Registration Dossier

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: BASF AG, Akute Inhalationstoxizitaet LC50 4 (Ratte) Stunden Dampfversuch von "Monoethylamin", (report No. 82/0234) equivalent or similar to OECD 403; rats, doses: 4.5, 2.9, 2.1, 0.72 mg/L, whole body exposure for 4 hours;


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 animals  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:
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
Value:
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
Study period:
15.09.1982 - 02.11.1982 (animal testing) - 17.08.1983 (Issuance of Study report)
Reliability:
1 (reliable without restriction)
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 403 (Acute Inhalation Toxicity)
Deviations:
yes
Principles of method if other than guideline:
Method: 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
- Strain: SPF-Wistar/Chbb :THOM
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: 8 weeks
- Weight at study initiation: male: 248 +/- 35 g; female: 175 +/- 15 g
- Housing: 5 animals per cage (without litter)
- Diet (e.g. ad libitum): Haltungsdiaet fuer Ratten, Maeuse und Hamster SSNIFF R 10 mm Pellet (Ssniff-Versuchetierdiäten GmbH, 4770 Soest)
- Water (e.g. ad libitum): tap water ad libitum

ANIMAL IDENTIFICATION
- Animals were uniquely marked via claw amputation

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


Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
whole body inhalation system (the animals were kept in groups of 5 in wire cages, which were placed into a 200 Litre Glas-Steel-Inhalation chamber)
Aminomethane was taken from a gas bottle. The dosage was accomplished using a Whitley needle valve (SS-22 R52 TFE). By supplying blower air, a substance gas-air mixture was generated.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
4.5, 2.9, 2.1, 0.72 mg/L
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 -15 days
- Frequency of weighing: beginning of the study, 7 days and 14 days after exposurt to the test (The body weight of the animals was measured pre-trial, after 7 days and at the end of the follow-up period. Moreover, it was graphically represented. The clinical findings were recorded from Monday to Friday. The lethality was checked daily.)
- Necropsy of survivors performed: yes (Following the 14 and 15-day follow-up period, the surviving animals were killed by CO2 and subjected to a pathological-anatomical examination (like all other animals deceased before)).
- Other examinations performed: clinical signs, body weight, histopathology and survival were recorded
Statistics:
The statistical evaluation of the concentration effect relationship was based on a probit analysis of D. J. Finney (Finney, D. J.: Probitanalysis 1971, page 1 - 150.
Published by the Syndics of the Cambridge University Press, Bentley House, 200 Euston Road, London N. W. 1) . The calculation was carried out in the BASF data center.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
>= 2.1 - <= 2.9 mg/L air
Exp. duration:
4 h
Mortality:
Dose 0.72 mg/L: 2/20 animals died within ten first days
Dose 2.1 mg/L: 5/20 animals died; three females died within the first day and one male each did in the first and second week, respectively
Dose 2.9 mg/L: 17/20 animals died within the first two days afte exposure
Dose 4.5 mg/L: 20/20 animals died
Clinical signs:
other:
Body weight:
Compared to the controls, the body weight of the male animals was especially affected after 7 days.
In the females, body weight after 7 days was also affected.
Gross pathology:
Animals found dead: often slight to moderate emphysema (lung); trachea file with mucous, effects of acute corrosion (nose)
Sacrificed animals: nothing abnormal detected

Mortality       

 Dose (mg/L)  No. of animals  died within 4h  1 day  2 days  7 days  14 days
 4.5  10 male  2/10  9/10  10/10 -  -
   10 female  2/10  9/10  10/10  -  -
 2.9  10 male  1/10  5/10  8/10  8/10  8/10
   10 female  1/10  3/10  9/10  9/10  9/10
 2.1  10 male  0/10  0/10  0/10  1/10  2/10
   10 female  0/10  3/10  3/10  3/10  3/10
 0.72  10 male  0/10  0/10  0/10  0/10  0/10
   10 female  0/10  2/10  2/10  2/10  2/10

Symptoms and findings

During exposure:

Fierce to extraordinarily strong eye and nose secretion, Snout wipe, eyelid closure, pulling to snapping breathing, suffocation cramps and abdominal position.

After exposure:

Pulling to snapping breathing with sounds at the inspiration, partly milky clouded corneae, etching wounds to noses and eyes and circulatory relief posture. The surviving ones were not yet free of symptoms.

