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Carcinogenicity

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Description of key information

1. Read across from Toluene diisocyanate, Loeser et al. (1983), similar to OECD TG451, rats and mice, inhalation, 0.05 or 0.15 ppm for approximately 2 years (6 h/day, 5 days a week), NOEAC 0.05 ppm for mice and 0.15 ppm (1.086 mg/m³) for rats

2. Read across from Toluene diisocyanate, Gordon et al. (1986), similar to OECD TG451, rats and mice, oral exposure, rats: 30 mg/kg (males), 60 mg/kg and 120 mg/kg (females),  mice: 60 mg/kg  (females), 120 mg/kg, and 240 mg/kg (males) for 105 or 106 weeks (5 days a week), carcinogenicity in rats, carcinogenicity in female mice from 60 mg/kg on, no carcinogenicity in male mice

3. Read-across from pMDI, OECD 453, inhalation, 2 year, NOAEC =0.2 mg/m³, LOAEC = 1 mg/m³, Reutzel et al, 1994

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

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Endpoint:
carcinogenicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Survival in all groups of dosed rats in the 2-year studies was shorter (P>0.005) than that of the controls. A dose-dependent pattern of cumulative toxicity began at 70 weeks and culminated in excessive mortality, indicating the estimated maximum tolerated dose had been exceeded for rats, Acute bronchopneumonia occurred at increased incidences in groups of dosed male and female rats (males: control, 2/50; low dose, 6/50; high dose, 14/50; females: 1/50, 10/50, 25 / 49). No other compound-related clinical signs were observed. See table 5.
Mortality:
mortality observed, treatment-related
Description (incidence):
In male rats, the survival of animals in the two dosed groups was significantly shorter than that of the controls (P<0.001). In females, the survival in each dosed group was significantly shorter than that in the controls (high dose, P<0.001; low dose, P=0.005), and the survival in the high dose group was significantly shorter than that in the low dose group (P=0.001). One control, six low dose, and three high dose males and one high dose female and five low dose females were accidentally killed and were censored from the statistical analysis of survival. In male rats, 36/50 (72%) of the controls, 14/50 (28%) of the low dose, and 8/50 (16%) of the high dose group lived to the end of the study at 108 weeks. In female rats, 36/50 (72%) of the controls, 19/50 (38%) of the low dose, and 6/50 (12%) of the high dose group lived to the end of the study at 108 weeks. The survival data included one control male and one high dose female that died during the termination period of the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Depressions in mean body weight gain relative to controls were greater than 10% in all dosed at groups throughout most of the study. Mean body weights of dosed rats were lower than those for the controls after week IO in males and week 20 in females. The depressions in mean body weight gains were dose related. See table 5.
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:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Subcutaneous tissue fibromas or fibrosarcomas (combined) in male rats, mammary gland fibroadenomas in female rats,pancreatic acinar cell adenomas in male rats occurred with a positive trend.Subcutaneous tissue fibromas or fibrosarcomas (combined) in male rats occurred with a positive trend (P<0.01; 3/50, 6/50, 12/50). The incidence in the high dose group was higher than that in the controls (P<0.01). The same tumour comparisons were significant (P<0.001) in female rats by the life table analysis. Mammary gland fibroadenomas in female rats occurred with a positive trend (P<0.001), and the incidences in low and high dose groups were significantly higher than that in controls (P<0.01).
Pancreatic acinar cell adenomas in male rats occurred with a positive trend (p<0.05; 1/47, 3/47, 7/49). The incidence in the high dose group was higher than that in the controls (p<0.05).
The incidences of pancreatic islet cell adenomas in female rats were higher by the incidental tumour test (p<0.01) in low dose (6/49) and high dose (2/47) groups than in controls (0/50). An islet cell carcinoma was also observed in a low dose female rat. The incidences of female rats with neoplastic nodules in the liver occurred with a positive trend (P<0.05; 3/50,8/50, 8/48), and the incidence in the high dose group was higher (p<0.05) than that in the controls.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Lung sections were examined from 11 male and 10 female rats that died during the first 4 months of the studies. All lungs showed marked congestion and variable amounts of pulmonary oedema. Oedema occurred in the bronchioles and alveoli and in a perivascular location. Slight to moderate amounts of perivascular lymphoplasmacytosis were observed in four rats. Necrotising suppurative pneumonia was detected in two rats, and the lungs of one of these animals contained numerous bacteria. Bacteria were also detected in the lungs of two other rats, and a clump of foreign material (presumably of vegetable origin) was found in the bronchus of another animal. Mucocellular exudate was observed in bronchiolar lumens in a moderate number of rats. The presence of trace to very small quantities of pale yellow, slightly refractile material was detected in terminal portions of the respiratory tree (alveoli and terminal bronchioles) in 13/21 lungs examined. In the bronchioles, the material was associated with a stringy pink substance that was suggestive of fibrin and that appeared as an aggregate of vacuoles and strands. Very pale, refractive material was sometimes observed in the vacuoles. Larger, pale yellow, globular bodies were found in respiratory bronchioles and alveoli. The bodies occasionally appeared “fractured’’ and were sometimes associated with an inflammatory reaction.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The incidences of female rats with neoplastic nodules in the liver occurred with a positive trend (P<0.05; 3/50,8/50, 8/48), and the incidence in the high dose group was higher (P<0.05) than that in the controls.
Details on results:
Fibromas or fibrosarcomas occurred in male rats with a statistically significant positive trend, and the incidence in the high dose males was significantly higher than that in the controls (Table 6).
Fibromas or fibrosarcomas also occurred in female rats with a statistically significant positive trend, and the incidence in the high dose females was higher than that in the controls by life table analysis (Table 6).
Mammary Gland: By life table and incidental tumour test analysis, there were statistically significant increases in the incidence of combined mammary gland tumours in female rats in both low dose and high dose groups (Table 7). Since these mammary gland tumours and subcutaneous tissue tumours were all found in the axillary and inguinal areas, they are regarded as all arising from mammary tissue. The survival-adjusted tumour incidences provide a more meaningful comparison than unadjusted overall tumour rates. For example, the first tumour was seen in an animal dying at week 84, and the proportions of animals surviving at least to week 84 with combined mammary gland tumours were: controls, 17/45 (38%); low dose, 25/36 (69%); and high dose, 2 1 / 28 (75%).
There we no differences in the incidence of mammary gland fibroadenomas in male rats after 30 or 60 mg/ kg TDl treatment compared to controls.
Haematopoietic System: Monocytic leukaemia was observed in male and female rats with a statistically significant decreasing trend (Table 8). and the pairwise comparisons between the control and dosed groups were significant. These decreases were not significant by life table analysis.
Pancreas: Acinar cell adenomas were observed in male rats with a statistically significant trend, and the incidence in the high dose group was significantly higher than that in the controls (Table 9). In high dose female rats one acinar cell adenoma and one acinar cell carcinoma were observed.
The adenomas were sharply demarcated from the surrounding tissue and were characterised by a loss of acinar structure, an increase in the number of basophilic cells, and enlarged and irregular nuclei with increased mitotic activity. (Mitoses often averaged one to three per highpower field.) The lesions were usually small, often less than I to 2 millimeters in diameter. A dose-related increase also was observed in the number of male rats with nodular hyperplasia of the pancreatic acinus (control, 0%; low dose, 4%; high dose, 8%).
Islet cell adenomas occurred in female rats with a statistically significant positive trend (Table 9); the incidences of dosed females with these tumours were significantly higher than those in the controls. An islet cell carcinoma was observed in a low dose female rat. The markedly reduced survival in high dose female rats may have been responsible for the lower incidence of islet cell tumours in this group relative to the low dose group. In male rats, pancreatic islet cell adenoma or carcinoma (combined) showed a positive trend and increased incidence in the high dose group by the life table test (Table 9).
Liver: The incidence of female rats with neoplastic nodules occurred with a statistically significant positive trend; the incidence of high dose females with these' nodules was significantly higher than that of the controls (Table 10).
Brain: Gliomas were found in two high dose male rats and a pinealoma was found in a third high dose male.
Lungs: Acute bronchopneumonia was found in increased incidence in dosed rats (males: control, 2/50, 4%; low dose, 6/50, 12%; high dose, 14/50, 28%; females: control, 1/50, 2%; low dose, 10/50,20%; high dose, 25/49,51%;).
Relevance of carcinogenic effects / potential:
The carcinogenic effects observed in male and female rats indicate that the test substance had a significant carcinogenic effect after oral gavage. A treatment related increase in tumour incidence as compared to controls was shown. As tumours subcutaneous tissue fibromas or fibrosarcomas (combined) in male rats, mammary gland fibroadenomas in female rats, pancreatic acinar cell adenomas in male rats occurred with a positive trend. However the tumours observed are due to metabolism of toluene diisocyanate to toluene diamine (mainly in the gastrointestinal tract) and that metabolite is known to be a potent carcinogen. Additionally the exposure route is not well chosen, since the inhalation route is most relevant to humans. Therefore the results obtained need to be judged carefully.
Dose descriptor:
LOAEL
Effect level:
>= 60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: neoplastic
Dose descriptor:
LOAEL
Effect level:
>= 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: neoplastic
Critical effects observed:
not specified

At week 87 untreated controls were sacrificed and examined. The incidence and type of tumors in individual rats did not appear different from the normal background of tumors in the F344/N rat. Thus these data are not given in this report.

