Registration Dossier

Administrative data

Description of key information

1) Non-GLP, 13 weeks, Fischer 344 rats, oral gavage, NOEAL males 30 mg/kg bw, females 60 mg/kg bw, questionable reliability
2) Non-GLP, 13 weeks, B6C3F1 mice, oral gavage, NOEAL males 240 mg/kg bw, females 60 mg/kg bw, questionable reliability
3) Non-GLP, 28 days, Spraque-Dawley rats, oral gavage, LOAEL 30 mg/kg kw, questionable reliability
4) carcinogenicity study, Sprague-Dawley rats, inhalation, whole- body, NOAEC 0.15 ppm
5) carcinogenicity study, CD1 mice, inhalation, whole-body, NOAEC 0.15 ppm
6) review on diisocyanates, OEL 0.005 ppm
7) carcinogen profile -Carex Canada, OEL 0.005 ppm for sensitization and for short term exposure 0.02 ppm.
8) TRGS - MAK 0.005 ppm for Isocyanates

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Significant methodological deficiencies: The test substance orally is degraded very rapidly to a variety of breakdown and polymerization products including 2,4-TDA and 2,6-TDA salts under the acidic conditions in the stomach; this study used a route of exposure inappropriate for assessing occupational risk in humans.
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Ten male and ten female rats per group were dosed by gavage at 2.5 mL TDI solution in corn oil per kg body weight. Rats were 11 weeks old at start of dosing and were housed 5 males or 5 females per cage. The animals were observed twice daily, body weights measured weekly and gross necropsy were performed on all rats. Histopathological examination was carried out on all control and high dose animals on 28 tissues as well as on intercurrent deaths. Low and mid dose animals were subjected to similar histopathologic examination if high dose animals displayed effects.
GLP compliance:
no
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Rats were 11 weeks old at start of dosing and were housed 5 males or 5 females per cage.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
no further details available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no further details available
Duration of treatment / exposure:
90 days
Frequency of treatment:
5 days per week, 13 weeks
Remarks:
Doses / Concentrations:
15, 30, 60, 120, 240 mg/kg bw day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
no further details available
Positive control:
no further details available
Observations and examinations performed and frequency:
The animals were observed twice daily, body weights measured weekly and gross necropsy were performed on all rats. Histopathological examination was carried out on all control and high dose animals on 28 tissues as well as on intercurrent deaths. Low and mid dose animals were subjected to similar histopathologic examination if high dose animals displayed effects.
Sacrifice and pathology:
The animals were observed twice daily, body weights measured weekly and gross necropsy were performed on all rats. Histopathological examination was carried out on all control and high dose animals on 28 tissues as well as on intercurrent deaths. Low and mid dose animals were subjected to similar histopathologic examination if high dose animals displayed effects.
Other examinations:
no further details available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1 of 10 males died in the 60 mg/kg bw group. 2 males died in the 120 mg/kg bw group. 1 of 10 males died in the 240 mg/kg bw group. 1 of 10 males (60 and 120 mg/kg bw) and 3 males (240 mg/kg bw) showed respiratory noises.
Mortality:
mortality observed, treatment-related
Description (incidence):
1 of 10 males died in the 60 mg/kg bw group. 2 males died in the 120 mg/kg bw group. 1 of 10 males died in the 240 mg/kg bw group. 1 of 10 males (60 and 120 mg/kg bw) and 3 males (240 mg/kg bw) showed respiratory noises.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight decrease in body weights of all groups of males was evident (down to 89.7 % of the controls in the 240 mg/kg bw dose group).
Food consumption and compound intake (if feeding study):
no effects observed
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
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mukoid bronchopneumonia was evident in 1 of 10 males (60 mg/kg bw), 3 of 10 males and 1 of 10 females (120 mg/kg bw) and in 8 of 10 males and 2 of 10 females (240 mg/kg bw).
Histopathological findings: neoplastic:
no effects observed
Details on results:
no further details available
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Sex:
male
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Sex:
female
Critical effects observed:
not specified

Table 1: Clinical signs and mortality

Dose (mg/kg bw)  

