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EC number: 203-207-6 | CAS number: 104-49-4
- 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
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Report date:
- 1980
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- 2 doses investigated
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
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
- Test material form:
- not specified
- Details on test material:
- Name of test material (as cited in study report): 80/20 TDI (99.8% TDI. Nippon Polyurethane Industry Co.Ltd.
Constituent 1
- Specific details on test material used for the study:
- As specified above.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- As per the guideline.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age at study initiation: 8 - 9 weeks
- Housing: 6 ♂ / 6 ♀ per cage
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: Unchanged
- Remarks:
- No vehicle
- 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:
- 6 h / day
- Frequency of treatment:
- daily, 5 days per week, up to 113 weeks. No post exposure period.
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
- Details on study design:
- As per guideline.
- Positive control:
- None; not applicable.
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.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- 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:
- 0.15 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:
- clinical signs
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 0.15 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- Key result
- 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
Chronic Toxicity:
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
Carcinogenicity
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
Applicant's summary and conclusion
- Conclusions:
- The animals were whole body exposed to 0, 0.05 and 0.15 ppm of TDI (80/20) vapour for 6 hours/day, 5 days/week. In both species, body weight gain was reduced at 0.15 ppm over the first 12 weeks that persisted but did not worsen over the remaining period of the study. In rats, rhinitis was observed in males at 0.15 ppm and in females beginning at 0.05 ppm, generally characterized by squamous metaplasia/hyperplasia of the respiratory mucosa, with and without exudate in the lumen, and leucocyte infiltration in the lamina propria. This finding is considered to be due to local irritation of the anterior nasal cavity. In mice, histopathology revealed marked inflammatory processes in trachea, larynx, bronchi, lungs and predominantly in nasal turbinates (chronic and necrotic rhinitis) of male and female animals beginning at 0.05 ppm. Therefore, the LOAEC for rats and mice is 0.05 ppm (0.362 mg/m3) after long-term inhalation of TDI vapour.
Inhalation exposure is the most appropriate route for assessing occupational risk in humans. Effects from repeated exposure of animals to TDI are limited to effects on the respiratory tract caused by local irritation, no signs of systemic toxicity were observed.
Simultaneously, other studies show that nose is the targeted organ of the respiratory system. Thus, the assessment confirmed the legal classification of the substance as STOT Single Exp.3 (Hazard statement H335, May cause respiratory irritation). - Executive summary:
The animals were whole body exposed to 0, 0.05 and 0.15 ppm of TDI (80/20) vapour for 6 hours/day, 5 days/week. In both species, body weight gain was reduced at 0.15 ppm over the first 12 weeks that persisted but did not worsen over the remaining period of the study. In rats, rhinitis was observed in males at 0.15 ppm and in females beginning at 0.05 ppm, generally characterized by squamous metaplasia/hyperplasia of the respiratory mucosa, with and without exudate in the lumen, and leucocyte infiltration in the lamina propria. This finding is considered to be due to local irritation of the anterior nasal cavity. In mice, histopathology revealed marked inflammatory processes in trachea, larynx, bronchi, lungs and predominantly in nasal turbinates (chronic and necrotic rhinitis) of male and female animals beginning at 0.05 ppm. Therefore, the LOAEC for rats and mice is 0.05 ppm (0.362 mg/m3) after long-term inhalation of TDI vapour.
Inhalation exposure is the most appropriate route for assessing occupational risk in humans. Effects from repeated exposure of animals to TDI are limited to effects on the respiratory tract caused by local irritation, no signs of systemic toxicity were observed.
Simultaneously, other studies show that nose is the targeted organ of the respiratory system. Thus, the assessment confirmed the legal classification of the substance as STOT Single Exp.3 (Hazard statement H335, May cause respiratory irritation).
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