatisation technique.
- Particle size distribution: The particle-size distribution was analysed using an Anderson or Berner cascade impactor. Approx. 90 % of the particles were < 5 µm and therefore respirable for the rat.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.5-3 µm / 1.7
Analytical verification of test atmosphere concentrations:
Duration of exposure:
4 h
150, 162, 283, 402, 438, 833, and 1033 mg/m³
No. of animals per sex per dose:
5 up to 10/sex and dose group
Control animals:
Details on study design:
- Duration of observation period following administration: 3 weeks
- Frequency of observations and weighing: Observations were done several times on testing day and twice per day thereafter. Bodyweights were recorded prior to exposure and once weekly thereafter.
- Necropsy of survivors performed: yes
LC50 calculation: According to A.P. Rosiello, J.M. Essigmann and G.N. Wogan (J. Tox. and Environ. Health 3, 797 -809, 1977). This method is based on the Maximum likelyhood method of C.I. Bliss (Q. J. Pharm. Pharmacol. 11, 192 -216, 1938).

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
Effect level:
543 mg/m³ air
95% CL:
431 - 687
Exp. duration:
4 h
Dose descriptor:
Effect level:
390 mg/m³ air
Exp. duration:
4 h
Remarks on result:
other: approximate value
Dose descriptor:
Effect level:
462 mg/m³ air
95% CL:
404 - 529
Remarks on result:
other: Value for combined sexes not reported in study, but published in Pauluhn, Toxicol. Sciences 58, 2000, 173-181.
Exposure to concentrations up to and including 162 mg/m³ were tolerated without mortality. Aerosol exposure starting from 283 mg/m³ and higher induced test substance related mortality. Deaths occurred in all groups on the day of exposure and first postexposure days, and in some cases up to the fourth postexposure day.
Mortality data (concentration - no. of deaths/total number of animals (time of death):
Males: 150 mg/m³ - 0/5, 162 mg/m³ - 0/10, 283 mg/m³ - 1/5 (1d), 402 mg/m³ - 3/10 (1d-4d), 438 mg/m³ - 3/10 (1d), 833 mg/m³ - 3/5 (7h-1d), 1033 mg/m³ - 10/10 (4h-1d)
Females: 150 mg/m³ - 0/5, 162 mg/m³ - 0/10, 283 mg/m³ - 0/5, 402 mg/m³ - 6/10 (4h-4d), 438 mg/m³ - 8/10 (1d), 833 mg/m³ - 5/5 (7h-1d), 1033 mg/m³ - 10/10 (4h-1d)).
Clinical signs:
other: Concentrations of 150 mg/m³ and higher were followed concentration-dependent by signs such as dyspnoea, bloody snouts, salivation, limp, constricted or closed eyelids, ataxia, reduced motility, ungroomed hair-coat and piloerection. In most instances, sign
Body weight:
Loss of body weight was observed at exposure concentrations of 402 mg/m³ and higher.
Gross pathology:
Animals which died during post-observation period: lungs distended, red-gray to dark-red foci and colloidal areas in lungs, serous liquid in thorax and lung, lobulation of liver, gastro-intestinal tract with yellowish mucous content, duodenum reddened, kidneys pale and marmorated.
Animals killed at the end of post-observation period: lungs distended, red-gray to dark-red foci and colloidal areas in lungs.
No other findings than at the respiratory tract observed.

Any other information on results incl. tables

For acute inhalation toxicity a read across to HDI oligomers, isocyanurate type (EC 931 -274 -8) is applied. This substance is a close structural analogue to HDI oligomers, iminooxadiazindione type, also derived from catalytic oligomerisation of 1,6 -hexamethylene diisocyanate (HDI; CAS 822 -06 -0) and also belonging to the CAS number 28182-81-2 (Hexane, 1,6 - diisocyanato-, homopolymer). The read across is based on physicochemical and toxicological similarity. In fact, comparison of the toxicological endpoints, that are available for both of the two substances (Acute oral toxicity, Acute inhalation toxicity, Skin and Eye Irritation/Corrosion, Skin Sensitisation, Bacterial mutagenicity (Ames)) reveal good correlation. With respect to Inhalation Toxicity an expert statement is available justifying the read across (Pauluhn, Comparison of pulmonary irritation potency..., Bayer HealthCare AG, 2008).

Therefore, test results obtained for HDI oligomers, isocyanurate type can be transferred to HDI oligomers, iminooxadiazindione type and the results of the acute inhalation toxicity study of HDI oligomers, isocyanurate type are also valid for HDI oligomers, iminooxadiazindione type. This approach is in accordance with Annex XI, section 1.5 of the REACH Regulation (Regulation (EC) No 1907/2006).

Applicant's summary and conclusion

Executive summary:

An acute (4h) inhalation toxicity study with according to OECD TG 403 was conducted with groups of 5 to 10 male and 5 to 10 female Wistar rats. In this study animals were head-nose exposed to the aerosolised test substance in concentrations of 150 up to 1033 mg/m³. The aerosol was of adequate respirability for the rats (90 % particles < 5 µm; MMAD 2.5-3 µm / GSD 1.7).

Exposure to concentrations up to and including 162 mg/m³ were tolerated without mortality. Aerosol concentrations starting from 283 mg/m³ and higher induced test substance related mortality. Deaths occurred in all groups on the day of exposure and first postexposure days; in some cases up to the fourth postexposure day. Exposure to concentrations of 150 mg/m³ and higher were followed by concentration-dependent signs suggestive of irritation to the respiratory tract (e.g. dyspnoea, bloody snouts, salivation) and non-specific signs such as limp, reduced motility, and loss of body weight. In most instances, signs resolved completely within the first four postexposure days. At necropsy changes in lung parenchyma (toxic lung oedema) were reported and were seen in the context of local irritating properties of the substance. No other necropsy findings than at the respiratory tract were observed. The LC50 (4 h) in rats was calculated to be 543 mg/m³ for males and approx. 390 mg/m³ for females.