60

120

240

Mortality

(intercurrent deaths)

1/10 males

2/10 males

1/10 females

Respiratory noises

1/10 males

1/10 males

3/10 males

Table 2: Body weight

Dose (mg/kg bw)

Body weight (percent controls at week 12

Males

Females

60

97.7

100

120

90.7

96.4

240

89.7

94.8

Table 3: Histopathology

Dose (mg/kg bw)  

60

120

240

Mucoid bronchopneumonia

(accumulation of mucoid material in the bronchioles)

- mild to moderate

- moderate to severe

- less severe

1/10 males

3/10 males

1/10 females

8/10 males

2/10 females

Conclusions:
The study is considered to be not reliable (reliability Klimisch 3). However, the validity criteria of the test system were fulfilled. The test material did induce slight signs of toxicity (depression in body weight gain, mucoid bronchopneumonia, mortality). The test material was considered to be toxic via the oral exposure route under the conditions of the test, which is based on the NOEAL values derived from this study (NOAEL: 30 mg/kg bw (male rats) and 60 mg/kg bw (females).
Executive summary:

The study was conducted to provide information on the possible health hazards likely to arise from repeated treatment with the test article m-tolylidene diisocyanate (Gordon, 1978). The test material was administered once daily via oral gavage, 5 days a week, for 13 weeks. The test material was solved in corn oil and administered to six groups, each of ten male and ten female Fischer344 rats, at dietary concentrations of 15, 30, 60, 120 and 240 mg/kg/day. A further group of ten males and ten females was exposed to vehicle only to serve as a control. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of organs and tissues was performed.

There were mortalities and clinically observable signs of toxicity in the test animals the study period. Of the Males treated with 60 mg/kg bw 1 animal died. Additionally 2 males died in the 120 mg/kg bw group and 1 died in the 240 mg/kg bw group. One intercurrent death was noted in females treated at 240 mg/kg bw, which was judged to be related to treatment. 1 of 10 males (60 and 120 mg/kg bw) and 3 males (240 mg/kg bw) showed respiratory noises. A slight decrease in body weights of males treated with 60 mg/kg bw and above was evident (down to 89.7 % of the controls in the 240 mg/kg bw dose group) and in females treated with 120 mg/kg bw and above . Toxicological significant effects (respiratory noises) noted were detected in male animals treated with 60, 120 and 240 mg/kg bw. Histopathological findings were detected in males treated at 60 mg/kg bw and above and in females treated at 120 mg/kg bw and above a dose-related appearance of accumulated mucoid material in the pulmonary bronchioles. Thus, in this rat subchronic repeat dose toxicity study, the No-Observable-Adverse-Effect Level (NOAEL) of the test article m-tolylidene diisocyanate for males is 30 mg/kg/day and for females 60 mg/kg/day.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
No repeated dose toxicity studies are available for TRIDI. Therefore, subchronic study in rats conducted with TDI, the nearest analogue, is used for the DNEL derivation and further risk assessment.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: Carcinogenicity study
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented publication, which meets basic scientific principles
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
other: OECD 451 - Carcinogenicity studies
Deviations:
yes
Remarks:
6-9 weeks of age at study initiation, only 21 animals per sex/level, no detailed information on housing, diet and water, only 2 dose levels tested, no detailed information which tissues were examined
Principles of method if other than guideline:
Groups of male and female rats 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.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, UK
- Age at study initiation: 6-9-week-old, randomly allocated to exposure and control groups
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: TDI-vapour was generated by the passage of dry nitrogen through liquid TDI maintained at 21 °C, The vapour produced was then diluted with air in all-glass systems to produce the exposure concentrations.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel/glass cubical chambers with pyramidal ceilings of approx. 10 m³ were used.
- System of generating particulates/aerosols: TDI-vapour was generated by the passage of dry nitrogen through liquid TDI maintained at 21 °C, The vapour produced was then diluted with air in all-glass systems to produce the exposure concentrations.
- Temperature, humidity, pressure in air chamber: Temperature and humidity in the chambers were recorded daily.

