Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: secondary literature (review)
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
review article or handbook
Title:
Toxicology, industrial hygiene and medical control of TDI, MDI and PMPPI
Author:
Woolrich, P.F.
Year:
1982
Bibliographic source:
American Industrial Hygiene Association Journal

Materials and methods

Type of study / information:
Due to secondary literature, no principles of method are given.
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Not applicable.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not applicable.

Results and discussion

Any other information on results incl. tables

EFFECTS OF INHALATION

The mortality data in the study by Duncan et al. (1962) were obtained through exposure of four animal species (mice, rats, guinea pigs and rabbits) to one of the following concentrations: 0.1, 1.0, 2.0, 5, 10, 20 and 34 ppm of TDI for one 4 -hour period. They were observed for 28 days following the exposure. The inhalation 14 -day LC50 for each of the four species was as follows:

LC50 (rat): 14 ppm/4h

LC50 (mouse): 10 ppm/4h

LC50 (rabbit): 11 ppm/4h

LC50 (gpg): 13 ppm/4h

EFFECTS OF INGESTION

Data developed by Litton Bionetics (1976) (cross-reference not available) in connection with the National Cancer institute's Chemical Carcinogenesis Bioassay Program (cross-reference not available) points out that oral administration of TDI to rats is associated with the accumulation of an abnormal amount of mucinous material in the pulmonary bronchioles. These data present:

Oral LD50 (male rats): 5110 mg/kg

Oral LD50 (female rats): 4130 mg/kg

Oral LD50 (male mice): 4130 mg/kg

Oral LD50 (female mice): 5620 mg/kg

EFFECTS OF SKIN

TDI was applied separately to the intact and abraded skin of albino rabbits at single dosage levels of 2.5, 3.9, 6.0 and 9.4 g/kg as described by the International Research and Development Corp. (January, 1964). No pharmacodynamic signs were observed at any time during the 14-day observation period following the single application of TDI. All rabbits survived the course of study. The application of TDI at all dosage levels resulted in delayed dermal irritation, including moderate-to-marked erythema, oedema, atonia and coriaceousness, followed by desquamation and fissuring of the skin. All skin lesions had repaired by the 14th day of observation.

EFFECTS ON EYES

Investigations by the International Research and Development Corp. (March, 1964) gave the following results. Application of TDI to the eyes of rabbits produced corneal opacity in two animals which failed to clear in 30 days. All seven other rabbits appeared normal by the seventh post-treatment day. Circumcorneal injection of the iris was observed in all groups treated. In some animals this continued through the seventh day post-treatment, but cleared by the eighth day. Irritation of the conjunctivae appeared within a few hours after instillation of TDI and persisted in some animals from 18 to 20 days. Purulent ocular discharge was exhibited in all animals treated. In a few animals purulent discharge continued for 20 days after treatment. TDI was also observed to cause a loss of hair around the treated eyes of 7 of the 9 rabbits subjected to this chemical.

MUTAGENITY AND CARCIONOGENITY

A publication by Anderson et al. (1980) reports that TDI is mutagenic to Salmonella typhimurium strains TA1538 and TA98 after activation. The authors ascribe the effect to the amine analogue (TDA) formed during the hydrolysis of the isocyanate. Earlier reports by the U.S. Department of Health, Education and Welfare (1978) show that TDI is not mutagenic to Salmonella lyphimurium in the presence of a mammalian liver activating system.

Applicant's summary and conclusion

Conclusions:
As a secondary literature, the results cannot lead to a classification but the information can be used for a complete understanding of toxicity of diisocyanates.
Executive summary:

The report reviews different publications and international research reports concerning animal toxicity test results for toluene diisocyanate (TDI). Effects of inhalation, ingestion, skin, eyes as well as mutagenicity and carcinogenicity are considered and compared to one another.

The LC50 value of 10 ppm/4h for mice (inhalation) and the LD50 value of 4130 mg/kg for female rats as well as male mice (oral) are described as the most critical ones. The exposure of 2.5 g/kg (single dose) TDI to the intact and abraded skin of albino rabbits caused delayed dermal irritation, including moderate-to-marked erythema, edema, atonia and coriaceousness, followed by desquamation and fissuring of the skin. In addition, skin lesions occur. Eye effects such as irritation and loss of hair around treated eyes were observed. Contradictory results referring to mutagenicity were provided by different publications applying Ames test. Furthermore, no evidence of carcinogenicity, teratogenicity or reproductive effects in humans or animals were reported.

Furthermore, the NIOSH (National Institute for Occupational Safety and Health) has set the TLV (Threshold Limit Value) for diisocyanates at 0.005 ppm for a time-weighted average for up to a 10 -hour workshift, 40 -hours workweek and 0.02 ppm as a ceiling concentration for any 10 -minute sampling period.