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EC number: 247-722-4 | CAS number: 26471-62-5
- 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
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- chronic toxicity: inhalation
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1976-10 to 1978-11
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1976-10 to 1978-11
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- 2 doses investigated
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 8 - 9 weeks
- Housing: 6 ♂ / 6 ♀ per cage - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 9 m³ chambers - Analytical verification of doses or concentrations:
- yes
- Remarks:
- Atmospheres monitored at least 5 times each day by two methods: Marcali test and test paper monitor.
- Duration of treatment / exposure:
- 6 h / day
- Frequency of treatment:
- daily, 5 days per week, up to 113 weeks
- Post exposure period:
- no
- Dose / conc.:
- 0.05 ppm (nominal)
- Dose / conc.:
- 0.15 ppm (nominal)
- No. of animals per sex per dose:
- 126
- Control animals:
- yes, sham-exposed
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, before and after exposure
BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the firt 8 weeks, thereafter monthly.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 6, 12, 18 months, and termination.
- How many animals: 7♂/ 7♀
- Parameters checked: Hb, RBC, PCV, WBC
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 6, 12, 18 months, and termination.
- How many animals: 7♂/ 7♀
- Parameters checked: BUN, AlkP, GPT
URINALYSIS: Yes
- Time schedule for collection of urine: after 6, 12, 18 months, and termination. - Sacrifice and pathology:
- GROSS PATHOLOGY:
Yes, interim sacrifices on 7♂ and 7♀ at 6, 12, and 18 months. Gross examination on all rats dying and at scheduled sacrifice. Organ weights on brain, liver, heart, gonads, and kidneys.
HISTOPATHOLOGY:
Yes, on 35 tissues from each rat. - Statistics:
- Survival probabilities for each group were calculated by the method of Kaplan and Meier (J. Am. Statist. Ass. 53: 457 (1958)). The survival of the individual treatment groups was compared using the log rank method of Peto and Pike (Biometrics 29: 579 (1973)). All tumors observed where the difference between tumor incidence in treated animals and controls was 4 or less were not statistically significant (United States of America, National Research Council, Food Protection Committee, Nat. Acad. Sci. Publ., 749 (1959)).
Since neither in the publication (Loeser, 1983) nor in the study report (Owen, 1980+1984) statistics for tumor incidences were presented, the tumor data for rats were reassessed using both the method cited in the original protocol and the more current one-sided Fisher's exact test (Müller, 2008). - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.15 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
The results for general toxicity of this study are described in chapter 7.5.2
With respect to the assessment of tumour formation, there were slight increases in the tumour incidence for some locations when compared to the incidence in the controls. In Table 1, specific tissues and the number of tumours in the various treatment and control groups are listed only if there were at least two more tumours in the groups treated with TDI than in the controls. The author concluded, that the type and incidence of tumours and the numbers of tumour-bearing rats were similar in both control and TDI treated groups.
A statistical analysis of the results was not carried out, but the tumour spectrum in all groups was in the range of the general experience (Loeser, 1983). A full assessment of the original tumour data by both the protocolled method and more current methodology has been reported by Müller (2008). Overall, and taking into account the statistical results, contemporary control animal data from the laboratory and the tumour profiles of the animal strain used, Müller concluded that there was no toxicologically significant increase in the tumour incidences of this long-term TDI rat study.
The overall evaluation of the study therefore led to the conclusion, that TDI is not carcinogenic in rats under the conditions described.
Table 1: Tumour incidences of the 2-year rat study with TDI (80/20)
TDI (ppm) |
Sex |
0 |
0.05 |
0.15 |
Number of animals investigated |
M/F |
104/104 |
104/105 |
104/105 |
Types of tumours for which there were at least 2 more tumours in the groups treated with than in the controls: |
||||
Adenomas (skin) |
M |
0 |
0 |
3 |
Papillomas (skin) |
F |
1 |
3 |
3 |
Benign tumours (mammary gland) |
F |
24 |
27 |
22 |
Carcinomas (mammary gland) |
F |
9 |
9 |
14 |
Fibromas (subcutis/muscle/bones) |
M/F |
29/1 |
22/1 |
35/4 |
Histiocytomas (subcutis/muscle/bones) |
M |
1 |
4 |
1 |
Malignant lymphomas (haematopoietic system) |
F |
1 |
1 |
3 |
Haemangiomas (haematopoietic system) |
M |
1 |
1 |
4 |
Islet cell adenomas (pancreas) |
M |
1 |
2 |
3 |
Adenomas (pituitary gland) |
F |
64 |
62 |
67 |
Meningiomas (brain) |
M |
0 |
0 |
2 |
Lipomatous tumours (kidney) |
M |
1 |
3 |
0 |
M = male; F = female
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 980
- Report date:
- 1980
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 983
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- 2 doses investigated
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- m-tolylidene diisocyanate
- EC Number:
- 247-722-4
- EC Name:
- m-tolylidene diisocyanate
- Cas Number:
- 26471-62-5
- Molecular formula:
- C9H6N2O2
- IUPAC Name:
- 2,4-diisocyanato-1-methylbenzene, 2,6-diisocyanato-1-methylbenzene
- Details on test material:
- - Name of test material (as cited in study report): 2,4/ 2,6-TDI (80:20), production grade
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 8 - 9 weeks
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION:
- Method of holding animals in test chamber: Animals were housed 6 ♂ / 6 ♀ per cage and exposed in 9 m³ chambers.
- Method of conditioning air: Passage of dry nitrogen through liquid TDI maintained at 21°C. The vapour produced was then diluted with air in all-glass systems to produce the desired exposure concentration.