TEST ATMOSPHERE
- Brief description of analytical method used: exposure levels have been monitored using both the U.E.I. Model 7000 TDI Tape monitor and a colorimetric method.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The exposure levels have been monitored using both the U.E.I. Model 7000 TDI Tape monitor and a colorimetric method, The actual levels were: 0.052 ± 0.007 ppm, 0.146 ± 0.014 ppm.
Duration of treatment / exposure:
108 (females) or 110 weeks (males) = approximately 2 years
Frequency of treatment:
6 h/day, 5 days/week
Remarks:
Doses / Concentrations:
0.0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0.05 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0.15 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
21 rats per sex per level = in total 126 (including animals for interim kill)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale:
Range-finding study
A range-finding study was carried out at another laboratory, and has been reported [2] prior to starting the lifetime studies. Sprague-Dawley rats (Spartan), Fisher 344 rats (Charles River), CD-I mice (Charles River), and Syrian hamsters (Engle Labs.) in groups of 10 animals of each sex and strain were exposed to TDI-vapour for 6 h/day, 5 days/week for a total of 20-22 exposures at levels of 0 (control), 0.1 or 0.3 ppm. Exposure was conducted under dynamic airflow conditions in chambers with quadrangular, pyramidal ceilings. TDI-vapour was generated by metering a calculated amount of liquid TDI into a heated vaporization flask at 220°C. The actual chamber concentrations of TDI were monitored analytically using a modified colorimetric method based on Marcali [1],
Clinical observations and body weights were recorded; haematological (RBC, haemoglobin, haematocrit, total and differential WBC counts) and biochemical (BUN, SGPT, AP) parameters were measured at the end of the study for animals of each sex, species and strain.

- Rationale for animal assignment (if not random): randomly allocated to exposure and control groups

- Other: An additional 5 rats per sex per level were exposed for 4 weeks to conduct the micronucleus test.
Positive control:
No data on positive controls available.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical signs were recorded at regular intervals

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical signs and ophthalmoscopic observations were recorded at regular intervals

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded at regular intervals

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: ophthalmoscopic observations were recorded at regular intervals
- Dose groups that were examined: 0 ppm, 0.05 ppm and 0.15 ppm

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Haematological (hemoglobin, RBC, PCV, total and differential, white cell count) were measured after 6, 12, 18 months of exposure and terminally.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: blood biochemical parameters (urea nitrogen, alkaline phosphatase and alanine-aminotransferase) were measured after 6, 12, 18 months of exposure and terminally.
- Animals fasted: No data
- How many animals: all animals

URINALYSIS: Yes
- Time schedule for collection of urine: measured after 6, 12, 18 months of exposure and terminally
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

Animals found dead, killed in extremis or scheduled for interim or terminal kills were subjected to gross and histopathology. Organ weights were recorded at all scheduled necropsies. The following tissues were examined histologically in both studies: adipose tissue, adrenal glands, aorta, blood film, brain (3 levels), caecum, colon, epididymides, eyes, femur (including bone marrow), gonads, heart, intestine, kidneys, liver, lungs (infused), lymph nodes, mammary gland, nasal turbinate (2 levels; mouse terminated, rat in progress), oesophagus, pancreas, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle (m. quadriceps), spinal cord (high cervical), spleen, stomach, thyroid, trachea, urinary bladder, uterus.
Other examinations:
Micronucleus test in rats
The results of the micronucleus test indicate that there was no dose- or treatment-related percentage increase of micronucleated erythrocytes in rats exposed to TDI at levels up to and including 0.15 ppm for 4 weeks.
Statistics:
No additional information on statistics available.
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.
Dose descriptor:
NOAEC
Effect level:
0.15 ppm
Sex:
male/female
Critical effects observed:
not specified

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. 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
0.058 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
No repeated dose toxicity studies are available for TRIDI. Therefore, subchronic study in rats conducted with TDI, the nearest analogue, is used for the DNEL derivation and further risk assessment.

