Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
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):
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

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: not specified
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.