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Description of key information

The test item is of low oral and inhalative acute toxicity with an oral LD50 (rat) of > 14000 mg/kg bw (IBR, Bio-Research, 1976) and an inhalative LC50 (rat, aerosol, 4 hrs) of > 5010 mg/m3 (Bayer AG, 1996).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment, restriction: no data on test substance purity
Principles of method if other than guideline:
Method: other: Based on "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics", FDA (1959)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Number of animals: 5 per dose group and sex
- Source: Winkelmann, Paderborn (Germany)
- Weight at study initiation: 115 - 140 g
- Diet: Ssniff/Intermast
- Water: ad libitum
ENVIRONMENTAL CONDITIONS:
- Temperature (°C): 22
- Humidity: 45 - 55 %
- Photoperiod (hrs dark/ hrs light): 12 hours/day
- Housing: one per cage
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no details
Doses:
Doses: 10000 (equivalent to 7000 mg/kg bw IPDI homopolymer), 20000 mg/kg bw (equivalent to 14000 mg/kg bw IPDI homopolymer)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Post exposure period: 7 days
Examinations: central nervous system (awareness, emotion, vital symptoms, coordination, tonus, reflexes, autonomic functions)
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 14 000 mg/kg bw
Remarks on result:
other: no mortalities; test substance: isophorone diisocyanate homopolymer, 70 % solution in 2:1 xylene/2-ethoxyethyl acetate (pH: 6.0)
Mortality:
no mortalities
Clinical signs:
10 minutes post application (p.a.) the animals showed: ataxia, abnormalities in posture, piloerection;
24 hours p.a. and during the observation period no signs of toxicity or treatment related effects were observed anymore.
Body weight:
not examined
Gross pathology:
not examined
Other findings:
no other findings

no remarks

Conclusions:
The LD50 value (oral) of IPDI homopolymer (approx. 70 % in solvent) in female and male rats was estimated to be > 14000 mg/kg bw.
No mortalities were observed. Clinical signs like ataxia, abnormalities in posture and piloerection were observed beginning 10 min after dosing and lasting 24 hours. Therefore, under the conditions of this study the acute toxicity of IPDI homopolymer after oral exposure in rats is very low.
Executive summary:

In this standard acute method IPDI homopolymer (approx. 70% in solvent) was administered once to 2 dose-groups of Wistar rats (5 male and 5 female rats per dose-group) in doses of 10000 and 20000 mg/kg bw of undiluted test substance. The animals were observed for mortality and any sub-lethal effects for 7 days after dosing. No death occurred during the study. Clinical signs like ataxia, abnormalities in posture and piloerection were observed beginning 10 min after dosing and lasting 24 hours. According to this study the LD50 value (oral) was determined to be > 14000 mg/kg bw. Therefore under the conditions of this study the acute toxicity of IPDI homopolymer after oral application in rats is very low.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
14 000 mg/kg bw
Quality of whole database:
The study is valid with restrictions (Klimisch score 2).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995-02-15 - 1195-03-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study; GLP study without deviations
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: 92/69/EEC
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: TSCA § 798.1150 (1989)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: 93/21/EEC
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS: 
- Strain: Hsd Cpb:WU (formerly BOR:WISW (SPF-Cpb))
- Source: Harlan Winkelmann GmbH, Borchen (Germany)
- Age: 2-3 months
- Weight at study initiation: males 190-207 g, females 173-193 g
- Number of animals: 5 per concentration and sex
- Controls: conditioned air
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
other: directed-flow nose-only inhalation
Vehicle:
other: compressed air
Details on inhalation exposure:
- Particle size:    
489 mg/m3: MMAD ca. 1.9 µm, GSD ca. 1.8, relative mass < 3 µm ca. 70 %   
2830 mg/m3: MMAD ca. 3.4 µm, GSD ca. 1.7, relative mass < 3 µm ca. 42 %   
5010 mg/m3: MMAD ca. 3.5 µm, GSD ca. 1.7, relative mass < 3 µm ca. 39 %

- Type or preparation of particles: micronization followed by 489 mg/m3: Wright-Dust-Feeder followed by cyclone   
higher concentrations: Exactomat 4200
- Concentration monitoring: samples from breathing zone to  cellulose-acetate filter, gravimetric evaluation
- Particle size determination: samples from breathing zone to cascade  impactors
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
489; 2830; 5010 mg/m3
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Post dose observation period: 2 weeks

