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Administrative data

Description of key information

Acute oral toxicity: BASF AG, Bericht ueber die Pruefung der akuten oralen Toxizitaet, Report Nr. 82/0162, 1982; similar to the OECD Gudeline 401, Wistar rats, 215, 464 and 825 mg/kg bw.

Acute inhalation toxicity: International Research and Development Corporation (1992), Acute inhalation toxicity evaluation on monomethylamine in rats (Report No. IRDC 214-053); OECD 433; Exposure times: 6, 20 and 60 min.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards and is described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Method: other: BASF-Test
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: ca. 12 weeks
- Weight at study initiation: animals were on comparable body weights (+/- 20 g)
- Fasting period before study: 16 hours
- Housing: 5 animals per cage
- Diet (e.g. ad libitum): SSNIFFR, Versuchstierdiaeten
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
water
Doses:
825, 464, 215 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Other examinations performed: clinical signs, body weight, histopathology and suvival wre recorded
Sex:
male/female
Dose descriptor:
LD50
Effect level:
698 mg/kg bw
Mortality:
825 mg/kg: 7 animals died
464 mg/kg: 1 animal died within 2 days
Clinical signs:
825 mg/kg: dyspnea, apathy, ataxia, ecxidosis (males), cachexia (males)
464 mg/kg: apathy, gasping, bad general condition (males)
Gross pathology:
Animals found dead:
825 mg/kg: strong irritation and bloody content in stomach and intestine
464 mg/kg: no pathology possible due to starting putrefaction
Sacrifced animals:
Nothing abnormal detected.

Mortality

 Dose (mg/kg)  No. of animls  died within1h  1 day  2 days  7 days  14 days
 825  5 male  0  1  1  1  2
   5 female  0  5  5  5  5
 464  5 male  0  0  1  1  1
   5 female  0  0  0  0  0
 215  5 male  0  0  0  0  0
   5 female  0  0  0  0  0

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information: According to the criteria in CLP Annex I, 3.1.2 to 3.1.3.4.
Conclusions:
Methylamine caused corrosive injury to the stomach if ingested
Executive summary:

An oral acute toxicity study performed by BASF AG in 1982, Methylamine as aqueous solution of 40% was administered orally to rats (test group consisting of 5 rats, strain: Wistar/sex) at doses of 215, 464 and 825 mg/kg bw. Observations for mortality and for clinical symptoms of toxicity were performed. At the end of the observation period of 14 days, the surviving animals were sacrificed for the purpose of necropsy. As effect level the LD50 was considered to be around 698 mg/kg bw. Bad general condition, dyspnea, gasping, apathy, ataxia, exsiccosis and cachexia were observed in treated animals. The effects were more pronounced in males. The severity of effects carried a clear dose-dependent character. Strong irritation and bloody content in stomach and intestine were recorded in animals that died after exposures. At the highest dose administered (825 mg/kg) 7 animals died. At 464 mg/kg one animal died in the first 48 hours after drug administration. There were no abnormalities in sacrificed animals, beside the strong irritation of the stomach and the intestines in rats treated with 825 mg/kg. Additionally a bloody content was found in the stomach and the intestine of the rats treated with the highest dose administered. Based on the findings methylamine is classified a toxicity category IV (GLP Annex I).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
698 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
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
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
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"
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
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
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.

Endpoint conclusion
Dose descriptor:
LC50
4 589 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity: oral