Table 5. Mean body weights and survival of rats in the two-year gavage studies of Toluene diisocyanate
Weeks on Study Vehicle Control Low Dose High Dose
Av.Wt (grams) No. of Survivors Av.Wt. (grams) Wt (percent of veh controls) No. of Survivors Av. Wt. (grams) Wt (percent of veh controls) No. of Survivors
MALE
0 184 50 182 99 50 198 108 50
1 200 50 190 95 50 200 100 50
2 211 50 210 100 50 212 100 50
3 224 50 227 101 50 228 102 49
4 240 50 240 100 50 239 100 48
5 233 50 238 103 48 237 102 48
e 233 50 249 98 48 256 101 47
7 282 50 260 99 47 268 102 47
8 272 50 263 97 45 266 98 45
9 288 50 277 96 44 276 96 44
10 283 50 288 95 43 286 94 43
11 288 50 280 95 41 266 90 42
12 297 50 284 96 41 272 92 40
13 302 50 290 96 41 278 92 40
16 323 50 306 95 41 294 91 39
20 3S3 50 338 96 41 309 88 39
24 357 49 338 95 41 323 90 39
28 371 49 351 95 39 330 89 36
32 384 49 368 95 39 341 89 36
36 396 49 367 93 39 338 85 36
40 402 49 378 94 37 341 85 35
44 411 49 378 92 37 339 82 33
48 418 49 387 93 37 343 82 32
52 418 49 385 92 35 337 81 32
56 426 49 388 91 33 335 79 30
60 421 49 379 90 33 325 77 29
64 429 49 386 90 33 332 77 29
68 425 49 382 90 31 324 76 29
72 427 49 376 88 31 324 76 27
76 430 48 377 88 30 325 76 25
80 425 47 370 87 28 329 77 23
84 424 47 370 87 27 327 77 20
88 410 46 354 86 27 323 79 20
92 408 45 358 88 26 314 77 16
96 412 42 365 89 22 316 77 14
100 ??? 39 358 87 20 309 75 13
104 ??? 36 350 86 18 318 78 10
FEMALE
0 130 50 134 103 50 139 107 50
1 137 50 138 101 50 145 106 50
2 146 50 145 99 50 149 102 50
3 154 50 151 98 50 156 101 50
4 161 50 157 98 50 162 101 50
5 161 50 161 100 48 166 103 50
6 167 50 166 99 47 166 99 50
7 171 50 171 100 46 173 101 50
8 174 50 172 99 44 173 99 49
9 178 50 178 100 43 182 102 47
10 180 50 178 98 42 175 97 47
11 181 50 182 101 42 176 97 47
12 185 50 179 97 41 181 98 47
13 186 50 182 98 41 179 96 47
16 191 50 186 97 41 183 96 47
20 205 50 197 96 41 193 94 45
24 209 50 203 97 41 199 95 44
28 211 50 200 95 39 191 91 43
32 220 50 206 94 39 195 89 43
36 228 50 210 92 39 195 86 43
40 232 50 211 91 39 193 83 43
44 236 50 208 88 39 193 82 43
48 237 50 211 89 39 196 83 41
52 237 50 206 87 39 192 81 40
56 246 50 212 86 39 192 78 40
60 242 50 209 86 39 187 77 40
64 252 50 214 85 39 191 76 40
68 261 49 214 82 38 185 71 39
72 267 49 215 81 36 189 71 37
76 275 48 218 79 36 190 69 35
80 277 47 216 78 36 184 66 30
84 284 45 216 76 35 189 67 28
88 282 45 215 76 34 192 68 26
92 286 44 214 75 30 189 66 23
96 291 41 216 74 30 196 67 20
100 293 41 218 74 26 208 71 15
104 297 38 219 74 23 224 75 10

Table 6.Incidences of rats with subcutaneous tumors
  MALES
Vehicle 30 60
  Control mg/kg mg/kg
Fibroma
Overall Incidence 3/50 (6%) 3/50 (6%) 9/50(18%)
Adjusted Incidence 8.3% 16.5% 56.6%
Terminal Incidence 3/36 (8%) 1/14(7%) 3/8 (38%)
Life Table Test P<0.001 P=0.258 P<0.001
Incidental Tumor Test P=0.002 P=0.415 P=0.004
Fibrosarcoma
Overall Incidence 0/50 (0%) 3/50 (6%) 3/50 (6%)
Adjusted Incidence 0.0% 19.0% 23.1%
Terminal Incidence 0/36 (0%) 2/14(14%) 0/8 (0%)
Life Table Test P=0.003 P=0.020 P=0.008
Incidental Tumor Test P=0.021 P=0.044 P=0.089
Fibroma or Fibrosarcoma
Overall Incidence 3/50 (6%) 6/50(12%) 12/50 (24%)
Adjusted Incidence 8.3% 33.5% 66.6%
Terminal Incidence 3/36 (8%) 3/14(21%) 3/8 (38%)
Life Table Test P<0.001 P=0.016 P<0.001
Incidental Tumor Test P<0.001 P=0.056 P<0.001
  FEMALES
Vehicle 60 120
  Control mg/kg mg/kg
Fibroma
Overall Incidence 0/50 (0%) 1/50 (2%) 3/50 (6%)
Adjusted Incidence 0.0% 5.3% 35.7%
Terminal Incidence 0/36 (0%) 1/19(5%) 1/6(17%)
Life Table Test P<0.001 P=0.373 P=0.001
Incidental Tumor Test P=0.019 P=0.373 P=0.083
Fibroma or Fibrosarcoma
Overall Incidence 2/50 (4%) 1/50 (2%) 5/50(10%)
Adjusted Incidence 5.3% 5.3% 51.8%
Terminal Incidence 1/36(3%) 1/19 (5%) 2/6 (33%)
Life Table Test P<0.001 P=0.715N P<0.00l
Incidental Tumor Test P=0.038 P=0.609N P=0.092

Table 7: Combined incidence of mammary gland tumours and subcutaneous tissue tumours in female rats
  Vehicle 60 120
  Control mg/kg mg/kg
Overall Incidence 17/50 (34%) 25/50 (50%) 21/50 (42%)
Adjusted Incidence 43.1% 88.8% 91.1%
Terminal Incidence 14/36 (39%) 16/19(84%) 4/6 (67%)
Life Table Test P<0.001 P<0.00l P<0.001
Incidental Tumor Test P<0.001 P<0.001 P=0.009

Table 8:.Incidences of monocytic leukemia in rats
  MALES
Vehicle 30 60
  Control mg/kg mg/kg
Overall Incidence 11/50 (22%) 4/50 (8%) 4/50 (8%)
Adjusted Incidence 25.5% 19.0% 19.2%
Terminal Incidence 5/36 (14%) 0/14 (0%) 0/8 (0%)
Life Table Test P=0.559N P=0.423N P=0.574
Incidental Tumor Test P=0.027N P=0.053N P=0.039N
  FEMALES
Vehicle 60 120
  Control mg/kg mg/kg
Overall Incidence 21/50 (42%)(a) 7/50(14%) 4/50 (8%)
Adjusted Incidence 47.4% 26.3% 32.9%
Terminal Incidence 13/36 (36%) 2/19(11%) 1/6(17%)
Life Table Test P=0.168N P=0.120N P=0.392N
Incidental Tumor Test P<0.001N P=0.006N P=0.001N
(a)One lymphoma was observed in this group.

Table 9: Incidences of pancreatic lesions in rats
  MALES
Vehicle 30 60
  Control mg/kg mg/kg
Acinar Cell Nodular Hyperplasia Adenoma      
0, 47 (0%) 2 47 (4%) 4 49 (8%)
Overall Incidence 1/47(2%) 3 47(6%) 7 49 (14%)
Adjusted Incidence 2.9% 18.2% 59.2%
Terminal Incidence 1 35(3%) 2 14(14%) 4 8 (50%)
Life Table Test P<0.001 P=0.075 P<0.001
Incidental Tumor Test P<0.001 P=0.128 P=0.001
  MALES
Vehicle 30 60
  Control mg/kg mg/kg
Islet Cell Adenoma or Carcinoma      
Overall Incidence 1,47 (2%) 0 47 (0%) 4 49 (8%)
Adjusted Incidence 2.9% 0.0% 24.2%
Terminal Incidence 1, 35 (3%) 0 14(0%) 1 8 (13%)
Life Table Test P=0.007 P=0.682N P=0.0I3
Incidental Tumor Test P=0.075 P=0.682N P=0.180
  FEMALES
Vehicle 60 120
  Control mg/kg mg/kg
Islet Cell Adenoma      
Overall Incidence 0/50 (0%) 6/49 (12%)(a) 2/47 (4%)
Adjusted Incidence 0.0% 24.2% 33.3%
Terminal Incidence 0/36 (0%) 3/19(16%) 2/6(33%)
Life Table Test P=0.008 P=0.003 P=0.006
Incidental Tumor Test P=0.054 P=0.010 P=0.006
(a)One islet cell carcinoma was also observed in this group.

