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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guideline
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TDI unspecified.

Test animals

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.

Administration / exposure

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
Doses / concentrations
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

Examinations

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

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)
Sex:
male
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Sex:
female

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.