EXAMINATIONS:  - body weights: before exposure, days 3 and 7, weekly thereafter
- clinical signs and mortality: several times on day of exposure, twice  (weekends: once) daily thereafter, including: changes in skin and fur;  
eyes; mucous membranes; respiratory, circulatory, autonomic and central  nervous system; somatomotor activity and behavior pattern; Functional  Observational Battery; rectal temperatures.
- necropsy: all animals (macroscopic)
Statistics:
With graphs of means of data, the indicated parameters were evaluated relative to controls (mean = 100 %). The single standard deviations are also
shown relative to the means of the controls. Statistically significant differences (versus control) are indicated by asterisks ('*' for p <0.05 and '**' for
p<0.01).
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 010 mg/m³ air
Exp. duration:
4 h
Remarks on result:
other: No deaths occurred.
Mortality:
No deaths occurred.
Clinical signs:
other: Concentration-dependent signs pertinent to mild  respiratory tract irritation (bradypnea, labored breathing pattern,  serous discharge from the nose, hypothermia); secondary nonspecific signs  (motility reduced, ungroomed hair-coat, piloerection).  All si
Body weight:
Body weight gain was transiently decreased in the 5010 mg/m3 group.
Gross pathology:
No evidence of macroscopically discernible organ  changes was found. A slightly increased number of red foci on the lungs had no clear 
concentration-dependence and was considered to be of no  toxicological relevance.
Other findings:
No other treatment related effects were observed within this study.

no remarks

Conclusions:
The aerosolized test substance (dust) proved to have no significant acute inhalation toxicity to rats. The clinical observations demonstrate that the
dust acts as mild respiratory tract irritant.
Executive summary:

The study on the acute inhalation toxicity of IPDI homopolymer in rats has been conducted in accordance with OECD Guideline No. 403. Ten male and ten female rats were exposed to a solid aerosol (dust) average concentration of 489, 2830, and 5010 mg/m3 air. Attempts were made so that aerosol generated was respirable to rats. The animals were observed for 14 days after application. The LC50 (inhal., aerosol, 4 hr) in rats (male, female) value was estimated to be > 5010 mg/m3.

Aerosol (dust) concentrations up to and including 5010 mg/m3 did not induce test substance related mortality. In all groups exposed to the test compound concentration-dependent signs pertinent to mild respiratory tract irritation (bradypnea, laboured breathing pattern, serous discharge from nose, hypothermia) as well as secondary nonspecific signs (motility reduced, ungroomed hair-coat, piloerection) were observed. The body weight gain was decreased in the 5010 mg/m3 group. All signs were transient in nature and disappeared within the first 3 postexposure days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 010 mg/m³
Quality of whole database:
The study is valid without restriction (Klimisch score 1).

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The test item is of low oral and inhalative acute toxicity with an oral LD50 (rat) of > 14000 mg/kg bw (IBR, Bio-Research, 1976) and an inhalative LC50 (rat, aerosol, 4 hrs) of > 5010 mg/m3 (OECD 403: Bayer AG, 1996). No mortalities were observed. Clinical signs after oral administration like ataxia, abnormalities in posture and piloerection were observed beginning 10 min after dosing and lasting 24 hours. After inhalative administration the aerosolized test substance (dust) proved to have no significant acute inhalation toxicity to rats (secondary nonspecific signs like motility reduced, ungroomed hair-coat, piloerection were observed). The clinical observation demonstrate that the dust acts as mild respiratory tract irritant (bradypnea, laboured breathing pattern, serous discharge from nose, hypothermia).

Assessment of the acute inhalation toxicity data from another study with rats (Pauluhn, Bayer AG, 2003) also indicates that the exposure of respirable aerosols of 3 -isocyanatomethyl-3,5,5 -trimethylcyclohexylisocyanate homopolymer, isocyanurate type (IPDI homopolymer) causes irritation of the respiraton tract as indicated by biochemical and cytological parameters in BALF, increased weights of lung and concentration dependent increased incidence of macroscopic alterations of the respiratory tract. At the very high exposure level of 462.5 mg/m3 clinical evidence existed that the aerosol elicited both a lower as well as an upper tract irritation potential whereas at 153.4 mg/m3 clinical evidence of respiratory tract irritation was minimal or absent. The data generated show unequivocally that the concentration of respirable particulates required for the elicitation of irritant-related pulmonary response is in the range of 153.4 mg/m3. With respect to pulmonary irritation 50 mg/m3 is considered to be the non-irritant threshold concentration (NOAEC).

In consideration of risk management measures inhalation is the most probably route of exposure. Dermal exposure has to be avoided because of sensitizing properties.


Justification for selection of acute toxicity – oral endpoint
Only one valid study available.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available.
The objective of the second study (Pauluhn, 2003) was to analyze the concentration- and time-dependence of changes in bronchoalveolar lavage endpoints as a result of a single 6 hours inhalation exposure. No calculation of LC50 value but derivation of NO(A)EC.

Justification for selection of acute toxicity – dermal endpoint
According to REACH Annex VIII (Column 2 of section 8.5.3) acute dermal study is not needed, because inhalation is considered to be the relevant route of exposure during use.

Justification for classification or non-classification

Based on the results of the acute oral and inhalation studies and according to the criteria of EC Directive 67/548/EEC and EC Regulation 1272/2008 3-isocyanatomethyl-3,5,5 -trimethylcyclohexylisocyanate homopolymer, isocyanurate type (IPDI homopolymer) has a very low acute toxicity if swallowed or inhaled. Therefore, the test substance must not be classified.