Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The GLP and guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
The exposure duration was 6, 20 or 60 minute. For the purpose of classification and labelling the 60-min LC50 value should by devided by 2. The deviation does not affect the validity of the test method used.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)
Deviations:
no
GLP compliance:
yes
Test type:
other: no data
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): monomethylamine, anhydrous
- Physical state: gaseous
- Analytical purity: 99.96%
- Stability under test conditions: chemically stable and insensitive to light
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Charles River Crl:cd BR VAF/Plus; Sprague-Dawley derived
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: approx. 49-65 days
- Weight at study initiation: males 208-293 and females 151-216 grams on day of exposure
- Fasting period before study: Diet and water freely available except during exposure
- Housing: individual stainless steel wire mesh cages
- Diet (e.g. ad libitum): certified pelleted rodent chow #5002, Purina Mills, Inc, St-Louis, Missouri. Diet and water freely available except during exposure
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C), Humidity (%), Photoperiod (hrs dark / hrs light): maintained in accordance with the recommendations contained in the D.H.E.W. Publication entitled "Guide for the care and use of Laboratory animals"

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber:150L plexi-glass and glass aquarium
- Source and rate of air: air flow between 50.19-51.90 L/min, temperature 22-23°C, relative humidity 16-47 %
- vapour atmospheres of the test material were generated as follows: the test materail was provided by the sponsor in low pressure cylinders under its own vapor pressure. The test material was metered from the cylinder, diluted to the desired concentration with a metered flow of compressed air and piped to the chamber inlet.
- Total chamber airflow was approximately 50 L/min (17 air changes/hour)

TEST ATMOSPHERE
- Brief description of analytical method used: gas-phase infrared spectrophotometry



Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 min
Remarks on duration:
6, 20, 60 min
Concentrations:
6 min exposure were conducted at concentrations of 17,600; 22,500; 26,200; 26,500 and 35,300 ppm
20 min exposure were conducted at concentrations of 10,600; 10,800; 11,000; 11,600; 13,900 and 17,400 ppm
60 min exposure were conducted at concentrations of 4,100; 6,370; 7,000; 7,100 and 8,670 ppm

6 minutes exposure duration:
- Desired: 16000, 22000, 26500, 27000, 37000 ppm
- Actual: 17600, 22500, 26200, 26500, 35300 ppm

20 minutes exposure duration:
- Desired: 10000, 10800, 10900, 12000, 14000, 17000 ppm
- Actual: 10600, 10800, 11000, 11600, 13900, 17400 ppm

60 minutes exposure duration:
- Desired: 4000, 6000, 7000, 7000, 8000 ppm
- Actual: 4100, 6370, 7000, 7100, 8670 ppm
No. of animals per sex per dose:
5 male and 5 female albino rats ( 5 /sex/dose, 50 in total)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at 7 and 14 days post-exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
- Duration of observation period following administration: 14 days (or other?)
- Frequency of observations and weighing:
- Necropsy of survivors performed: yes at study termination
- Other examinations performed: clinical signs (daily), mortality (twice daily), body weight (pre-exposure), organ weights, histopathology,

Statistics:
The concentration-mortality data were statistically analysed for the LC50 and its confidence limits by: "The determination of the dosage-mortality curve from small number." described in C.I. Bliss, Quart. J. Pharm.Pharmacol., Vol. 11, 1938. T

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LC50
Effect level:
24 400 ppm
95% CL:
22 500 - 26 500
Exp. duration:
6 min
Sex:
male/female
Dose descriptor:
LC50
Effect level:
9 600 ppm
95% CL:
7 560 - 12 200
Exp. duration:
20 min
Sex:
male/female
Dose descriptor:
LC50
Effect level:
7 110 ppm
95% CL:
6 680 - 7 560
Exp. duration:
60 min
Remarks on result:
other: corresponds to about 9.23 mg/L/60 min
Mortality:
6 min exposure: concentrations of 17,600; 22,500; 26,200; 26,500 and 35,300 ppm resulted in deaths of 0, 30, 90, 60 and 90 %, respectively
20 min exposure: concentrations of 10,600; 10,800; 11,000; 11,600; 13,900 and 17,400 ppm resulted in deaths of 30, 70, 60, 100, 80 and 90 %, respectively
60 min exposure: concentrations of 4,100; 6,370; 7,000; 7,100 and 8,67 ppm resulted in deaths of 0, 20, 40, 60 and 90 %, respectively.

