Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 223-861-6 | CAS number: 4098-71-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2005-11-14 to 2006-02-02
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate
- EC Number:
- 223-861-6
- EC Name:
- 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate
- Cas Number:
- 4098-71-9
- Molecular formula:
- C12H18N2O2
- IUPAC Name:
- 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane
- Details on test material:
- Isophorone diisocyanate of Bayer MaterialScience AG, batch no.LL48/3-55, purity: 99.8%
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sex: male
- Strain: Hsd/win: NMRI
- Source: Harlan Winkelmann GmbH, Borchen
- Age: 6-12 weeks
- Weight at study initiation: 34 - 40 g
- Number of animals: 6/group/sacrifice timepoint (5 for the 24h positive control group)
- Housing: single in conventional Makrolon Typ II cages
- Diet: standard fixed-furmula diet 3883 (PROVIMI Kliba; Kaiseraugst.; CH) ad libitum
- Water: tab water ad libitum
- Acclimation period: at least 5 days, prior to exposure mice were adapted to exposure tubes on 3 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/- 2 °C
- Humidity (%): approximately 40 - 60 %
- Air changes (per hr): approximately 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 h/ 12h
Administration / exposure
- Route of administration:
- other: nose-only inhalation (vapor/aerosol)
- Vehicle:
- air
- Details on exposure:
- ISOPHORONE DIISOCYANATE EXPOSURE:
- Mice were assigned to four exposure groups and were exposed to the aerosolized test substance to target concentrations of
0 air (--), 5(4.3), 15 (16.1) and 40 (39.6) mg/m³ (1 x 6 hr); target concentrations (analytical concentrations)
- number of animals per concentration of test substance and air control: 18 (main study) and additionally 5 (satellite mice for respiratory function measurements)
PARAMETERS ASSESSED
- Clinical observations: several times on the day of exposure and at least once daily thereafter
- Body weights: daily
- Body temperature: rectal body temperature directly after cessation of exposure; subcutaneous body temperature (transponders) during exposure (at intervals of 30 min.) up to 3 hours after ceasing exposure
- Respiratory function measurements (restricted to the satellite mice)
CONDUCT OF THE MICRONUCLEUS TEST
- Experimental Group Target Concentration Sacrifice Time
(mg/m³) (hours)
---------------------------------------------------------
Negative Control 0 24
Isophorone Diisocyanate 5 24
Isophorone Diisocyanate 15 24
Isophorone Diisocyanate 40 24
Positive Control
Cyclophosphamide 20 mg/kg
Negative Control 0 48
Isophorone Diisocyanate 5 48
Isophorone Diisocyanate 15 48
Isophorone Diisocyanate 40 48
Negative Control 0 72
Isophorone Diisocyanate 5 72
Isophorone Diisocyanate 15 72
Isophorone Diisocyanate 40 72
number of animals in the positive control group: 5
2000 polychromatic erythrocytes were counted per animal - Duration of treatment / exposure:
- 1 x 6 hours
- Frequency of treatment:
- 1 time
- Post exposure period:
- 24, 48, 72 hours
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 5, 15, 40 mg/m³ (target concentration)
Basis:
other: target concentration
- Remarks:
- Doses / Concentrations:
--, 4.3, 16.1, 39.6 mg/m3
Basis:
analytical conc.
- Remarks:
- Doses / Concentrations:
--, 33, 94.2, 212 mg/m3
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
--, 2.1, 15.9, 44.0 mg/m3
Basis:
other: gravimetric concentration
- No. of animals per sex per dose:
- test substance: 6
negativ control: 6
positive control: 5 - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamid (Endoxan) 20 mg/kg single intraperitoneal treatmaent
Examinations
- Tissues and cell types examined:
- polychromatic erythrocytes of the bone marrow from femur
- Details of tissue and slide preparation:
- A method described by Schmid (1975) was used to produce the smears (Schmid, W.; The Micronucleus Test; Mutation Res. 31, 9-15, 1975 ; and: Schmid, W. Der Mikrokerntest; Deutsche Forschungsgemeinschaft. Kommission für Mutagenitätsfragen. Mitteilung III, 53-61, 1975). The smears were stained automatically with an Ames Hema-Tek slide Stainer (Mile Company), destrained with methanol, rinsed with deionized water, dried and covered.
- Evaluation criteria:
- ASSESSMENT CRITERIA:
- A test was considered positive if there was at any time point a biologically relevant and statistically significant increase in the number of
polychromatic erythrocytes showing micronuclei in comparison to the negative control.
