Registration Dossier

Toxicological information

Additional toxicological data

Currently viewing:

Administrative data

Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Falling short of highest standards concerning aspects of protocol or reporting. Good test report, but derivations of test guidelines.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Type of study / information:
Biochemical or cellular interactions
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A short-term inhalation toxicity study of polymeric MDI in rats was designed to investigate both the relationship between acute irritation and alteration of surfactant activity. The first was addressed by analysis of changes in breathing patterns during an acute inhalation exposure, the second was addressed in a 2-week repeated nose-only inhalation study.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Polymeric diphenylmethane-4,4'-diisocyanate, PMDI CAS No. 9016-87-9, containing ca 50% monmeric 4,4'-MDI, ca 4% monomeric 2,4'-MDI, ca 34% 3-oligomeric MDI, ca 9% 4-oligomeric MDI, balance higher oligomers.

Results and discussion

Any other information on results incl. tables

The results show that rats exposed to 3.3 and 13.7 mg/m³ experienced mild signs of respiratory tract irritation which appear to exacerbate during the course of the study. Analysis of arterial blood gases did not demonstrate appreciable effect in terms of oxygenation of blood or any imbalance of the ventilation: perfusion relationship. There were no appreciable concentration-dependent effects on lung mechanics. Analysis of BAL-fluid and BAL-cells did not reveal any changes indicative of marked inflammatory response or cytotoxicity in rats exposed to 1.1 and 3.3 mg/m³ whilst in rats exposed to 13.7 mg/m³ statistically significantly increased activities/concentrations of LDH, β-NAG, γ-GT, APh, intracellular ACPh and intra-/extracellular phospholipids were observed. Mild, but statistically significant effects on intracellular ACPh, γ-GT, and mildly increased cellular volumes were already observed in rats exposed to 3.3 mg/m³ air.

Staining of BAL-cells using the tannic acid-osmium tetroxide and polychrome stain for polar phospholipids demonstrated a concentration-dependent increase of lipid material in alveolar macrophages in all pMDI-exposure groups which appeared to be causally related with an increase in BrdU-labelled cells in the bronchiolo-alveolar region. Light and transmission electron microscopy suggested that exposure to 3.3 and 13.7 mg pMDI/m³ resulted in an accumulation of refractile, yellowish-brownish material in alveolar macrophages with concomitant activation of type II pneumocytes. Histopathological evaluation demonstrated a Goblet-cell hyperplasia in the anterior location of the nasal cavity in male rats of the high exposure group.

The authors suggest that polymeric MDI interacts directly with pulmonary surfactant lining fluids, the first line of pulmonary defence. The pulmonary irritation threshold seemed to be ca. 1 mg pMDI/m³.

Applicant's summary and conclusion

Conclusions:
The pulmonary irritation threshold seemed to be ca 1 mg PMDI/m³.

The results are said to suggest that PMDI appears to interact directly with pulmonary surfactant constituents required for its physiological function. This, in turn, appears to stimulate type II pneumocytes to increase their production of surfactant and to proliferate. The changes observed appear to reflect responses initiated by the innate defense mechanisms.
Executive summary:

Pauluhn et al. (1999) examined the pulmonary response of Wistar rats to respirable polymeric diphenylmethane-4,4'-diisocyanate (pMDI) aerosol in a 2-week repeated nose-only inhalation exposure study. Exposure concentrations were 1.1, 3.3, and 13.7 mg pMDI/m³ (6 h/day, 15 exposures). The level of 13.7 mg/m³ was actually a combination of an initial target concentration of 10 mg/m³ in week 1, which was raised to 16 mg/m³ in week 2, due to a lack of signs suggestive of pulmonary irritation. Shortly after the 2-week exposure period, rats were subjected to pulmonary function and arterial blood gas measurements. Lungs were examined by light and transmission electron microscopy, and labeling indices in terminal bronchioles were measured. Bronchoalveolar lavage (BAL) was performed to assess various indicators of pulmonary inflammation, including neutrophil and macrophage numbers, protein, lactate dehydrogenase (LDH), γ-glutamyltranspeptidase (γ-GT), alkaline phosphatase (APh), acid phosphatase (ACPh), and β-N-acetylglucosaminidase (β-NAG). Phosphatidylcholine in BAL fluid and BAL cells was determined as aggregated endpoint suggestive of changes in pulmonary surfactant. Rats exposed to 3.3 and 13.7 mg/m³ experienced concentration-dependent signs of respiratory tract irritation. Determination of arterial blood gases, lung mechanics, and carbon monoxide diffusing capacity did not demonstrate specific effects. Analysis of BAL fluid and BAL cells revealed changes indicative of marked inflammatory response and/or cytotoxicity in rats exposed to 13.7 mg/m³ the changes were characterized by statistically significantly increased activities of LDH, β-NAG, and protein. Phospholipid concentrations were increased in rats exposed to 1.1 mg/m³ and above (elevated levels of lipid material in alveolar macrophages demonstrated by polychrome stain) and 3.3 mg/m³ and above (increased intracellular ACPh activity and intracellular phospholipids). In these groups, γ-GT was statistically significantly increased. These findings suggest that changes in phospholipid homeostasis appear to occur at lower levels than those eliciting inflammation and cytotoxicity. Light and transmission electron microscopy suggest that exposure to 3.3 and 13. 7 mg/m³ resulted in focal inflammatory lesions and an accumulation of refractile, yellowish-brownish material in alveolar macrophages with concomitant activation of type II pneumocytes. In the terminal bronchioles a concentration-dependent increase of bromodeoxyuridine (BrdU)-labeled epithelial cells was observed in all pMDI exposure groups. In summary, it appears that respirable pMDI aerosol interacts with pulmonary surfactant, which, in turn, may stimulate type II pneumocytes to increase their production of surfactant and to proliferate.