4-methyl-m-phenylene diisocyanate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

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 10 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

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

Molecular formula:

C9 H6 N2 O2

IUPAC Name:

m-tolylidene diisocyanate

Details on test material:

- Name of test material (as cited in study report): TDI unspecified.

Data on physical and chemical properties, eco-toxicity and toxicity can be used for read-across from 2,4-TDI to 2,6-TDI and mixed TDI isomers (i.e. 80/20, 65/35, 2,4/2,6 ratios). 2,4 TDI is the major component of the TDI mixed isomers and so has the major influence on their properties and effects. The reactivity of the 2,6-TDI isomer is somewhat less than that of 2,4-TDI but is of the same order of magnitude. It may therefore be concluded that the effects of 2,6-TDI will be similar to those of 2,4-TDI. This is in fact observed where there are overlapping data.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

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

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

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

Histopathological findings: neoplastic:

no effects observed

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Sex:

male

2

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

Executive summary:

Administration of m-tolylidene diisocyanate in corn oil to rats by oral gavage for five times per week for 13 weeks at dose levels of 0, 15, 30, 60, 120, and 240 mg/kg bw produced evidence of toxicity as seen by a depression in body weight gain in males treated at 60 mg/kg and above and in females treated at 120 mg/kg and above. Histopathologically, a dose-related appearance of accumulated mucoid material in the pulmonary bronchioles was observed in males treated at 60 mg/kg and above and in females treated at 120 mg/kg and above. One intercurrent death in females at 240 mg/kg was judged to be related to treatment.

In this subchronic rat study the NOAEL for males is 30 mg/kg/day and for females 60 mg/kg/day.