In an oral acute toxicity study performed by BASF AG in 1982, methylamine as aqueous solution of 40% was administered orally to rats (test group consisting of 5 rats, strain: Wistar/sex) at doses of 215, 464 and 825 mg/kg bw.Observations for mortality and for clinical symptoms of toxicity were performed. At the end of the observation period of 14 days, the surviving animals were sacrificed for the purpose of necropsy. As effect level the LD50 was considered to be around 698 mg/kg bw. Bad general condition, dyspnea, gasping, apathy, ataxia, exsiccosis and cachexia were observed in treated animals. The effects were more pronounced in males. The severity of effects carried a clear dose-dependent character. Strong irritation and bloody content in stomach and intestine were recorded in animals that died after exposures. At the highest dose administered (825 mg/kg) 7 animals died. At 464 mg/kg one animal died in the first 48 hours after drug administration. There were no abnormalities in sacrificed animals, beside the strong irritation of the stomach and the intestines in rats treated with 825 mg/kg. Additionally a bloody content was found in the stomach and the intestine of the rats treated with the highest dose administered. Based on the findings methylamine is classified in toxicity category IV (GLP Annex I).

Acute toxicity: inhalation

 

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, 20 and 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). These values are in accordance with the values reported by BASF in 1983.

An inhalation acute toxicity test was performed by a dynamic inhalation method by BASF AG (1983). Each 10 male and female rats (strain: Wistar) were exposed to whole body gas inhalation within a time period of 4 hours. After the 4 h MMA exposure, the animals were observed for 14 days. The concentrations of the test substance were 4.5, 2.9, 2.1, 0.72 mg/L. Deaths occurred in a dose-dependent manner. During exposure the animals showed eyelid closure, eye & nose discharge, dragging & gasping respiration, convulsions and after exposure dragging & gasping respiration, blurred cornea, effects of acute corrosion occurred. The clinical effects were irreversible in some animals. The mortality found was as follows: 0.72 mg/L: two of twenty animals died within 10 days, at 2.1 mg/L five of twenty animals died; at 2.9 mg/L already 17 of twenty animals died within 2 days. At the highest concentration tested (4.5 mg/L) all animals died. The LC50 value was determined to be between 2.1 and 2.9 mg/L air for both sexes. Slight to moderate emphysema of lungs; trachea file with mucous, effects of acute corrosion of nose have been recorded in necropsied animals.

Sarkar et al. investigated in 1992 the acute toxicity by inhalation of monomethylamine with rats (albino). The route of exposure was inhalation by whole body exposure. The exposure times were 2.5 hours with different concentrations (It is unclear whether exposure is against 100, 200, 300, 400, 500 ppm methylamine or against a saturated atmosphere derived from of a solution of 0.1, 0.2, 0.3, 0.4, 0.5 mL methylamine/L). Necropsy and clinical chemistry (GOT; GPT; LDH, Alkaline phosphatase and lipid peroxidation were performed at the end of the study. Different clinical signs, as labored breathing, dyspnoea, lacrimation and excitement, as well as facial skin necrosis were found. The necropsy revealed haemorrhagic lungs and skin necrosis. Concerning the clinical chemistry no effect on serum ALP, GOT, GPT and LDH was established, but the lipid peroxidation values were significantly increased at 400 and 500 ppm. So a LC50 was determined: LC50 (2.5h) = 0.569 mg/L (LC50= 0.448 mL/L vapor aerosol = 448 ppm = 0.569 mg/L).

Another inhalation acute toxicity test was performed by a whole body inhalation method by BASF AG (1983). Each 10 rats were exposed to gas for 1 hour. The concentrations of the test substance were 1500, 3000, 6000, 12000, 24000 ppm (1.9, 3.8, 7.6, 15.2, 30.5 mg/L). During exposure the animals showed huddling. Deaths occurred in a dose-dependent manner. Necropsy revealed pulmonary congestion, hepatic congestion and congestion of the upper respiratory mucosa. The mortality found was as follows: 1500 ppm: none of ten animals died, at 3000 ppm two of ten animals died; at 6000 ppm already six of ten animals died within 2 days. At the two highest concentrations tested (24000 ppm) all animals died. All animals died within 2 days post-exposure, except for 3 animals (6000 ppm) which died between days 3 and 4. The LC50 value was determined to be at 6.5 mg/L air.