- A test was considered negative if there was no relevant or significant increase in the rate of micronucleated polychromatic erythrocytes.
A test was also considered negative if there was a significant increase in that rate which, according to the laboratory's experience was within
the range of historical negative controls.
- In addition, a test was considered equivocal if there was an increase of micronucleated polychromatic erythrocytes above the range of attached
historical negative controls, provided the increase was not significant and the result of the negative control was not closely related to the data
of the respective treatment group. A test was also considered equivocal, if its result was implausible. In both case, normally a second test will be
performed. - Statistics:
- BIOMETRY:
- Normally 2000 polychromatic erythrocytes were counted per animal.
- Per sacrifice time the Isophorone diisocyanate group with the highest mean (provided this superceded the negative control mean) and the
positive control were checked by Wilcoxon's non-parametric rank sum test with respect to the number of polychromatic erythrocytes having
micronuclei and the number of normochromatic erythrocytes. A variation was considered statistically significant if its error probability was
below 5% and the treatment group figure was higher than that of the negative control.
- The rate of normochromatic erythrocytes containing micronuclei was examined if the micronuclear rate for polychromatic erythrocytes was
already relevantly increased. In this case, the group with the highest mean was compared with the negative control using the one-sided
chi2-test. A variation was considered statistically significant if the error probability was below 5% and the treatment group figure was higher
than that of the negative control.
- In addition, standard deviations (1s ranges) were calculated for all the means.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Remarks:
- no relevant indications of a clastogenic effect of the test substance under conditions of this study in male mice
- Toxicity:
- yes
- Remarks:
- all concentrations: evidence of respiratory tract irritation and clinical symptoms caused by exposure to the test substance observed (see "Add. information on results")
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- ISOPHORONE DIISOCYANATE EXPOSURE
- Target Concentration (mg/m³): 0, 5, 15, 40
- Nominal Concentration (mg/m³): --, 33, 94.2, 212
- Gravimetric Concentration (mg/m³):--, 2.1, 15.9, 44.0
- Analytical Concentration (mg/m³): --, 4.3, 16.1, 39.6
- The Mass Median Aerodynamic Diameters (MMAD) was <4 µm (MMAD 1.3 µm, Geometric Standard Deviation 2). At the lowest concentration IPDI at mospheres consisted of vapor rather than aerosol to an appreciable extent.
PARAMETERS ASSESSED:
- Mortality: did not occur at any exposure level:
- Clinical Observations:
Target Deaths/signs/total Onset and Duration
Concentration of Signs
(mg/m³)
0 0 / 0 / 18 -- --
5 0 / 18 / 18 0d - 3d
15 0 / 18 / 18 0d - 3d
40 0 / 18 / 18 0d - 3d
0d = day of exposure.
3d: terminal sacrifice
Values given in the 'Deaths/signs/total' column are as follows:
1st number = number of dead animals
2nd number = number of animals with signs after exposure cessation
3rd number = number of animals exposed
0 mg/m³: All mice tolerated the exposure/dosing without signs.
5 mg/m³: Bradypnea, labored breathing patterns, stridor, motility reduced, high-legged gait, piloerection, eyelids closed.
15 mg/m³: Bradypnea, labored breathing patterns, breathing sounds, stridor, motility reduced, high-legged gait, piloerection, hair-coat
ungroomed, eyelids closed, blepharospasm.
40 mg/m³: Bradypnea, labored breathing patterns, breathing sounds, stridor, motility reduced, high-legged gait, piloerection, hair-coat
ungroomed, eyelids closed, blepharospasm, tremor, prostration, salivation, cyanosis.
- Body weights: Marked, concentration-dependent decrease in body weights which was most pronounced at 15 mg/m³ and 40 mg/m³.
- Body temperature: The mean body temperatures were significantly decreased at the end of the 6-h exposure period in all test material-exposure
groups.
0 mg/m³: 38.1 °C
5 mg/m³: 33.3* °C
15 mg/m³: 27.9** °C
40 mg/m³: 25.6** °C * = p < 0.05, ** = p < 0.01
Subcutaneously measured body temperatures were consistent with rectal temperatures. The subcutenously measured values showed that the
duration of hypothermia was more pronounced in 40 mg/m³-group as compared to 15 mg/m³-group.
