TDI Biuret

Repeated dose toxicity: inhalation

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

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Reference 3

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

Test material information

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

1

Dose descriptor:

NOAEC

Effect level:

0.05 ppm (nominal)

Sex:

male

2

Dose descriptor:

NOAEC

Effect level:

< 0.05 ppm (nominal)

Sex:

female

Basis for effect level:

other: no NOAEC identified

3

Dose descriptor:

LOAEC

Effect level:

0.15 ppm (nominal)

Sex:

male

4

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.