Original tables in the study report:

Table 1

Time until letal outcome

groups (conzentration)
1  (4,5 mg/L) 2 (2,9 mg/L) 3 (2,1 mg/L) 4 (0,72 mg/L)
No. Of animals deceased No. Of animals exposed
m f m f m f m f
4 h 2/10 2/10 1/10 1/10 0/10 0/10 0/10 0/10
1 d 9/10 9/10 5/10 3/10   3/10   2/10
2 d 10/10 10/10 8/10 9/10        
7 d         1/10      
14 d         2/10      
No. at the end of experiment 20/20 17/20 5/20 2/20
m = male f = female
h = hour/s, d = day/s
 - = Letality unchanged

Table 2 - Bodyweight (gr.)
Mean Bodyweight pre-trial after 7 days after 14 /15 days
m w m w m w
Group 1 - Bodyweight - in grams
(No. Of Animals)
247
(10)
175
(10)
       
Group 2 - Bodyweight in grams
(No. Of Animals)
239
(10)
175
(10)
191
(2)
177
(1)1
240*
(2)
213*
(1)
Group 3 - Bodyweight in grams
(No. Of Animals)
257
(10)
179
(10)
243
(9)
178
(7)
292
(8)
200
(7)
Group 4 - Bodyweight in grams
(No. Of Animals)
250
(10)
170
(10)
248
(10)
175
(8)
294
(10)
202
(8)

Control group (exposed to air) - Bodyweight in grams 

(No. Of Animals)

231 176 274 197 311 214

Procedural and analytical measurement results

Calibration: The calibration curve had a linearity range of 0.5 to 4 mg.

Concentration provisions: Each sample (11 - 15 ; 21 - 25, 30 - 34, 40 - 44) was analysed (sample numbers 1 - 10, 16 - 20, 26- 29, 35 39 characterize technical preliminary tests)

The following individual values of the concentration groups were retrieved

Table 3 - Analytical concentration - Group 1
Sample-ID analytical conzentration (mg/L)
30 3,60
31 3,92
32 4,24
33 4,56
Mean 4,08
(Fritten bottle) 34 + 0,41
Mean of Sum 4,5
S.E. of the mean  + 0,41 mg/L

Table 4 - Analytical concentration - Group 2
Sample-ID analytical conzentration (mg/L)
40 2,36
41 2 ,80
42 2,65
43 2,67
Mean 2,62
(Fritten bottle) 44 + 0,31
Mean of Sum 2,9
S.E. of the mean  + 0,19 mg/L

Table 5 - Analytical concentration - Group 3
Sample-ID analytical conzentration (mg/L)
21 1 ,48
22 1 ,86
23 2,16
24 1 ,93
Mean 1 ,86
(Fritten bottle) 44 + 0,23
Mean of Sum 2,1
S.E. of the mean  + 0,28 mg/L

Table 6 - Analytical concentration - Group 4
Sample-ID analytical conzentration (mg/L)
11 0,61 5
1 2 0,565
13 0,645
1 4 0,800
Mean 0,656
(Fritten bottle) 44 + 0,066
Mean of Sum 0,72
S.E. of the mean  + 0,10 mg/L

Pathology

Section findings:

Dead (male and female) animals:

- General congestion hyperemia

- Lung: Often mild to moderate emphysema.

- Trachea: Multiple subtotal with tough rubbery mucus filled tracheas.

- Stomach opening: Smeared several times with bloody secretion.

- Kidneys: 2 female animals in the Rindenmark border finest white-grey radiar streak.

- Nose mirror: Occasionally corroded with bonding until detachment skin and hair. Occasionally cyanosis of tongue and gums.

Killed (male and female) animals:

- Organs without observations

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Methylamine is highly irritating if inhaled.

Statistical evaluation:
LC50 values (4 hours exposure): LC50 (males + female) : 2,1 mg/L < LC50 < 2,9 mg/L // LC50 (males): 2.5 mg/L ( 2,1 - 2,9) *// LC50 (females): ca. 2,3 mg/ L
The statistical security for the specified trust limits is 95 %.
A change in concentration by the slope factor 1.21 results in a change of the effect by 1 probit in the Calculation for male animals.

Conversion of the above mentionned 4-hour LC50 values according to the Haber rule C x t = k:
LC50 values (1 hour exposure): LC50 (males + female) :8,3 < LC50 < 11,7 mg/L // LC50 (males): 9,9 mg/L // LC50 (females): ca. 9.2 mg/ L
Executive summary:

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..

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
2 100 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

 

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 (corresponding to an LC50 value between 1600 and 2300 ppm). Slight to moderate emphysema of lungs; trachea file with mucous, effects of acute corrosion of nose have been recorded in necropsied animals.

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).

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 performed 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 are well-documented. The LC50 values are correctly calculated according to known statistical methods. The study conducted by BASF in 1983 is taken as key study, in which the study design is similar to the approach outlined in the draft OECD guideline 403.

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. For the purpose of classification and labelling, the short-term (4 -hour) LC50 value serves as key value. In case of gaseous MMA, 4-hour LC50 of 2.1 - 2.9 mg/L air (corresponding to an LC50 value between 1600 and 2300 ppm) indicates the classification into the Category 3: H331: Toxic if inhaled.