- Respiratory function measurements (satellite groups): Moderate effects on respiration were observed in 5 mg/m³, whilst in 15 mg/m³-group and 40 mg/m³-group a maximal depression of respiration was observed. This was caused specifically by increases in the bradypnoic period (pause
between end inspiration and start of expiration).
CONDUCT OF THE MICRONUCLEUS TEST
- As may be seen from the tables below, the ratio of polychromatic to normochromatic erythrocytes in males was altered by the treatment with
Isophorone diisocyanate for all sacrifice times at all concentration groups.
- As may be further deduced from the tables below, no biologically important or statistically significant variations existed for males between the
negative control and the groups treated by inhalation with isophorone diisocyanate, with respect to the incidence of micronucleated
polychromatic erythrocytes.
- Similarly, there could be no biologically significant variation between the negative control and Isophorone diisocyanate groups in the number of
micronucleated normochromatic erythrocytes, since normochromatic erythrocytes originated from polychromatic ones. As expected, relevant
variations were not observed.
- The positive control, cyclophosphamide, caused a clear increase in the number of polychromatic erythrocytes with micronuclei. The incidence of
micronucleated cells represents biologically relevant increases in comparison to the negative control.
Any other information on results incl. tables
RS-Freetext:
SUMMARY OF RESULTS OF 24 HOURS INTERVAL
Experimental number of number of MNNCE per MNPCE per
groups evaluated of NCE per 2000 NCE 2000 PCE
PCE 2000 PCE
(1s range) (1s range) (1s range)
-----------------------------------------------------------
negative
control 12000 1988 2.3 2.0
(412) (2.3) (0.6)
5 mg/m³ 12000 3117 2.1 1.7
(997) (1.2) (0.8)
15 mg/m³ 12000 4598* 3.0 3.0
(1617) (1.0) (0.6)
40 mg/m³ 12000 3679 2.8 4.5
(1959) (3.3) (2.2)
positive 10000 2515 1.9 26.2**
control (768) (0.8) (12.4)
SUMMARY OF RESULTS OF 48 HOURS INTERVAL
Experimental number of number of MNNCE per MNPCE per
groups evaluated of NCE per 2000 NCE 2000 PCE
PCE 2000 PCE
(1s range) (1s range) (1s range)
-----------------------------------------------------------
negative
control 12000 1682 2.4 4.3
(154) (1.6) (2.3)
5 mg/m³ 12000 2039 2.8 2.2
(635) (2.5) (1.5)
15 mg/m³ 12000 3874 2.1 3.3
(2810) (0.9) (2.3)
40 mg/m³ 12000 4236* 2.5 3.5
(1568) (0.6) (1.4)
SUMMARY OF RESULTS OF 72 HOURS INTERVAL
Experimental number of number of MNNCE per MNPCE per
groups evaluated of NCE per 2000 NCE 2000 PCE
PCE 2000 PCE
(1s range) (1s range) (1s range)
-----------------------------------------------------------
negative
control 12000 1353 3.2 2.3
(209) (2.3) (1.8)
5 mg/m³ 12000 1800 1.7 1.8
(541) (2.5) (1.0)
15 mg/m³ 12000 3387 2.4 3.7
(2810) (0.9) (2.3)
40 mg/m³ 12000 7168** 2.6 4.5
(2577) (0.7) (1.8)
-----------------------------------------------------------
*P < 0.05 in non-parametric Wilcoxon ranking test
**P < 0.01 in non-parametric Wilcoxon ranking test
Applicant's summary and conclusion
- Conclusions:
- There were no biologically relevant indications of a clastogenic effect after inhalative exposure of Isophorone diisocyanate in the micronucleus test on the male mouse under the experimental conditions of this study.
Analytical monitoring data of the exposure conditions, clinical signs of respiratory tract irritation, hypothermia and respiratory depression
appear to suggest adequate bioavailability by this route. - Executive summary:
The micronucleus test was conducted to investigate the test substance Isophorone Diisocyanate in male NMRI mice for a possible clastogenic effect on the chromosomes of bone-marrow erythroblasts. Male mice treated with Isophorone Diisocyanate received for 6 hours inhalative target concentrations of 0 (air control), 5, 15 and 40 mg/m3 respectively. The animals were sacrificed 24, 48 and 72 hours after exposure. After inhalative treatment for 6 hours of males with concentrations up to and including 40 mg/m3 (target concentration) no biologically relevant indications of a clastogenic effect of Isophorone Diisocyanate were found in male NMRI mice under the experimental conditions of this study.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.