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity oral:

Gordon, 1978 – rats

A study was conducted in Fischer 344 rats to provide information on the possible health hazards likely to arise from repeated treatment with the test article toluene diisocyanate (Gordon, 1978). The test material was administered once daily via oral gavage, 5 days a week, for 13 weeks. The test material was solved in corn oil and administered to six groups, each of ten male and ten female Fischer 344 rats, at dietary concentrations of 15, 30, 60, 120 and 240 mg/kg/day. A further group of ten males and ten females was exposed to vehicle only to serve as a control. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of organs and tissues was performed. However, the study is problematic, as the stability of the test item under the acidic conditions in the stomach is not likely to be guaranteed. Therefore the results were considered to be not reliable (Klimisch 3).

There were mortalities and clinically observable signs of toxicity in the test animals during the study period. Of the males treated with 60 mg/kg bw 1 animal died. Additionally 2 males died in the 120 mg/kg bw group and 1 died in the 240 mg/kg bw group. One intercurrent death was noted in females treated at 240 mg/kg bw, which was judged to be related to treatment. 1 of 10 males (60 and 120 mg/kg bw) and 3 males (240 mg/kg bw) showed respiratory noises. A slight decrease in body weights of males treated with 60 mg/kg bw and above was evident (down to 89.7 % of the controls in the 240 mg/kg bw dose group) and in females treated with 120 mg/kg bw and above . Toxicological significant effects (respiratory noises) noted were detected in male animals treated with 60, 120 and 240 mg/kg bw. Histopathological findings were detected in males treated at 60 mg/kg bw and above and in females treated at 120 mg/kg bw and above a dose-related appearance of accumulated mucoid material in the pulmonary bronchioles. Thus, in this rat subchronic repeated dose toxicity study, the No-Observable-Adverse-Effect Level (NOAEL) of the test article toluene diisocyanate for males is 30 mg/kg/day and for females 60 mg/kg/day. The NOAEL of 30 mg/kg bw was used for preliminary derivation of DNELs, but in the following DNELs were derived based on the available OELs for TDI.

Gordon, 1978 - mice

The study was conducted in B6C3F1 mice to provide information on the possible health hazards likely to arise from repeated treatment with the test article toluene diisocyanate (Gordon, 1978). The test material was administered once daily via oral gavage, 5 days a week, for 13 weeks. The test material was solved in corn oil and administered to six groups, each of ten male and ten female B6C3F1 mice, at dietary concentrations of 15, 30, 60, 120 and 240 mg/kg/day. A further group of ten males and ten females was exposed to vehicle only to serve as a control. Clinical signs, bodyweight development and food consumption were monitored during the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of organs and tissues was performed. However, the study is problematic, as the stability of the test item under the acidic conditions in the stomach is not likely to be guaranteed. Therefore the results were considered to bei not reliable (Klimisch 3). No effects on clinical signs, food consumption, body weights, necropsy or tissue histopathology were noted. There were mortalities but no clinically observable signs of toxicity in the test animals during the study period. Of the females treated with 240 mg/kg bw 2 animals died, which were judged as intercurrent. Additionally 1 female died in the 120 mg/kg bw group. Thus, in this mice subchronic repeat dose toxicity study, the No-Observable-Adverse-Effect Level (NOAEL) of the test article toluene diisocyanate for males is 240 mg/kg/day and for females 60 mg/kg/day.

