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REACH

2,4,6-triisopropyl-m-phenylene diisocyanate

EC number: 218-485-4 | CAS number: 2162-73-4

Life Cycle description
Uses advised against

Toxicological information

Carcinogenicity

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Administrative data

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

Referenceopen all close all

Reference 1

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
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.

Reference 2

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):

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
	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
	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
	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
	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.

Reference 3

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.

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 all close all

Reference 1

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
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.

Reference 2

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
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.

Reference 3

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:

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:

Executive summary:

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

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.

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.

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

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.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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
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
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 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 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

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 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
	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 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

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 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

Registration Dossier

Registration Dossier

Diss Factsheets

2,4,6-triisopropyl-m-phenylene diisocyanate

Carcinogenicity

Administrative data

Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Untreated Controls:

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

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

Table 16: Incidences of female mice with liver tumours

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

Reference 3

Endpoint conclusion

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Reference 3

Endpoint conclusion

Carcinogenicity: via dermal route

Endpoint conclusion

Justification for classification or non-classification

Carcinogenicity:

Additional information

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

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

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

Conclusion:

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