OTHER:
Because of the known chemical reactivity and thus its potential storage instability, TDI lots were renewed every three months and fresh TDI was placed in the respective vapour-generating apparatus at the beginning of each daily exposure period. The measured mean test concentrations of TDI were 0.052 ppm and 0.146 ppm over a period of up to 113 weeks, with standard deviations of 0.007 ppm and 0.014 ppm, respectively.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- 5/day, each exposure group.
U.E.I. Model 7000 TDI tape monitor and the Marcali colorimetric method. - Duration of treatment / exposure:
- up to 113 weeks
- Frequency of treatment:
- 6 hours/day, 5 days per week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.05 ppm (nominal)
- Dose / conc.:
- 0.15 ppm (nominal)
- No. of animals per sex per dose:
- 126
- Control animals:
- yes, sham-exposed
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes
Interim sacrifices were performed after 6, 12, and 18 months of exposure consisting of 7 animals/sex/dose. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGAN WEIGHTS: Yes - Other examinations:
- Special histopathology of the nasal cavity.
- Statistics:
- Survival probabilities for each group were calculated by the method of Kaplan and Meier (J. Am. Statist. Ass. 53: 457 (1958)). The survival of the individual treatment groups was compared using the log rank method of Peto and Pike (Biometrics 29: 579 (1973)).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Compared to control rats, there were significantly reduced body weight gains in males and in females of the highest dose groups up to study week 12 that remained significantly reduced throughout the study for female rats.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In rats sacrificed as scheduled (interim sacrifices after 6, 12 and 18 months + terminal sacrifice), lesions were localized primarily in the anterior respiratory mucosa of the nasal cavity. Rhinitis was increased in incidence and severity (grades1-4: minimal - marked rhinitis, generally characterized by squamous metaplasia and hyperplasia of the epithelium, leucocyte infiltration in the lamina propria and exudate in the lumen) in a dose-dependent manner and is considered to be due to local irritation.
- Histopathological findings: neoplastic:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.05 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- < 0.05 ppm (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no NOAEC identified
- Dose descriptor:
- LOAEC
- Effect level:
- 0.15 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- Dose descriptor:
- LOAEC
- Effect level:
- 0.05 ppm (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
No exposure-related clinical signs of toxicity were observed during the study. No treatment-related changes in hematology, blood biochemistry, urinalyses, ophthalmoscopy or organ weights were recorded.
Compared to control rats, there were significantly reduced body weight gains in males and in females of the highest dose groups up to study week 12 that remained significantly reduced throughout the study for female rats. Mortality occurred in both test and control groups, with generally higher mortality rates at earlier time points in test groups than in the controls for males, providing additional supporting evidence indicating that MTD was reached.
Table 1: Body weight gain and mortality rate of rats during exposure
Males |
Females |
|||||
Control |
Low dose |
High dose |
Control |
Low dose |
High dose |
|
Group mean body weight gain (g): week 0 –12 |
298 |
296 |
275* |
136 |
132 |
121* |
Group mean body weight gain (g): week 0 - termination |
554 |
579 |
525 |
395 |
378 |
345* |
Mortality before interim sacrifice after 6 m |
3/126 |
13/126 |
11/126 |
0/126 |
1/126 |
0/126 |
Mortality before interim sacrifice after 12 m |
4/116 |
1/106 |
1/108 |
1/119 |
3/118 |
1/119 |
Mortality before interim sacrifice after 18 m |
7/105 |
8/97 |
13/100 |
14/111 |
20/108 |
9/110 |
Mortality before terminal sacrifice |
52/89 |
46/81 |
50/80 |
53/88 |
55/81 |
46/84 |
* P <0.01 when compared to the controls
In rats sacrificed as scheduled (interim sacrifices after 6, 12 and 18 months + terminal sacrifice), lesions were localized primarily in the anterior respiratory mucosa of the nasal cavity. Rhinitis was increased in incidence and severity (grades1-4: minimal - marked rhinitis, generally characterized by squamous metaplasia and hyperplasia of the epithelium, leucocyte infiltration in the lamina propria and exudate in the lumen) in a dose-dependent manner and is considered to be due to local irritation.
Table 2: Incidence of rhinitis in the anterior nasal cavity of rats
Males |
Females |
|||||
Control |
Low dose |
High dose |
Control |
Low dose |
High dose |
|
Grade 0* |
30/58 |
30/55 |
6/51 |
46/56 |
27/47 |
17/57 |
Grade 1* |
11/58 |
7/55(13 %) |
5/51 |
7/56 |
8/47(17 %) |
16/57(28 %) |
Grade 2* |
13/58 |
15/55 (27 %) |
13/51(25 %) |
3/56 |
9/47(19 %) |
18/57(32 %) |
Grade 3* |
4/58 |
3/55 |
23/51 (45 %) |
0 |
3/47(6 %) |
5/57(9 %) |
Grade 4* |
0 |
0 |
4/51 |
0 |
0 |
0 |
No section |
0 |
0 |
0 |
0 |
2 |
|
Percent rats with grade1- 4 rhinitis |
48 % |
45 % |
88 % |
18 % |
43 % |
70 % |
* Grade 0 = unremarkable; Grade 1 = minimal rhinitis, Grade 2 = slight rhinitis, Grade 3 = moderate rhinitis, Grade 4 = marked rhinitis generally characterized by squamous metaplasia and hyperplasia of the epithelium, leucocyte infiltration in the lamina propria and exudate in the lumen
Applicant's summary and conclusion
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