Table 10: Incidences of neoplastic nodules of the liver in female rats
  Vehicle 60 120
  Control mg/kg mg/kg
Overall Incidence 3/50 (6%) 8/50(16%) 8/48(17%)
Adjusted Incidence 8.0% 30.6% 60.1%
Terminal Incidence 2/36 (6%) 3/19(16%) 3/6 (50%)
Life Table Test P<0.001 P=0.014 P<0.001
Incidental Tumor Test P=0.035 P=0.068 P=0.022
Conclusions:
The study was performed equivalent of similar to the OECD TG451 with only minor deviations and therefore considered to be of high quality (reliability Klimisch 2). The validity criteria of the test system are still fulfilled. The accuracy of the TDI dose mixtures were uncertain because of reactivity with water and the unknown nature of the decomposition products that resulted from preparation of the TDI-corn oil mixtures. Although not every potential discrepancy identified in the audit was fully resolved it was concluded that the data reported were adequate to support the conclusions presented in this Technical Report. Carcinogenic potential of orally administered TDI was evident in rats and in female mice. The test material was considered to be carcinogenic under the conditions of the test.
Executive summary:

The carcinogenicity of toluene diisocyanate after oral administration to rats was investigated by Gordon et al. (1986). The study was conducted equivalent or similar to the OECD Guideline 451. The duration of the study was approximately 2 years. As doses 30 and 60 mg/kg bw (for male rats) and 60 or 120 mg/kg bw (for female rats) of the test substance were administered via gavage. The test substance was analysed analytically and the results revealed that it reacted quickly with the water content of the solvent corn oil. Therefore the actual gavage concentrations were 77% to 90% of theoretical values.Despite the reduced doses, mean body weight gains of male and female rats were less than those of the controls after week 20. Early deaths occurred in groups of dosed male and female rats, but by week 60 only the high dose male rats were dying as a result of TDI administration.An apparent dose-related pattern of mortality began to emerge at week 70, and persisted until the end of the study. The delayed cumulative toxicity caused by TDI administration indicated that the estimated maximum tolerated doses had been exceeded in rats.Bronchopneumonia was the most prominent non-neoplastic effect seen in these gavage studies. In the present study, the late-appearing pattern of mortality in rats could be a reflection of delayed hypersensitivity, as well as direct respiratory irritation. The incidences of bronchopneumonia were dose related in male and female rats, and this effect may have weakened the animals’ resistance to further chemical challenge. The increased rate of mortality may also be due, in part, to TDI’s inhibition of acetylcholinesterase, which could have compounded the animals’ respiratory difficulty. Despite the reduced survival, there was unequivocal evidence of dose-related increases in tumours in rats and mice in the 2-year studies. About 50% of the tumours detected were observed in animals killed at the end of these studies; the rest were found in animals dying between weeks 77 and 108. Tissues associated with the digestive system were primary sites of tumour induction and included acinar cell adenomas of the pancreas in male rats, and liver tumours in female rats. There were also increased incidences of islet cell adenomas in low dose female rats. Dose-related increases were observed in the number of male rats with nodular hyperplasia of the pancreatic acinus (control, 0%; low dose, 4%; high dose, 8%) and in the incidence of acinar cell adenomas (control, 2%; low dose, 6%; high dose, 14%). The corn oil vehicle used in these gavage studies may have contributed to the incidences of acinar cell tumours in male and female rats. The systemic nature of the carcinogenicity of TDI was demonstrated by the appearance of tumours at multiple sites in male rats (fibromas and fibrosarcomas of the skin), in female rats (mammary gland fibroadenomas, adenomas, papillary adenomas, cystadenomas and subcutaneous fibroadenomas and fibromas). The tumours observed in the liver, pancreas, mammary gland, and subcutaneous tissues of F344/N rats in these studies are the same type as those seen when 2,4-diaminotoluene-a possible hydrolysis product of 2,4-toluene diisocyanate was administered to the same strain(NC1, 1979). Differences in mean body weight gains, hypersensitivity, and the incidences of neoplastic and non-neoplastic lesions in animals in the present studies emphasize differences in the degree to which TDI is toxic in different species and sexes. . Both female rats and female mice received doses of 60 or 120 mg/ kg, and most of the rats died during the study. Male mice received higher doses ( 120 and 240 mg/ kg) than male rats (30 and 60 mg/ kg), yet mortality and decreases in mean body weights were less severe in the former group, and no tumours were detected at statistically significant incidences in male mice.

Under the conditions of these gavage studies, the commercial mixture of 2,4- and 2,6-toluene diisocyanate in corn oil was carcinogenic for F344/ N rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females.

Endpoint:
carcinogenicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Survival of high dose male mice in the 2-year study was significantly shorter than that of the controls (p<0.001). In male mice, the survival of the high dose group was significantly shorter than that of the controls (p<0.001) and of the low dose group (p=0.003). In female mice, the survival of the high dose group was significantly shorter than that of the low dose group (p=0.028). One female control mouse was accidentally killed. In male mice, 46/50 (92%) of the controls, 40/50 (80%) of the low dose, and 26/50 (52%) of the high dose group lived to the termination period of the study at 107 weeks. In female mice, 34/50 (68%) of the controls, 43/50 (86%) of the low dose, and 331 50 (66%) of the high dose group lived to the termination period of the study at 107 weeks. No other compound-related clinical signs were observed.
Mortality:
mortality observed, treatment-related
Description (incidence):
Survival of high dose male mice in the 2-year study was significantly shorter than that of the controls (p<0.001). In male mice, the survival of the high dose group was significantly shorter than that of the controls (p<0.001) and of the low dose group (p=0.003). In female mice, the survival of the high dose group was significantly shorter than that of the low dose group (p=0.028). One female control mouse was accidentally killed. In male mice, 46/50 (92%) of the controls, 40/50 (80%) of the low dose, and 26/50 (52%) of the high dose group lived to the termination period of the study at 107 weeks. In female mice, 34/50 (68%) of the controls, 43/50 (86%) of the low dose, and 331 50 (66%) of the high dose group lived to the termination period of the study at 107 weeks.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of dosed male mice (throughout the study) and of high dose female mice (after week 56) were lower than those of the controls. The depressions in mean body weight were dose related. During the second year of the study, mean body weight gains of high dose male mice were less than those of the controls.
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:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In male mice, no tumours occurred at statistically significant incidences.
Haemangiosarcomas (of the liver, ovaries, or peritoneum) were observed with a statistically significant positive trend in female mice. The combined incidences of haemangiomas (of the spleen, or subcutaneous tissue) or haemangiosarcomas occurred with a statistically significant positive trend, and the results of pairwise comparisons between the control and high dose groups were significant.
Haemangiomas or haemangiosarcomas (combined) of the circulatory system in female mice occurred with a positive trend (p<0.01; control, 0/50; low dose, 1/50; high dose, 5/50). The incidence in the high dose group was significantly higher than that in the controls (p<0.05).
Hepatocellular adenomas in female mice occurred with a positive trend (p<0.001; 2/ 50, 3/ 50, 12/50), and the incidence in the high dose group was higher than that in the controls (p<0.01).
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Kidney: Cytomegaly, mainly in tubules near the corticomedullary junction, was observed. Cytomegaly of kidney tubular epithelium was found in 45/48 (94%) low dose male mice and 41 / 50 (82%) high dose male mice but not in any of the controls.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: Hepatocellular adenomas occurred in female mice with a statistically significant positive trend, and the pairwise comparisons between the control and high dose groups were significant (Table 16). Adenomas or carcinomas (combined) occurred with a significant positive trend, and the results of pairwise comparisons between the control and high dose groups were significant.
Haematopoietic System: Leukaemia was observed in female mice with a statistically significant, decreasing trend (Table 17). The results of pairwise comparisons were not significant. Malignant lymphoma in female mice was observed with a statistically significant, increasing trend, and the results of pairwise comparisons between the control and high dose group were significant. The incidence of leukaemia or lymphoma (combined) was not significantly different for dosed or control male or female mice.
Details on results:
HISTORICAL CONTROL DATA
Because of the reduced survival observed in dosed groups relative to controls, a direct comparison of overall tumour incidences in dosed groups and historical controls may be misleading. The historical control data are included primarily to determine how representative the tumour incidences observed in concurrent vehicle controls are with respect to other studies in the bioassay program.
Relevance of carcinogenic effects / potential:
The carcinogenic effects observed in female mice indicates that the test substance had a significant carcinogenic effect after oral gavage. A treatment related increase in tumour incidence as compared to controls was shown in female mice. In male mice, no tumours occurred at statistically sig. incidences. As tumours haemangiosarcomas (of liver, ovaries, or peritoneum) were observed with a statistically sig. positive trend in female mice. Additionally liver adenomas & leukaemia was found in females. However the tumours observed are due to metabolism of toluene diisocyanate to toluene diamine (mainly in the gastrointestinal tract) and that metabolite is known to be a potent carcinogen. Additionally the exposure route is not well chosen, since the inhalation routs is most relevant to humans. Therefore the results obtained need to be judged carefully.
Dose descriptor:
NOAEL
Effect level:
< 240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Dose descriptor:
LOAEL
Effect level:
>= 60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: neoplastic
Critical effects observed:
not specified

Untreated Controls:

At week 87 untreated controls were sacrificed and examined. The incidence and type of tumours in individual mice did not appear different from the normal background of tumours in the B6C3F1 mouse. Thus these data are not given in this report.

