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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: subacute and chronic
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable well-documented publication, which meets basic scientific principles
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats
Author:
Sriramachari S., Jeevaratnam K.
Year:
1994
Bibliographic source:
Arch Toxicol 69: 45-51 (1994)

Materials and methods

Principles of method if other than guideline:
Long-term (subacute and chronic) histopathological effects in the lungs of rats subjected to a single exposure to methyl isocyanate (MIC) by both the inhalation and subcutaneous (s.c.) routes as well as the role of methylamine (MA) and N,N'-dimethylurea (DMU), the hydrolytic derivatives of MIC in eliciting the observed changes.
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): methylamine

Test animals

Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
other: inhalation and subcutaneous application
Type of inhalation exposure:
not specified
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
For MA by the inhalation route for each period of study, four rats were exposed to 19 µmol/L (~1.0 LC50 MIC in terms of mol).
In addition, either MA or DMU at 5.75 mmol/kg was injected s.c. into a group of four rats each for each period of the study.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
no data
Frequency of treatment:
no data
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations: Inhalation: 19 µmol/L
Basis: nominal conc.
Remarks:
Doses / Concentrations: s.c. : 5.75 mmol/L
Basis:
No. of animals per sex per dose:
4
Control animals:
yes
Details on study design:
In the corresponding control groups for each duration of study, four rats each were subjected to either the inhalation procedure without the test material or s.c. administration of the vehicle, olive oil.

Examinations

Observations and examinations performed and frequency:
The appearance and behavior of animals exposed to MIC and its hydrolytic derivatives have already been described in the preceding paper (Jeevaratnam and Sriramachari 1994). Nearly similar findings were found in all the rats after the exposure to varied concentrations of MIC. The animals continued to be moribund and scarcely consuming any feed or water. After 2 or 3 days, the general condition of the animals improved and they were moving about, Although many of them exhibited the signs and symptoms of acute respiratory distress syndrome (ARDS) up to 4 weeks, there was a gradual improvement in ARDS beyond 4 weeks. Thereafter, the animals were apparently normal without any signs of underlying gross pathology of the lung.
Sacrifice and pathology:
Only a group of four rats of those that survived were killed at the end of each duration of the experiment by cervical dislocation. They were subjected to post-mortem examination.
Other examinations:
Although all the viscera were removed at autopsy and fixed in 10% neutral formalin, only the histopathological changes of the lungs are dealt in this communication. The tissues wereb processed through paraffin and stained by H&E, PAS, reticulin (silver) and collagen (tfichrome) using standard procedures.
Statistics:
no data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see in examinations
Mortality:
mortality observed, treatment-related
Description (incidence):
see in examinations
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
bronchial lumen and the epithelial lining were apparently normal in both the MA groups, peculiar and extensive edema in rats exposed to MA via inhalation
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see in details
Details on results:
Methylamine: at all periods of the study, the bronchial lumen and the epithelial lining were apparently normal in both the MA groups.
A peculiar and extensive edema was observed at the end of 1 week in rats exposed to MA vapors through inhalation route. The lungs were uniformly pale and had a washed out appearance. Histologically, lung parenchyma was filled with transparent clear aqueous fluid with the widespread separation of tissue spaces. Thus, the mucosal lining was lifted off the submucosa. Similarly, the perivascular areas were filled with clear edematous fluid extending throughout the pulmonary interstitium and alveoli. This phenomenon was seen to extend into the walls of blood vessels whose adventitial muscular coats were widely separated (Fig. 10). The faintly PAS positive reaction indicated that the fluid is an exudate rather than a transudate.

After 1 week: In both the MA groups, the interstitial spaces showed varying degrees of infiltrates characterized by mononuclear cells and histiocytes without any foamy cells. The connective tissue fibers were sparse and inconspicuous as revealed by both the silver and trichrome preparation.

After 4 weeks: A moderate to severe interstitial pneumonitis without edema was noticed in lungs of rats exposed to MA by either route, the severity being more pronounced in the subcutaneous route of exposure. The reticulin staining showed moderately severe fibrillogenesis in the highly cellular interstitial septa.

After 10 weeks: In both the groups, the lung showed severe interstitial pneumonitis extending into peribronchial and perivascular areas (Fig. 12a). The silver preparation showed abundance of collagen fibers in the corresponding areas (Fig. 12b). By comparison, the intensity of the above lesions is less in MA treated rats than in the MIC treated rats.

Effect levels

Dose descriptor:
NOAEC
Basis for effect level:
other: one dose level tested; severe interstitial pneumonitis
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
MA causes pumonary edema 1 week after expose to MA by inhalation.
MA causes interstitial pneumonitis progressing to fibrosis.
Executive summary:

Sriramachari et al. performed in 1994 a subacute and chronic test in rats with monomethylamine by the route of inhalation or subcutaneous administration. The test duration was 4 weeks; the substance was administered at concentrations of 19 µmole or 5.75 mmol/kg respectively. The animals showed a treatment-induced accumulation of hemorrhagic fluid in the pleural cavity. Histological examination revealed a severe interstitial pneumonitis and fibrosis.

At the subacute phase, the intraalveolar and interstitial edema were prominent only in the inhalation group as against the more pronounced inflammatory response in the s.c. route. With the progress of time the evolution of lesions appeared to be similar, culminating in the development of significant interstitial pneumonitis and fibrosis. MA, one of the hydrolytic derivatives of MIC, also caused interstitial pneumonitis progressing to fibrosis, albeit to a lesser extent than MIC, indicating its contribution to the long-term pulmonary damage.

Though the mechanisms by which either MIC or MA elicit the observed long-term effects are not known presently, the fact that the lung is the target organ for both MIC and MA, which cause the progressing changes leading to a unified picture of chronic puhnonary fibrosis, merits further consideration.