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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Remarks:
Carcinogenicity study
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to Read-across statement in section 13

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No exposure-related signs occurred during the study. At termination of the study total percentage deaths were 65% in controls, 67% low dose, 71% high dose males & 68% in controls, 75% low dose, 64% high dose females.
Mortality:
mortality observed, treatment-related
Description (incidence):
No exposure-related signs occurred during the study. At termination of the study total percentage deaths were 65% in controls, 67% low dose, 71% high dose males & 68% in controls, 75% low dose, 64% high dose females.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
in all groups during the main part of the study. Significantly less weight gain in the 0.15 ppm group in both sexes in the first 12 weeks of exposure. Weight increases 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:
not specified
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):
The examination of the tissues did not reveal any evidence of treatment-related effects. Macroscopically no changes were seen in the upper respiratory tract.
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.
Details on results:
CLINICAL SIGNS AND MORTALITY
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. Statistical analysis indicated that TDI did not significantly affect mortality.

BODY WEIGHT AND WEIGHT GAIN
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.

OPHTHALMOSCOPIC EXAMINATION
No effects reported.

HAEMATOLOGY
No treatment-related changes in haematological parameters were recorded.

CLINICAL CHEMISTRY
No treatment-related changes in blood biochemical parameters were recorded.

URINALYSIS
No treatment-related changes in urinary parameters were recorded.

ORGAN WEIGHTS
The statistical analysis of the organ weights of the animals from interim and terminal kills did not reveal treatment-related differences.

GROSS PATHOLOGY
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.

HISTOPATHOLOGY: NON-NEOPLASTIC
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.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Statistical evaluation demonstrated no treatment-related effect on the incidence of tumours, their multiplicity or malignancy.

Effect levels

Dose descriptor:
NOAEC
Effect level:
0.15 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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. The results of the study did not reveal a substantial carcinogenic potential of TDI, when administered via inhalation to rats.
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.