In male mice, no tumours occurred at statistically significant incidences.

Haemangiosarcomas (of the liver, ovaries, or peritoneum) were observed with a statistically significant positive trend in female mice (Table 15). The combined incidences of haemangiomas (of the spleen, or subcutaneous tissue) or haemangiosarcomas occurred with a statistically significant positive trend, and the results of pairwise comparisons between the control and high dose groups were significant.

Table 14. Mean body weights and survival of mice in the two-year gavage studies of toluene diisocyanate

Weeks on Study Vehicle Control Low Dose High Dose
Av.Wt (grams) No. of Survivors Av.Wt (grams) Wt (percent of veh controls) No. of Survivors Av.Wt (grams) Wt (percent of veh controls) No. of Survivors
MALE
0 24.5 50 24.9 102 50 25.1 102 50
1 26.3 50 25.6 97 50 24.7 94 49
2 27.0 50 27.1 100 50 25.4 94 49
3 26.9 50 26.6 99 50 26.2 97 49
4 29.0 50 .. .. .. 25.2 87 46
5 29.4 50 27.1 92 50 26.4 90 44
6 29.8 50 28.6 96 47 26.4 89 44
7 30.0 50 29.0 97 47 27.3 91 44
8 31.1 50 30.1 97 47 28.3 91 44
9 31.7 50 30.8 97 47 29.3 92 44
10 30.9 50 30.3 98 47 29.0 94 44
11 32.0 50 31.1 97 47 29.4 92 44
12 32.3 50 31.0 96 47 28.8 89 44
13 31.9 50 30.1 94 47 28.9 91 44
16 32.8 50 31.0 95 47 29.6 90 43
20 33.6 50 32.8 98 46 30.0 89 43
24 34.3 50 33.0 96 46 30.0 87 42
28 36.0 50 33.7 94 46 31.4 87 41
32 34.5 50 33.6 97 46 32.6 94 41
36 38.5 50 35.9 93 46 34.6 90 41
40 38.0 50 36.0 95 46 34.1 90 41
44 38.9 50 36.7 94 46 34.2 88 41
48 37.7 50 35.8 95 46 33.8 90 41
52 37.5 50 35.7 95 46 33.2 89 40
56 37.4 50 35.9 96 46 33.4 89 40
60 38.0 50 36.3 96 46 33.6 88 40
64 37.5 50 36.1 96 46 32.9 88 40
68 38.0 50 36.3 96 46 33.4 88 40
72 38.8 50 37.2 96 46 34.8 90 40
76 37.8 50 37.0 98 45 34.4 91 39
80 39.7 50 37.0 93 45 33.2 84 36
84 39.8 50 37.5 94 45 34.4 86 34
88 38.9 49 36.7 94 45 33.9 87 33
92 38.8 49 36.2 93 45 33.6 87 33
96 38.4 47 36.2 94 42 33.9 88 31
100 36.9 47 35.4 96 40 33.0 89 30
104 36.1 46 35.1 97 40 32.8 91 29
FEMALE
0 19.3 50 19.2 99 50 19.5 101 50
1 20.5 50 18.3 89 50 18.1 88 49
2 21.0 50 20.0 95 48 19.8 94 45
3 21.5 50 21.0 98 48 20.3 94 44
4 22.2 50 21.7 98 48 20.3 91 41
5 22.0 50 21.7 99 48 21.7 99 41
6 22.2 50 21.8 96 48 21.6 97 41
7 22.1 50 22.6 102 48 22.3 101 41
8 23.1 50 23.1 100 48 23.5 102 40
9 24.4 50 23.6 97 48 23.9 98 40
10 23.8 50 23.5 99 48 24.2 102 40
11 23.8 50 23.9 100 48 24.2 102 40
12 23.8 50 23.5 99 48 23.8 100 40
13 23.4 50 23.3 100 48 24.1 103 40
16 23.6 50 23.9 101 48 24.5 104 40
20 24.7 50 24.7 100 47 24.6 100 40
24 25.0 50 25.0 100 47 25.0 100 40
28 26.0 50 26.5 102 47 26.7 103 40
32 27.5 50 27.7 101 47 27.4 100 40
36 29.0 50 29.1 100 47 28.6 99 40
40 29.4 50 30.1 102 47 29.5 100 40
44-45 30.0 50 30.2 101 47 28.9 96 40
48 29.3 50 29.7 101 47 28.5 97 40
52 29.4 50 29.8 101 47 28.7 96 40
56 29.5 50 30.4 108 47 29.1 99 40
60 30.7 50 30.8 100 47 29.0 94 40
64 31.4 50 31.4 100 47 30.0 96 40
68 31.7 50 31.8 100 47 30.2 95 39
72 32.8 49 33.3 102 47 31.6 96 39
76 33.0 47 33.5 102 47 31.7 96 39
80 34.9 45 34.5 99 45 31.8 91 39
84 34.4 45 35.2 102 45 31.9 93 38
88 34.8 44 34.6 99 45 31.4 90 38
92 34.8 42 34.8 100 45 31.1 89 37
96 34.9 40 34.4 99 45 31.6 91 37
100 34.2 39 33.4 98 45 31.2 91 34
104 33.9 34 32.7 98 44 31.0 91 33

Table 15. Incidences of female mice with tumours of the circulatory system

  Vehicle Control 60 mg/kg 120 mg/kg
 
Haemangiosarcoma
Overall Incidence 0/50 (0%) 0/50 (0%) 3/50(6%)
Adjusted Incidence 0.0% 0.0% 8.0%
Terminal Incidence 0/34 (0%) 0/43 (0%) 0/33 (0%)
Life Table Test P=0.029 P=0.105
Incidental Tumour Test P=0.015 P=0.037
Haemangioma or Haemangiosarcoma
Overall Incidence 0/50 (0%) 1/50(2%) 5/50(10%)
Adjusted Incidence 0.0% 2.3% 13.3%
Terminal Incidence 0/34 (0%) 1/43(2%) 1/33 (3%)
Life Table Test P=0.008 P=0.547 P=0.029
Incidental Tumour Test P=0.003 P=0.547 P=0.005

Table 16: Incidences of female mice with liver tumours

  Vehicle Control 60mg/kg 120mg/kg
Hepatocellular Adenoma
Overall Incidence 2/50 (4%) 3/50 (6%) 12/50 (24%)
Adjusted Incidence 5.3% 6.7% 36.4%
Terminal Incidence 1/34 (3%) 2/43 (5%) 12/33 (36%)
Life Table Test P<0.001 P=0.571 P=0.003
Incidental Tumour Test P<0.001 P=0.325 P=0.003
Hepatocellular Carcinoma
Overall Incidence 2/50 (4%) 2/50 (4%) 3/50 (6%)
Adjusted Incidence 5.0% 4.7% 8.8%
Terminal Incidence 1/34 (3%) 2/43 (5%) 2/33 (6%)
Life Table Test P=0.376 P=0.629N P=0.463
Incidental Tumour Test P=0.248 P=0.644 P=0.308
Hepatocellular Adenoma or Carcinoma
Overall Incidence 4/50 (8%) 5/50(10%) 15/50 (30%)
Adjusted Incidence 10.1% 11.2% 44.1%
Terminal Incidence 2/34 (6%) 4/43 (9%) 14/33 (42%)
Life Table Test P=0.001 P=0.601 P=0.004
Incidental Tumour Test P<0.001 P=0.321 P=0.001

Table 17: Incidences of female mice with tumours of the haematopoetic system

  Vehicle Control 60mg/kg 120mg/kg
Leukaemia
Overall Incidence 3/50 (6%) 0/50 (0%) 0/50 (0%)
Adjusted Incidence 7.4% 0.0% 0.0%
Terminal Incidence 0/34 (0%) 0/43 (0%) 0/33 (0%)
Life Table Test P=0.040N P=0.102N P=0.147N
Incidental Tumour Test P=0.119N P=0.414N P=0.240N
Malignant Lymphoma
Overall Incidence 10/50 (20%) 17/50 (34%) 16/50 (32%)
Adjusted Incidence 25.8% 38.6% 44.2%
Terminal Incidence 7/34(21%) 16/43 (37%) 13/33 (39%)
Life Table Test P=0.082 P=0.241 P=0.101
Incidental Tumour Test P=0.029 P=0.085 P=0.033
Lymphoma or Leukaemia
Overall Incidence 13/50 (26%) 17/50 (34%) 16/50 (32%)
Adjusted Incidence 31.3% 38.6% 44.2%
Terminal Incidence 7/34(21%) 16/43 (37%) 13/33 (39%)
Life Table Test P=0.241 P=0.503 P=0.273
Incidental Tumour Test P=0.089 P=0.151 P=0.098
Conclusions:
The study was performed equivalent of similar to the OECD TG451 with only minor deviations and therefore considered to be of high quality (reliability Klimisch 2). The validity criteria of the test system are still fulfilled. The accuracy of the TDI dose mixtures were uncertain because of reactivity with water and the unknown nature of the decomposition products that resulted from preparation of the TDI-corn oil mixtures. Although not every potential discrepancy identified in the audit was fully resolved it was concluded that the data reported were adequate to support the conclusions presented in this Technical Report. Carcinogenic potential of orally administered TDI was evident in rats and in female mice. The test material was considered to be carcinogenic under the conditions of the test.
Executive summary:

