Methylamine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic 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 for cross-reference:

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

Test material information

Constituent 1

Reference substance name:

Methylamine

EC Number:

200-820-0

EC Name:

Methylamine

Cas Number:

74-89-5

Molecular formula:

CH5N

IUPAC Name:

methanamine

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 or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

19 other: µmol/L

Remarks:

Basis: nominal conc.

Doses / concentrations 2

Dose / conc.:

5.75 other: µmol/L (s.c.)

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.