Ministry of Health Labour & Welfare - rats

The Ministry of Health Labour & Welfare performed a study to provide information on the possible health hazards likely to arise from repeated treatment with the test article toluene disocyanate (Ministry of Health Labour & Welfare, Japan, 2001). The test material was administered by gavage to four groups, each of five male and five female Sprague-Dawley Crl:CD(SD) strain rats, for twenty-eight consecutive days, at nominal dose levels of 30, 100 and 300 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (Corn oil). Clinical signs and bodyweight development were monitored during the study.Blood and urinalysis were evaluated. All animals were subjected to a gross necropsy examination and histopathological evaluation of organs and tissues was performed. However, the study is problematic, as the stability of the test item under the acidic conditions in the stomach is not likely to be guaranteed. Therefore the results were considered to be not reliable (Klimisch 3). Oral administration of the test material to rats did not result in mortalities. Clinical signs (salivation) during the administration period were noted in both sexes at 100 and 300 mg/kg bw. Reduced body weight development was noted in males at 100 and 300 mg/kg bw. However, recovery was seen during the recovery period. Repeated oral dosing of rats with toluene diisocyanate over 28 days led to histopathological changes in lungs (males at >=100 mg/kg; females at >= 30 mg/kg), trachea (both sexes at >= 30 mg/kg), stomach (both sexes at 300 mg/kg), liver (both sexes at 300 mg/kg) and spleen (both sexes at 300 mg/kg). After a 14 -day recovery period all changes in lungs, trachea, stomach, small intestine and liver were considered to be reversible. The NOEL for the oral subacute rat study was considered to be less than 30 mg/kg/day for males and females. The LOAEL is 30 mg/kg/day based on histopathological changes in lungs (females only) and trachea (both sexes).

Repeated dose toxicity inhalation

Loeser, 1983 - rats

The carcinogenicity of toluene-diisocyanate (TDI) 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 (correspomds to 0.05 (correspomds to 0.58 mg/m³ for TRIDI)and 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) 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 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.

Loeser, 1983 – mice

The carcinogenicity of the toluene-diisocyanate 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 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. 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 occured 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.

Wolf and Stirn, 2000

The publication of Wolff and Stirn (2000) deals with diisocyanates in general and gives information about the health hazard arising after exposure. Diisocyanates (DI) are reactive compounds. In the presence of an alcohol or a phenol they form polyurethanes, i.e.highly resistant polymers. DI are constituents of high quality paints and varnishes, adhesives and coating agents or of foams used in building and construction. Exposure to DI is irritative for the respiratory tract and the eyes and worsens lung function. A single exposure to high DI concentration or chronic exposure to lower concentrations above the maximum workplace concentration (MAK-value) are capable of causing “isocyanate asthma”, the symptoms of which are closely similar to allergic asthma bronchiale and chronic obstructive bronchitis. Low molecular weight polymers of DI (prepolymers) that have been in use for a long time to replace DI in commercial products can also cause symptoms of asthma. Moreover the occupational exposure limits are given (0.005 ppm). Indoor use of DI-containing varnishes and paints on large areas may result in an exposure near the MAK-values. Subsequently, the DI-concentration rapidly decreases. There is no evidence that DI are continuously emitted after termination of the polymerisation process. Therefore, an assessment of a short-term exposure limit for indoor use is not reasonable. It is recommended that DI containing products in buildings be applied by professionals. Safety measures that should be taken are effective air circulation, avoidance of skin contact, attention to polymerisation time and prevention of dust when coats of freshly dried paint are ground.

CAREX Canada, 1999

The publicly available document of CAREX Canada deals with the hazardous characteristics of toluene diisocyanates (Carex Canada, 1999). Toluene diisocyanates (TDI) are colourless to pale yellow liquids, solids, or crystals with a distinctive pungent odour. Toluene diisocyanates are highly reactive compounds widely used in the manufacturing of polyurethane foams and coatings. TDI is typically available as a mixture of 80% 2,4-TDI isomer and 20% 2,6-TDI isomer, or sometimes as a 65-35% mix. IARC classifies toluene diisocyanates as Group 2B (possibly carcinogenic to humans), based on sufficient evidence in animals. Ingestion exposure causes liver and blood-related cancers in rats, and tumours of the liver, pancreas, and mammary glands in mice. The few available studies in occupationally-exposed people have not found a strong association or a consistent pattern. CAREX Canada ranks toluene diisocyanates as Group A (immediate high priority) for occupational settings and as Group B (possible high priority) for environmental settings and an OEL of 0.005 ppm for sensibilisation and an OEL of 0.02 ppm for short-term exposure are given.