A study on the carcinogenicity of toluene diisocyanate after oral administration to mice was conducted by Gordon et al. (1986). The study was conducted equivalent or similar to the OECD Guideline 451. The duration of the study was approximately 2 years. As doses 120 and 240 mg/kg bw (for male mice) and 60 or 120 mg/kg bw (for female mice) of the test substance were administered via gavage. The test substance was analysed analytically and the results revealed that it reacted quickly with the water content of the solvent corn oil. Therefore the actual gavage concentrations were 77% to 90% of theoretical values. Despite the reduced doses, mean body weight gains of all male and female mice of the high dose group were less than those of the controls. Mortality in male mice was also dose related and significantly higher than in controls, but it was not as excessive as that in rats.Despite the reduced survival, there was unequivocal evidence of dose-related increases in tumours in rats and mice in the 2-year studies. About 50% of the tumours detected were observed in animals killed at the end of these studies; the rest were found in animals dying between weeks 77 and 108. The systemic nature of the carcinogenicity of TDI was demonstrated by the appearance of tumours at multiple sites in female mice (haemangiomas and haemangiosarcomas).Differences in mean body weight gains, hypersensitivity, and the incidences of neoplastic and non-neoplastic lesions in animals in the present studies emphasize differences in the degree to which TDI is toxic in different species and sexes. . Both female rats and female mice received doses of 60 or 120 mg/ kg, and most of the rats died during the study. Male mice received higher doses ( 120 and 240 mg/ kg) than male rats (30 and 60 mg/ kg), yet mortality and decreases in mean body weights were less severe in the former group, and no tumours were detected at statistically significant incidences in male mice.Female mice showed positive evidence of carcinogenicity associated with TDI administration. The species and sex differences in sensitivity to TDI may be metabolic, but no experimental data are available.

Under the conditions of these gavage studies, commercial grade toluene diisocyanate in corn oil was carcinogenic for female B6C3F1 mice, causing haemangiomas or haemangiosarcomas (combined), as well as hepatocellular adenomas. No carcinogenic effect was revealed in male mice.

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Major effects of inhaled MDI on the lung included increased lung weights, bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis.

HISTOPATHOLOGY: NEOPLASTIC
Two bronchiolo-alveolar adenomas were found in top-dose animals. Increased incidences of grade 4 and 5 alveolar type bronchiolo-alveolar hyperplasia (regarded as a preneoplastic change) were seen in the top-dose group. Incidence and/or severity of lower grade (grades 1, 2 and 3) alveolar type bronchiolo-alveolar hyperplasia were increased in the top-dose group. Bronchiolar type bronchiolo-alveolar hyperplasia, predominantly of minimal or slight degree (grades 1 and 2), was increased in incidence and/or severity in the mid- and top-dose groups. Mixed and flat type bronchiolo-alveolar hyperplasia were seen in low incidences in several groups with no obvious relationship with MDI treatment.


HISTOPATHOLOGY: NON-NEOPLASTIC
Interstitial fibrosis was increased in incidence and degree in both the mid- and top-dose group. Particle-laden macrophages were observed in all exposed groups and the macrophages were heavily laden with clear yellow particles. No increase in haemosiderin storage was observed. Mononuclear cell infiltration was clearly increased in incidence in the top-dose group, the increase being predominantly due to an increase in interstitial cell infiltration.
Dose descriptor:
NOAEC
Effect level:
0.2 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Effect level:
0.19 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
1 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
0.98 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
The study showed a very low incidence of tumour formation. Furthermore, the experimental evidence does not support a genotoxic mode of action.The concentrations tested in the study are only possible to form in the laboratory due to the physical-chemical properties of MDI. Therefore the exposure conditions are not representative for human exposure.
Executive summary:

In a combined chronic toxicity and carcinogenicity study, rats (whole body) were exposed for 6 hours/day, 5 days/week for 2 years to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m³ (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m³) (Reuzel et al., 1994). This GLP reliability 2 key study was conducted according to OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies). Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ was related to the occurrence of pulmonary tumours in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). Therefore, polymeric MDI was carcinogenic in rats after long-term inhalation to aerosol concentrations of 6.0 mg/m³. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumours.

The study showed a very low incidence of tumour formation. Furthermore, the experimental evidence does not support a genotoxic mode of action.The concentrations tested in the study are only possible to form in the laboratory due to the physical-chemical properties of MDI. Therefore the exposure conditions are not representative for human exposure.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
30 mg/kg bw/day
Study duration:
chronic
Species:
rat
Organ:
liver
mammary gland
pancreas
skin

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No exposure-related signs occurred during the study.
Mortality:
mortality observed, treatment-related
Description (incidence):
At termination of the study (at week 110 for males and at week 108 for females) total percentage deaths were 65% in controls, 67% low dose, 71% high dose males and 68% in controls, 75% low dose, 64% high dose females. Statistical analysis indicated that TDI did not significantly affect mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was similar in all groups during the main part of the study. There was, however, significantly less weight gain in the 0.15 ppm group in both sexes in the first 12 weeks of exposure. The weight increases for the periods between weeks 12 and 108 show comparable weight gains for all groups.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in haematological parameters were recorded.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in blood biochemical parameters were recorded.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in urinary parameters were recorded.
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The statistical analysis of the organ weights of the animals from interim and terminal kills did not reveal treatment-related differences.
Gross pathological findings:
no effects observed
Description (incidence and severity):
At necropsy the examination of the tissues from control and TDI-exposed animals did not reveal any evidence of treatment-related effects. Macroscopically no changes were seen in the upper respiratory tract.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Microscopic evaluation of the tissues revealed some alterations in all groups which were considered incidental and not treatment-related. It should, however, be noted that histopathology of the nasal turbinates is still in progress.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Statistical evaluation demonstrated no treatment-related effect on the incidence of tumours, their multiplicity or malignancy.
Relevance of carcinogenic effects / potential:
The results of the study did not reveal a substantial carcinogenic potential of TDI, when administered via inhalation to rats.
Dose descriptor:
NOAEC
Effect level:
0.15 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic

Range-finding study:

Male rats of both the Fisher 344 and Sprague-Dawley strain exposed to 0.1 or 0.3 ppm TDI showed a slight but significant reduction in body weight gain. A greater incidence of sneezing occurred in the Sprague-Dawley males suggesting slight respiratory irritation. No adverse effects were observed in the mouse and hamster study.

Rats did not exhibit changes in the lower respiratory tract (histopathology of upper respiratory tract in progress) nor was there any trend of increased mortality in any group. Rats exposed at 0.15 ppm had significantly less increase in weight, only in the first 12 weeks of the study. No specific target tissue has been identified. The tumour pattern in the rat study was similar in the control and in the treated groups and corresponded to historical data. The study demonstrated no evidence of any neoplastic response. These results are supported by tests on mutagenicity. There was no evidence of a mutagenic response in vivo as demonstrated by the results of a micronucleus test on rats and mice exposed for four weeks to TDI at exposure concentrations up to and including 0.15 ppm. As far as the incomplete rat study can be interpreted, levels which cause no primary irritative effect also do not result in any other effect of toxicological significance. As a result of these studies the current occupational exposure levels are not considered to represent a serious health hazard. The possible sensitization to TDI, however, needs special attention.