Details:
6-minutes exposure:
17600, 22500, 26200, 26500, 35200 ppm:
Males: 0/5, 2/5, 5/5, 3/5, 4/5
Females: 0/5, 1/5, 4/5, 3/5, 5/5

20-minutes exposure:
10600, 10800, 10900, 11600, 13900, 17400 ppm:
Males: 2/5, 4/5, 4/5, 5/5, 3/5, 5/5
Females: 1/5, 2/5, 2/5, 5/5, 5/5, 4/5

60 minutes exposure:
4100, 6370, 7000, 7100, 8670 ppm:
Males: 0/5, 1/5, 4/5, 3/5, 5/5
Females: 0/5, 1/5, 0/5, 3/5, 4/5

- All animals died within 3 days post-treatment, except for 1 female: (37000 ppm for 6 minutes) died between 4-14 days post-treatment
Clinical signs:
The significant pharmacotoxic signs noted, which included death, labored breathing, rales, gasping and corneal opacities, were similar at all three exposure times. All but one death occured within the first 3 study days. There were no apparent differences between males and females.
Body weight:
Effects on body weights were also similar for the three exposure times, consisting of depressed weight gain during the first post-exposure week with significant recovery during the second week.
Gross pathology:
At necropsy, corneal opacities and pulmonary congestion were the prominent observations with little or no differences between the exposure times. The frequency of lung congestion increased with exposure concentration for the 60 minute exposure. Incidental findings: subdural clot, emphysema, discolored meninges, and liver foci

Applicant's summary and conclusion

Interpretation of results:
other: Acute Tox. 4
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
3 different LC50 were determined: LC50 (6min) = 24400 ppm, LC50 (20min) = 9600 ppm and LC50 (60min) = 7110 ppm.
This corresponds to: 6-minutes: ca. 31.7 mg/L, 20-minutes: ca. 12.5 mg/L, 60-minutes: ca. 9.2 mg/L
For the purpose of classification and labelling, for gaseous substances 1-hour LC50 value can be converted into the 4-hour value by dividing it by 2: 7110/2=3555 ppm.
Executive summary:

A study performed by International Research and Developmental Corporation in 1992, tested the acute toxicity by inhalation of monomethylamine. Male and female rats (strain: Charles River CD Crl VAF/Plus) were exposed to whole body gas inhalation within a time period of 6 to 60 min. After the MMA exposure, the animals were observed for 14 days. The concentrations of the test substance were for 6 min exposure nominal concentrations of 16000, 22000, 26500, 27000 and 37000 ppm; the actual concentrations were 17600, 22500, 26200, 26500 and 35300 ppm. For 20 min exposures the nominal concentrations were 10000, 10800, 10900, 12000, 14000 and 17000 ppm, the actual concentrations were 10600, 10800, 11000, 11600, 13900 and 17400 ppm. For 60 min exposures the nominal concentrations were 4000, 6000, 7000, 7000 and 8000 ppm, the actual concentrations were 4100, 6370, 7000, 7100 and 8670 ppm. Death occurred in a typical dose-dependent manner. The clinical findings were labored breathing, rales, gasping and corneal opacity. Additionally a decreased body weight gain was found during the first post-exposure week, but a significant recovery took place during the second week. Based on these findings LC50 values were determined: LC50 = 7110 ppm (60 min) (ca. 9.2 mg/L), LC50 = 9600 ppm (20 min) (ca. 12.5 mg/L), LC50 = 24400 ppm (6 min) (ca. 31.7 mg/L). They are in accordance to the values reported by BASF in 1983.