In nasal irritation and pulmonary toxicity study of 20 aliphatic amines in mice, Gagnaire et al. exposed mice to airborne MMA to determine RD50 values (Gagnaire et al., 1989). This value indicates 50% decrease in the respiratory rate and considered to be successfully used to predict safe industrial exposure. The onset of action of MMA was very rapid, ca. 30 sec. to 1 min. 141 ppm of MMA was determined as RD50 in mice. At the end of a 15 -min exposure period, the recovery of respiratory frequencies to the pre-exposure values was also rapid, ca.1 min. Due to the rapid recovery of respiratory frequency in mice, monomethylamine is considered to be moderately irritating to the upper respiratory airways.

In total the experimental results indicate, that monomethylamine is of acute toxicity in mammals: LD50 rat (oral) of 698 mg/kg bw/day,or a LC50 rat (inhalative, 4 hours) >2.1 – 2.9 mg/m³, or LC50 values of ca. 9.2 mg/L (inhalative, 1 hour), or ca. 12.5 mg/L (inhalative, 20 min) or ca. 31.7 mg/L (inhalative, 6 min). The main symptoms following exposure were labored breathing, rales, gasping and corneal opacity, dragging and gasping respiration, blurred cornea, effects of acute corrosion hunched posture. Some animals showed during exposure additionally convulsions.

Acute toxicity: dermal

In the acute toxicity by dermal application experiments performed by Goffmann and Maguire in 1980, three guinea pigs were used to assess dermal toxicity of liquefied methylamine. The animals received two to three drops of the liquefied gas unchanged onto the skin, and the skin reactions were observed for a period of 12 days.The clinical signs were immediate skin color change, and swelling with subsequent necrosis. Histology performed revealed after 48 h: necrotic skin, and after 12 days: fresh granulation tissue. So the test material caused skin necrosis.

Justification for classification or non-classification

The classification and labelling for methylamine is perfomed according to the decision logic on classification and labelling presented in the Guidance on the Application of Regulation (EC) 1272/2008 (section 3.1.2.6.).

Acute toxicity: oral

LD50 of 698 mg/kg bw established in the acute oral toxicity study in rat (BASF, 1982) indicates that aqueous methylamine should be classified in the acute toxicity Category 4: H302: Harmful if swallowed.

Acute toxicity:dermal

MMA is classified as corrosive to skin. Thus, the local effects prevail the systemic effects and therefore the classification and labelling is not required for acute dermal toxicity.

Acute toxicity:inhalation

There are several acute inhalation studies available for methylamine. The described above studies meet general scientific principles and well-documented. The LC50 values are correctly calculated according to known statistical methods. The more recent study conducted by International Developed Research Corporation in 1992 is taken as key study, in which the study design is similar to the approach outlined in the draft OECD guideline 433. This guideline is a revision of the existing OECD guideline 403 and its principle is the Fixed Concentration Procedure (FCP). According to this method animals shold be exposed to moderately toxic fixed concentrations in a stepwise procedure and for a short period of time especially if substance cause marked pain and distress due to its corrosivity.

As evident from all acute inhalation and irritation studies, monomethylamine caused eye, nose and throat irritation if inhaled. The severe irritation effects in treated animals appeared already after 3 min of inhalation. When animals were exposed to gas of MMA during 6, 20 and 60 minutes pharmacotoxic signs noted in test animals were similar at all tree exposure times. It is therefore evident that a longer exposure to MMA will not deliver new effects or clinical signs. Thus, a shorter than 4 -hour exposure period to this substance is certainly more appropriate to derive an acute LC50 value. Suprisingly, the LC50 of 9.2 mg/L (7110 ppm) for 1 -hour exposure in this study is the same value calculated in the old inhalation study with MMA (BASF, 1983). For the purpose of classification and labelling, such a short-term (1 -hour) LC50 value should be divided by 2 and then can serve as key value (Guidance on the Application of Regulation (EC) No. 1272/2008). In case of gaseous MMA, 1-hour LC50 of 7110 ppm/2 = 3555 ppm indicates the classification into the Category 4: H332: Harmfull if inhaled.