TABLE I
TDI: LONG-TERM INHALATION STUDY IN RATS
Synopsis of tumour incidence (malignant tumours in brackets).
  Atmospheric concentrations of TDI (ppm)
  0 0.05 0.15
Sex
Number of animals examined 104 104 104 105 104 105
Skin/Adnexa/Glands  
carcinoma (basal/squamous etc.) (5) (3) (3) (2) (6) 0
adenoma 0 0 0 0 3 0
papilloma 9 1 5 3 3 0
Mammary gland  
benign tumour (fibroadenoma etc.) 4 24 4 27 2 22
multiple benign tumours 1 55 0 42 1 52
carcinoma + benign tumour (1) (9) 0 (9) 0 (14)
multiple carcinoma + benign tumour 0 (3) 0 (1) 0 0
mammary tumour (unconf.) 0 1 0 0 0 0
Subcutis/muscle/bone  
fibroma 29 1 22 1 35 4
fibrosarcoma (1) (2) (2) 0 (2) 0
lipoma 10 3 6 0 6 3
osteoma 0 0 0 0 1 0
osteosarcoma (1) 0 (1) 0 (1) (1)
lymphangioma 0 0 0 0 1 0
histiocytoma (1) 0 (4) 0 (1) 0
rhabdomyosarcoma 0 0 (1) 0 0 0
sarcoma (unclass.) 0 0 (1) 0 0 0
Haemopoietic/lymphoreticular  
malignant lymphoma (6) (1) 0 (1) (3) (3)
haemangioma 1 1 1 2 4 0
thymus: thymoma 0 (1) 0 1+ (1) 0 1
squamous carcinoma 0 (1) 0 0 0 0
Uterus  
polyp - 5 - 2 - 3
leiomyoma   0 - 1 - 0
sarcoma - 0 - 0 - (1)
Cervix  
stromal tumour - 2 - 2 - 0
Pancreas  
islet cell adenoma 1 1 2 0 3 2
Liver  
angiosarcoma 0 (3) 0 (1) 0 (3)
carcinoma 0 0 (1) 0 0 (1)
cholangiocarcinoma 0 0 (1) 0 0 0
Jejunum  
sarcoma 0 0 (1) 0 0 0
Stomach  
adenocarcinoma 0 0 0 (1) 0 0
Caecum  
schwannoma 0 0 0 0 1 0
leiomyosarcoma 0 0 0 0 0 (1)
Rectum  
polyp 0 0 0 1 0 0
Lungs  
adenoma 2 3 3 0 1 1
Body cavities, membranes, surfaces etc.  
lipoma 0 1 0 0 0 0
mesothelioma 0 0 (1) 0 1 0
liposarcoma 0 0 0 0 (1) 0
haemangioma 0 0 0 0 1 0
lymphangioma 0 0 1 0 0 0
Adrenals  
phaeochromocytoma 1 0 1 0 1 0
cortical adenoma 2 1 1 0 0 1
cortical carcinoma 0 0 0 0 (1) 0
Pituitary  
adenoma 53 64 32 62 38 67
Thyroid  
c-cell carcinoma 0 0 0 (1) 0 0
c-cell adenoma 11 7 3 1 7 4
follicular adenoma 1 0 0 0 0 1
Parathyroids  
adenoma 0 1 0 0 0 0
Brain  
meningioma 0 0 0 0 2 0
astrocytoma 1 0 1 0 0 0
oligodendroglioma 1 0 0 0 0 0
Kidneys  
carcinoma 0 0 0 0 0 (1)
liposarcoma (1) 0 (1) 0 0 0
mesenchymal tumour 1 0 0 0 0 0
lipomatous tumour 1 0 3 0 0 0
nephroblastoma 0 0 1 0 0 0
Testes  
Leydig cell adenoma 2 - 2 - 1 -
Epididymides  
mesothelioma 0 - 1 - 0 -
Prostate  
adenocarcinoma 0 - 0 - (1) -
Ovaries  
granulosa-theca cell - 2 - 0 - 1
Heart  
angiosarcoma 0 (1) 0 0 0 0
Eyes  
leiomyoma 0 0 0 1 1 1
Miscellanous  
squamous cell carcinoma of unknown origin (1) 0 0 0 0 0
Nasal turbinates No macroscopically diagnosed tissue masses. Histopathology in progress.

TABLE II
TDI: LONG-TERM INHALATION STUDY IN RATS
Summary of total tumour incidence
  Males Females
  0 ppm 0.05 ppm 0.15 ppm 0 ppm 0.05 ppm 0.15 ppm
Total animals 104 104 104 104 105 105
Tumour bearers 86 67 81 105 98 101
Animals with malignant tumours 9 3 10 3 4 5
Animals with benign tumours 69 53 64 84 80 76
Animals with both malignant and benign tumours 8 11 7 18 14 20

TABLE III
MICRONUCLEUS TEST ON RATS EXPOSED TO TDI-VAPOUR FOR 4 WEEKS, PERCENTAGE OF MICRONUCLEATED ERYTHROCYTES, MEANS OF 5 ANIMALS PER SEX PER LEVEL ± STANDARD DEVIATION, 1000 RBC PER ANIMAL EXAMINED
  Atmospheric concentration of TDI (ppm)
  0 0.05 0.15
Sex
Rats 0.6 ± .9 0.5 ± .2 0.9 ± .4 0.8 ± .l 0.8 ± .2 0.8 ± .4
Conclusions:
The study is considered to be reliable (reliability Klimisch 2). The validity criteria of the test system were fulfilled. The test material did induce slight signs of toxicity but no increased incidence of tumours. The test material was considered to be not carcinogenic after exposure via the inhalation route under the conditions of the test.
Executive summary:

The carcinogenicity of the test material was investigated in rats by Loeser et al (1983). The test was conducted similar to OECD TG451. Groups of male and female rats (21 animals per sex per group) were exposed to 0.05 and 0.15 ppm of toluene-diisocyanate (TDI) by inhalation for 6 h/day, 5 days/week for approx. 2 years. Type and incidence of tumours and the number of tumour-bearing animals were recorded. Additionally clinical signs, mortality, body weight gain, haematology, biochemistry, urinalysis, and cytogenicity were recorded. At termination of the study necropsy and histopathological examination were performed and organ weights recorded. No exposure-related signs occurred during the study. At termination of the study (at week 110 for males and at week 108 for females) total percentage deaths were 65% in controls, 67% low dose, 71% high dose males and 68% in controls, 75% low dose, 64% high dose females. Male and female rats of the 0.15 ppm group gained less weight during the first 12 weeks of the study. Type and incidence of tumours and the number of tumour-bearing animals did not indicate any carcinogenic effect. Haematology, biochemistry, urinalysis, and cytogenicity did not reveal any untoward effect. Histopathological examination in the rat study has not been completed, but no effect in the respiratory tract or in any other tissue has yet been seen.

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Rhinitis in this group was considered to be associated with exposure and was predominantly seen in the animals dying during the study.
Mortality:
mortality observed, treatment-related
Description (incidence):
There was a statistically increased mortality in the low- and high-dose females (total 77 percentage deaths were 78% in controls, 70% low-dose, 70% high-dose males, and 60% in controls, 77% low-dose, 74% high-dose females). The differences were not strictly dose-related and the higher incidence of death rate in the 0.15 ppm group is related to a number of deaths within a 3 week period during the 10th month of the study. Rhinitis in this group was considered to be associated with exposure and was predominantly seen in the animals dying during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mice at the 0.15 ppm level gained less weight. There was also statistically significant reduced weight gain in the 0.15 ppm group which was considered to be exposure-related.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in haematological parameters were recorded.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in blood biochemical parameters were recorded.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related changes in urinary parameters were recorded.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The statistical analysis of the organ weights of the animals from interim and terminal kills did not reveal treatment-related differences.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Major pathological changes occurred in the nasal cavity of both exposure groups. There was a dose-related higher incidence and severity of either chronic or necrotic rhinitis (epithelial atrophy, mucous and squamous metaplasia, inflammation, focal destructive rhinitis with debris). The highest grade of chronic or necrotic rhinitis was associated with morbidity and mortality in a proportion of mice. Lesions of variable incidence and severity were also seen in the lower respiratory tract (interstitial pneumonitis, catarrhal bronchitis) and in the eyes (keratitis) of some mice, with a higher incidence in the 0.15 ppm group.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The non-neoplastic lesions of all other tissues correspond to a normal pattern of age-related pathology in this strain of mouse.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related oncogenic response can be deduced from the incidence and malignancy of the tumours found.
Relevance of carcinogenic effects / potential:
The results of the study did not reveal a substantial carcinogenic potential of TDI, when administered via inhalation to mice.
Dose descriptor:
NOAEC
Effect level:
0.15 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic

Range-finding study:

Male rats of both the Fisher 344 and Sprague-Dawley strain exposed to 0.1 or 0.3 ppm TDI showed a slight but significant reduction in body weight gain. A greater incidence of sneezing occurred in the Sprague-Dawley males suggesting slight respiratory irritation. No adverse effects were observed in the mouse and hamster study.

DISCUSSION

Long-term inhalation exposure to TDI vapour resulted in distinct effects in mice. Chronic and necrotic rhinitis, bronchitis and higher mortality (females only) were the predominant effects in the mice. Mice at the 0.15 ppm level gained less weight.

No specific target tissue, except the respiratory tract in mice, has been identified.

The tumour pattern in the mouse study was similar in the control and in the treated groups and corresponded to historical data. The study demonstrated no evidence of any neoplastic response. These results are supported by tests on mutagenicity. There was no evidence of a mutagenic response in vivo as demonstrated by the results of a micronucleus test on mice exposed for four weeks to TDI at exposure concentrations up to and including 0.15 ppm. The levels of exposure seem to be critical for a proportion of mice. As a result of these studies the current occupational exposure levels are not considered to represent a serious health hazard. The possible sensitization to TDI, however, needs special attention.

