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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Oct. 1976 - Nov. 1978
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1980
Report date:
1980
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984
Reference Type:
publication
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
- only 2 doses investigated
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
m-tolylidene diisocyanate
EC Number:
247-722-4
EC Name:
m-tolylidene diisocyanate
Cas Number:
26471-62-5
IUPAC Name:
2,4-diisocyanato-1-methylbenzene
Details on test material:
- Name of test material (as cited in study report): 2,4/ 2,6-TDI (80:20), production grade

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rats were 8-9 weeks old at start of exposure.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Animals were housed 6 males or 6 females per cage and exposed in 9m3 chambers.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
5 times each day, each exposure group. U.E.I. Model 7000 TDI tape monitor, and the Marcali colorimetric method.
Duration of treatment / exposure:
up to 113 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.05, 0.15 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
126
Control animals:
yes, sham-exposed

Examinations

Observations and examinations performed and frequency:
Mortality, clinical signs, body weights, ophthalmoscopy, haematology, blood chemistry, urinalysis.
Sacrifice and pathology:
Organ weights, gross pathology, histopathology.
Other examinations:
Special histopathology of the nasal cavity.
Statistics:
Survival probabilities for each group were calculated by the method of Kaplan and Meier (J. Am. Statist. Ass. 53: 457 (1958)). The survival of the individual treatment groups was compared using the log rank method of Peto and Pike (Biometrics 29: 579 (1973)).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.05 ppm (nominal)
Sex:
male
Dose descriptor:
NOAEC
Effect level:
< 0.05 ppm (nominal)
Sex:
female
Basis for effect level:
other: no NOAEC identified
Dose descriptor:
LOAEC
Effect level:
0.15 ppm (nominal)
Sex:
male
Dose descriptor:
LOAEC
Effect level:
0.05 ppm (nominal)
Sex:
female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No exposure-related clinical signs of toxicity were observed during the study. No treatment-related changes in hematology, blood biochemistry, urinalyses, ophthalmoscopy or organ weights were recorded.

Compared to control rats, there were significantly reduced body weight gains in males and in females of the highest dose groups up to study week 12 that remained significantly reduced throughout the study for female rats. Mortality occurred in both test and control groups, with generally higher mortality rates at earlier time points in test groups than in the controls for males, providing additional supporting evidence indicating that MTD was reached.

Table 1: Body weight gain and mortality rate of rats during exposure

Males

Females

Control

Low dose

High dose

Control

Low dose

High dose

Group mean body weight gain (g):

week 0 –12

298

296

275*

136

132

121*

Group mean body weight gain (g):

week 0 - termination

554

579

525

395

378

345*

Mortality before interim sacrifice after 6 m

3/126

13/126

11/126

0/126

1/126

0/126

Mortality before interim sacrifice after 12 m

4/116

1/106

1/108

1/119

3/118

1/119

Mortality before interim sacrifice after 18 m

7/105

8/97

13/100

14/111

20/108

9/110

Mortality before terminal sacrifice

52/89

46/81

50/80

53/88

55/81

46/84

* P <0.01 when compared to the controls

In rats killed as scheduled (interim sacrifices after 6, 12 and 18 months + terminal sacrifice), lesions were localized primarily in the anterior respiratory mucosa of the nasal cavity. Rhinitis was increased in incidence and severity (grades1-4: minimal - marked rhinitis, generally characterized by squamous metaplasia and hyperplasia of the epithelium, leucocyte infiltration in the lamina propria and exudate in the lumen) in a dose-dependent manner and is considered to be due to local irritation.

Table 2: Incidence of rhinitis in the anterior nasal cavity of rats

Males

Females

Control

Low dose

High dose

Control

Low dose

High dose

Grade 0*

30/58

30/55

6/51

46/56

27/47

17/57

Grade 1*

11/58

7/55(13%)

5/51

7/56

8/47(17%)

16/57(28%)

Grade 2*

13/58

15/55 (27%)

13/51(25%)

3/56

9/47(19%)

18/57(32%)

Grade 3*

4/58

3/55

23/51 (45%)

0

3/47(6%)

5/57(9%)

Grade 4*

0

0

4/51

0

0

0

No section

0

0

0

0

2

Percent rats with

grade1- 4 rhinitis

48 %

45 %

88 %

18 %

43 %

70 %

* Grade 0 = unremarkable; Grade 1 = minimal rhinitis, Grade 2 = slight rhinitis, Grade 3 = moderate rhinitis, Grade 4 = marked rhinitis generally characterized by squamous metaplasia and hyperplasia of the epithelium, leucocyte infiltration in the lamina propria and exudate in the lumen

Applicant's summary and conclusion

Executive summary:

In a combined chronic toxicity and carcinogenicity study rats were exposed for 6 hours/day, 5 days/week for approximately 2 years to TDI (80/20) vapour concentrations of 0, 0.05 or 0.15 ppm. Body weight gain was reduced in the high dose of males and females over the first 12 weeks that persisted but did not worsen over the remaining period of the study. Histopathologically, rhinitis was observed in males at 0.15 ppm and in females beginning at 0.05 ppm. This finding is considered to be due to local irritation of the anterior nasal cavity.

In this 2-year rat study the NOAEC for males is 0.05 ppm and for females below 0.05 ppm with regard to repeated dose toxicity.