The NTP’s 11th Report on Carcinogens classifies toluene diisocyanates as “reasonably anticipated to be a human carcinogen,” based on evidence in experimental animals. The toxicity of TDI has been recognized for many years. Exposure to high levels of TDI causes severe irritation of the skin, eyes, and nose, as well as nervous system effects. It is a potent skin and respiratory sensitizer and a well-known cause of occupational asthma. TDI can also cause hypersensitivity pneumonitis and chronic bronchitis.

BAuA, 2009 - TRGS

The TRGS describes the hazard assessment and safety precautions of workplaces, where isocyanates are present (BAuA, 2009). Besides, a method of determination and exposure assessment is given. This method may used during operations including isocyanates. Generally this means operations such as manufacture, formulation and application of polyurethanes (PU, PUR). Furthermore an assessment of possible hazards is described regarding the whole exposure to isocyanates. Isocyanates have acute as well as chronic effects mainly to the respiratory system. Cough, dyspnoea, coryza and conjunctivitis are described as acute effects which can appear delayed and lethal (pulmonary oedema). Obstructive respiratory diseases and particular immune responses (production of antibodies) can cause isocyanate asthma and less frequently allergic contact dermatitis.

According to determined test results such effects predominately occur on a regular basis of exposure which exceeds the maximum workplace concentration of 0.005 ppm. In addition particular circumstances such as accidents or lack of personal protective equipment, which lead to high exposures to lung and skin, can cause such effects as well. This is given by inappropriate use of adhesives, foams and coatings.

However, diseases were reported although an exposure could not be detected technically. Besides, effects in sensitized humans can occur in spite of a concentration below the maximum workplace concentration.

Isocyanates enter the human body through the skin but predominantly via the respiratory tract. For this reason, both exposure routes are considered regarding operating conditions of machinery and equipment. This includes starting, testing, cleaning and maintenance.

Conclusion

Considering oral exposure, the rat subchronic repeated dose toxicity study by Gordon (1978) set the No-Observable-Adverse-Effect Level (NOAEL) of the test article toluene diisocyanate to 30 mg/kg/day. As the results revealted the respiratory system to be the primary target of these chemicals. However inhalation is the most relevant route of exposure for humans. Thus studies on inhalation exposure are considered in detail.

The chronic inhalation study in rats (Loeser et al., 1983) was taken as key study for the chemical safety assessment. Although the exposure levels used by Loeser et al. may not have been optimal doses to detect all systemic effects (Screening Assessment for TDIs, 2008; NTP, 1986), they are the lowest doses tested which are known for the read-across substance toluene diisocyanate. The dose level of 0.15 ppm (1.75 mg/m³ for TRIDI) can be considered as a NOAEL since no treatment related effects were observed in any of the treated animals at this dose level. This NOAEL can serve as the starting point for DNEL derivation and should cover the risk of carcinogenicity arising after oral route of exposure, as well as the risk for respiratory hypersensitivity.

Additionally there are other sources for toxicity and safety exposure levels as described below.

The publication of Wolff and Stirn (2000) describes an occupational exposure limit (OEL) of 0.005 ppm for diisocyanates (DIs). An assessment of a short-term exposure limit for indoor use of diisocyanates is regarded as not reasonable.

CAREX Canada (1999) gives an OEL of 0.005 ppm for sensibilisation and an OEL of 0.02 ppm for short-term exposure regarding toluene diisocyanates (TDIs). Furthermore TDIs are categorised as Group A (immediate high priority) for occupational settings and as Group B (possible high priority) for environmental settings.

According to the TRGS isocyanates have acute as well as chronic effects mainly to the respiratory system. Such effects predominately occur on a regular basis of exposure which exceeds the maximum workplace concentration of 0.005 ppm.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study result has been used for preliminary DNEL derivation. However, as the evaluation showed the available OEL of 0.005 ppm for isocyanates to be more appropriate, in a second step the DNEL was derived using this OEL.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The study result has been used for preliminary DNEL derivation. However, as the evaluation showed the available OEL of 0.005 ppm for isocyanates to be more appropriate, in a second step the DNEL was derived using this OEL.

Justification for classification or non-classification

According to the European regulation (EC) No. 1272/2008 the test material does not meet the criteria for classification and will not require labelling.