TABLE I
TDI: LONG-TERM INHALATION STUDY IN MICE
Synopsis of tumour incidence (malignant tumours in brackets).
  Atmospheric concentrations of TDI (ppm)
  0 0.05 0.15
Sex
Number of animals examined 90 90 90 90 90 89
Ovaries  
granulosa theca cell tumour 0 1 0 1 0 1
tubular adenoma 0 2 0 2 0 0
papillary adenoma 0 1 0 1 0 0
unclassified tumour 0 1 0 0 0 0
Pituitary  
adenoma/microadenoma 0 3 0 0 0 1
Skin  
squamous carcinoma 0 0 ( 1) 0 0 0
fibrosarcoma ( 2) 0 0 0 0 0
Spleen  
haemangioma 1 0 0 1 0 0
haemangiosarcoma 0 ( 1) 0 ( 2) ( 1) (1)
Stomach  
cystadenoma 0 1 1 1 0 0
Subcutaneous tissue  
haemangiosarcoma 0 ( 1) ( 1) 0 0 (1)
Testes  
Leydig cell tumour 1 0 0 0 0 0
Thyroids  
follicular adenoma 1 1 0 0 0 0
follicular carcinoma 0 0 0 ( 1) 0 0
Tongue  
basal cell carcinoma 0 0 0 ( 1) 0 0
squamous papilloma 0 0 1 0 0 0
Uterus  
stromal sarcoma 0 ( 5) 0 ( 3) 0 (2)
stromal polyp 0 9 0 4 0 1
carcinoma 0 ( 1) 0 0 0 0
Miscellaneous  
carcinoma 0 0 0 ( 1) 0 0
sarcoma 0 0 0 ( 1) 0 0
Adrenals  
phaeochromocytoma 0 2 0 0 0 0
Connective tissue  
histiocytic sarcoma 0 0 0 0 ( 1) 0
Kidneys  
tubular carcinoma 0 0 ( 1) 0 ( 1) 0
papillary adenoma 0 0 1 0 0 0
Liver  
adenoma 17 5 14 0 8 1
multicentric/multiple adenoma 4 0 4 0 1 0
carcinoma (23) 0 (19) ( 1) (12) 0
multiple carcinoma ( 1) 0 ( 1) 0 0 0
haemangioma 2 0 0 1 0 0
haemangiosarcoma 0 ( 1) 0 0 0 0
histiocytic sarcoma 0 0 0 0 0 (1)
Lungs  
adenoma/microadenoma 17 22 22 18 16 9
multiple adenoma 0 1 9 2 6 2
carcinoma ( 6) ( 4) ( 4) ( 2) ( 4) 0
Lymph nodes - mesenteric  
haemangioma 0 0 0 0 1 0
Haemopoietic/lymphoreticular system  
leucosis ( 6) ( 1) ( 1) ( 3) 0 0
lymphoma ( 2) (14) (12) (13) ( 5) (6)
Mammary tissue  
mammary carcinoma 0 ( 2) 0 ( 3) 0 0
Nasal turbinates  
papilloma 0 0 0 1 0 0

TABLE II
TDI: LONG-TERM INHALATION STUDY IN MICE
Summary of total tumour incidence
  Males Females
  0 ppm 0.05 ppm 0.15 ppm 0 ppm 0.05 ppm 0.15 ppm
Total animals 90 90 90 90 90 89
Tumour bearers 64 65 43 56 50 22
Animals with malignant tumours 26 21 14 17 19 8
Animals with benign tumours 25 26 20 26 23 12
Animals with both malignant and benign tumours 13 18 9 13 8 2

TABLE III
MICRONUCLEUS TEST ON RATS AND MICE EXPOSED TO TDI-VAPOUR FOR 4 WEEKS, PERCENTAGE OF MICRONUCLEATED ERYTHROCYTES, MEANS OF 5 ANIMALS PER SEX PER LEVEL ± STANDARD DEVIATION, 1000 RBC PER ANIMAL EXAMINED
  Atmospheric concentration of TDI (ppm)
  0 0.05 0.15
Sex
Mice 0.5 ± .2 0.6 ± .2 0.4 ± .2 0.5 ± .2 0.4± .l 0.6 ± .3
Conclusions:
The study is considered to be reliable (reliability Klimisch 2). The validity criteria of the test system were fulfilled. The test material did induce slight signs of toxicity but no increased incidence of tumours. The test material was considered to be not carcinogenic after exposure via the inhalation route under the conditions of the test.
Executive summary:

The carcinogenicity of the test material was investigated in mice by Loeser et al (1983). The test was conducted similar to OECD TG451. Groups of male and female mice (30 animals per sex per group) were exposed to 0.05 and 0.15 ppm of toluene-diisocyanate (TDI) by inhalation for 6 h/day, 5 days/week for approx. 2 years. Type and incidence of tumours and the number of tumour-bearing animals were recorded. Additionally clinical signs, mortality, body weight gain, haematology, biochemistry, urinalysis, and cytogenicity were recorded. At termination of the study necropsy and histopathological examination were performed and organ weights recorded. At termination of the study (at week 104) most parameters did not indicate any treatment-related changes. There was a statistically increased mortality in the low- and high-dose females (total 77 percentage deaths were 78% / 70% / 70 % males and 60% / 77% / 74% females (control, low / high dose). Distinct effects occurred in mice: chronic and necrotic rhinitis, bronchitis and higher mortality (females only). Additionally mice at the 0.15 ppm level gained less weight. No specific target tissue, except the respiratory tract in mice, has been identified. The tumour pattern in the mouse study was similar in the control and in the treated groups and corresponded to historical data. The study demonstrated no evidence of any neoplastic response.

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Please refer to Read-across statement in section 13
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Major effects of inhaled MDI on the lung included increased lung weights, bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis.

HISTOPATHOLOGY: NEOPLASTIC
Two bronchiolo-alveolar adenomas were found in top-dose animals. Increased incidences of grade 4 and 5 alveolar type bronchiolo-alveolar hyperplasia (regarded as a preneoplastic change) were seen in the top-dose group. Incidence and/or severity of lower grade (grades 1, 2 and 3) alveolar type bronchiolo-alveolar hyperplasia were increased in the top-dose group. Bronchiolar type bronchiolo-alveolar hyperplasia, predominantly of minimal or slight degree (grades 1 and 2), was increased in incidence and/or severity in the mid- and top-dose groups. Mixed and flat type bronchiolo-alveolar hyperplasia were seen in low incidences in several groups with no obvious relationship with MDI treatment.


HISTOPATHOLOGY: NON-NEOPLASTIC
Interstitial fibrosis was increased in incidence and degree in both the mid- and top-dose group. Particle-laden macrophages were observed in all exposed groups and the macrophages were heavily laden with clear yellow particles. No increase in haemosiderin storage was observed. Mononuclear cell infiltration was clearly increased in incidence in the top-dose group, the increase being predominantly due to an increase in interstitial cell infiltration.
Dose descriptor:
NOAEC
Effect level:
0.2 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Effect level:
0.19 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
1 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
0.98 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
The study showed a very low incidence of tumour formation. Furthermore, the experimental evidence does not support a genotoxic mode of action.The concentrations tested in the study are only possible to form in the laboratory due to the physical-chemical properties of MDI. Therefore the exposure conditions are not representative for human exposure.
Executive summary:

In a combined chronic toxicity and carcinogenicity study, rats (whole body) were exposed for 6 hours/day, 5 days/week for 2 years to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m³ (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m³) (Reuzel et al., 1994). This GLP reliability 2 key study was conducted according to OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies). Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ was related to the occurrence of pulmonary tumours in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). Therefore, polymeric MDI was carcinogenic in rats after long-term inhalation to aerosol concentrations of 6.0 mg/m³. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumours.

The study showed a very low incidence of tumour formation. Furthermore, the experimental evidence does not support a genotoxic mode of action.The concentrations tested in the study are only possible to form in the laboratory due to the physical-chemical properties of MDI. Therefore the exposure conditions are not representative for human exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.086 mg/m³
Study duration:
chronic
Species:
rat

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Carcinogenicity study - Read across from Toluene diisocyanate, (Loeser et al., 1983)

The carcinogenicity of the toluene diisocyanate was investigated in rats and mice by Loeser et al (1983). The test was conducted similar to OECD TG451. Groups of male and female rats (21 rats per sex per group, 30 mice per group) were exposed to 0.05 and 0.15 ppm of test material by inhalation for 6 h/day, 5 days/week for approx. 2 years. Type and incidence of tumours and the number of tumour-bearing animals were recorded. Additionally clinical signs, mortality, body weight gain, haematology, biochemistry, urinalysis, and cytogenicity were recorded. At termination of the study necropsy and histopathological examination were performed and organ weights recorded.No exposure-related signs occurred during the study. At termination of the study (at week 110 for male rats and at week 108 for female rats) total percentage of deaths among the rats were 65% in controls, 67% low dose, 71% high dose males and 68% in controls, 75% low dose, 64% high dose females. Male and female rats of the 0.15 ppm group gained less weight during the first 12 weeks of the study. Type and incidence of tumours and the number of tumour-bearing rats did not indicate any carcinogenic effect. Haematology, biochemistry, urinalysis, and cytogenicity did not reveal any untoward effect. Histopathological examination in the rat study has not been completed, but no effect in the respiratory tract or in any other tissue has yet been seen.

At termination of the study (at week 104) most parameters did not indicate any treatment-related changes in mice . There was a statistically increased mortality in the low- and high-dose female mice (total 77 percentage deaths were 78% / 70% / 70 % male mice and 60% / 77% / 74% female mice (control / low / high dose). Distinct effects occurred in mice: chronic and necrotic rhinitis, bronchitis and higher mortality (females only). Additionally mice at the 0.15 ppm level gained less weight. No specific target tissue, except the respiratory tract in mice, has been identified. The tumour pattern in the mouse study was similar in the control and in the treated groups and corresponded to historical data. The study demonstrated no evidence of any neoplastic response.

0.15 ppm can be considered as NOAEC for carcinogenicity (corresponds to 1.75 mg/m³ for TRIDI).

Carcinogenitcity study - Read across from Toluene diisocyanate, (Gordon, 1986) - rats

The carcinogenicity of toluene diisocyanate after oral administration to rats was investigated by Gordon et al. (1986). The study was conducted equivalent or similar to the OECD Guideline 451. The duration of the study was approximately 2 years. As doses 30 and 60 mg/kg bw (for male rats) and 60 or 120 mg/kg bw (for female rats) of the test substance were administered via gavage. The test substance was analysed analytically and the results revealed that it reacted quickly with the water content of the solvent corn oil. Therefore the actual gavage concentrations were 77% to 90% of theoretical values. Despite the reduced doses, mean body weight gains of male and female rats were less than those of the controls after week 20. Early deaths occurred in groups of dosed male and female rats, but by week 60 only the high dose male rats were dying as a result of TDI administration. An apparent dose-related pattern of mortality began to emerge at week 70, and persisted until the end of the study. The delayed cumulative toxicity caused by TDI administration indicated that the estimated maximum tolerated doses had been exceeded in rats.Bronchopneumonia was the most prominent non-neoplastic effect seen in these gavage studies. In the present study, the late-appearing pattern of mortality in rats could be a reflection of delayed hypersensitivity, as well as direct respiratory irritation. The incidences of bronchopneumonia were dose related in male and female rats, and this effect may have weakened the animals’ resistance to further chemical challenge. The increased rate of mortality may also be due, in part, to TDI’s inhibition of acetylcholinesterase, which could have compounded the animals’ respiratory difficulty. Despite the reduced survival, there was unequivocal evidence of dose-related increases in tumours in rats and mice in the 2-year studies. About 50% of the tumours detected were observed in animals killed at the end of these studies; the rest were found in animals dying between weeks 77 and 108. Tissues associated with the digestive system were primary sites of tumour induction and included acinar cell adenomas of the pancreas in male rats, and liver tumours in female rats. There were also increased incidences of islet cell adenomas in low dose female rats. Dose-related increases were observed in the number of male rats with nodular hyperplasia of the pancreatic acinus (control, 0%; low dose, 4%; high dose, 8%) and in the incidence of acinar cell adenomas (control, 2%; low dose, 6%; high dose, 14%). The corn oil vehicle used in these gavage studies may have contributed to the incidences of acinar cell tumours in male and female rats. The systemic nature of the carcinogenicity of TDI was demonstrated by the appearance of tumours at multiple sites in male rats (fibromas and fibrosarcomas of the skin), in female rats (mammary gland fibroadenomas, adenomas, papillary adenomas, cystadenomas and subcutaneous fibroadenomas and fibromas). The tumours observed in the liver, pancreas, mammary gland, and subcutaneous tissues of F344/N rats in these studies are the same type as those seen when 2,4-diaminotoluene - a possible hydrolysis product of 2,4-toluene diisocyanate was administered to the same strain (NC1, 1979). Differences in mean body weight gains, hypersensitivity, and the incidences of neoplastic and non-neoplastic lesions in animals in the present studies emphasize differences in the degree to which TDI is toxic in different species and sexes. Both female rats and female mice received doses of 60 or 120 mg/ kg, and most of the rats died during the study. Male mice received higher doses (120 and 240 mg/ kg) than male rats (30 and 60 mg/ kg), yet mortality and decreases in mean body weights were less severe in the former group, and no tumours were detected at statistically significant incidences in male mice.

Under the conditions of these gavage studies, the commercial mixture of 2,4- and 2,6-toluene diisocyanate in corn oil was carcinogenic for F344/ N rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females.

Carcinogenitcity study - Read across from Toluene diisocyanate, Gordon et al. (1986) - mice

A study on the carcinogenicity of toluene diisocyanate after oral administration to mice was conducted by Gordon et al. (1986). The study was conducted equivalent or similar to the OECD Guideline 451. The duration of the study was approximately 2 years. As doses 120 and 240 mg/kg bw (for male mice) and 60 or 120 mg/kg bw (for female mice) of the test substance were administered via gavage. The test substance was analysed analytically and the results revealed that it reacted quickly with the water content of the solvent corn oil. Therefore the actual gavage concentrations were 77% to 90% of theoretical values. Despite the reduced doses, mean body weight gains of all male and female mice of the high dose group were less than those of the controls. Mortality in male mice was also dose related and significantly higher than in controls, but it was not as excessive as that in rats.Despite the reduced survival, there was unequivocal evidence of dose-related increases in tumours in rats and mice in the 2-year studies. About 50% of the tumours detected were observed in animals killed at the end of these studies; the rest were found in animals dying between weeks 77 and 108. The systemic nature of the carcinogenicity of TDI was demonstrated by the appearance of tumours at multiple sites in female mice (haemangiomas and haemangiosarcomas).Differences in mean body weight gains, hypersensitivity, and the incidences of neoplastic and non-neoplastic lesions in animals in the present studies emphasize differences in the degree to which TDI is toxic in different species and sexes. Both female rats and female mice received doses of 60 or 120 mg/ kg, and most of the rats died during the study. Male mice received higher doses (120 and 240 mg/ kg) than male rats (30 and 60 mg/ kg), yet mortality and decreases in mean body weights were less severe in the former group, and no tumours were detected at statistically significant incidences in male mice.Female mice showed positive evidence of carcinogenicity associated with TDI administration. The species and sex differences in sensitivity to TDI may be metabolic, but no experimental data are available.

Under the conditions of these gavage studies, commercial grade toluene diisocyanate in corn oil was carcinogenic for female B6C3F1 mice, causing haemangiomas or haemangiosarcomas (combined), as well as hepatocellular adenomas. No carcinogenic effect was revealed in male mice.

Carcinogenicity study - Read-across from pMDI (Reutzel et al., 1994)

In a combined chronic toxicity and carcinogenicity study, rats (whole body) were exposed for 6 hours/day, 5 days/week for 2 years to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m³ (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m³) (Reuzel et al., 1994). This GLP reliability 2 key study was conducted according to OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies). Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ was related to the occurrence of pulmonary tumours in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). Therefore, polymeric MDI was carcinogenic in rats after long-term inhalation to aerosol concentrations of 6.0 mg/m³. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumours.

The study showed a very low incidence of tumour formation. Furthermore, the experimental evidence does not support a genotoxic mode of action.The concentrations tested in the study are only possible to form in the laboratory due to the physical-chemical properties of MDI. Therefore the exposure conditions are not representative for human exposure.

Conclusion:

The evaluation of the National Toxicology Program revealed toluene diisocyanate to be carcinogenic only after oral exposure (due to formation of toluene diamine). The evaluation of Loeser and colleagues revealed toluene diisocyanate not to be carcinogenic after exposure via inhalation.

The data of toxicokinetic studies revealed that the carcinogenic potential of toluene diisocyanate depends highly on the exposure route. By oral exposure, TDI undergoes hydrolysis in the stomach to form toluene diamine (TDA). By inhalation exposure, TDI is absorbed in the upper respiratory tract and results in the formation of acid-labile conjugates with little diamine formed. The differential formation of TDA via the two routes of exposure may contribute to the mechanism by which TDI was carcinogenic in mice and rats by oral but not inhalation exposure (Doe and Hoffman 1995; IARC 1999; Collins 2002, cited in Screening Assessment for TDIs , 2008). However, the potential occurrence of neoplasms from inhalation exposure cannot be discounted, as it is uncertain whether maximum tolerable doses were attained in the chronic inhalation studies conducted by Loeser et al. (Screening assessment for TDIs, 2008; NTP, 1986).

Although the inhalation exposure is more likely to occur in humans than oral exposure, the exposure levels used by Loeser et al. may not have been optimal doses to adequately detect a potential carcinogenic response. The test substance is therefore judged based on the results obtained by the study of Gordon et al (1986) and the revealed carcinogenic potential provides the basis for classification.


Justification for classification or non-classification

Carcinogenicity:

The test material requires classification and labelling for carcinogenicity (Cat. 2) in accordance with Regulation (EC) No 1272/2008.