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Description of key information

Oral: BASF, Gewerbetoxikologische Grundprüfung, 1980.
Dermal: BASF, Gewerbetoxikologische Grundprüfung, 1980.
Inhalation: International research and development corporation, 1992, rats (1 hour exposure) (for C&L).

Inhalation: Gagnaire, 1989, mice.

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: Comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Method: other: BASF-Test, experimental result
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Gassner
- Weight at study initiation: male 192 g (mean); female 160 g (mean)
- Diet: Herilan MRH-Haltung, Heinrich Eggersmann KG, Rinteln



Route of administration:
oral: gavage
Vehicle:
other: dissolved in water with 0.5 % CMC
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 6.81 - 46.4 %
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


Doses:
681, 1000, 1470, 2150, 3160 and 4640 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
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, histopathology
Dose descriptor:
LD50
Effect level:
ca. 1 000 mg/kg bw
Mortality:
No animal died in the lowest dose group. Four out of 10 died in the 1000 mg/kg group. All animals died in the four highest dose groups.
Clinical signs:
staggering, atony, spatic gait, exsiccosis, tremor, salivation, opisthotonus, poor general state, reduction in body weight, "morphinschwanz"
Gross pathology:
Animals that died:
Heart: acute dilatation and congestive hyperemia
Lung: slight emphysema
Gastro-intestinal tract: redness, bloody content
Liver: peripheral lobule marking


Interpretation of results:
Category 4 based on GHS criteria
Executive summary:

In an oral acute toxicity study performed by BASF AG in 1980, DMA was administered to rats (test group consisting of 5 rats, strain: Sprague-Dawley/sex) by single gavage with an aqueous solution of the test substance. 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; animals that died during the observations period also were subjected to necropsy. The initial concentrations were 681, 1000, 1470, 2150, 3160 and 4640 mg/kg bw. As effect level the LD50 was considered to be around 1000 mg/kg bw. No animals died in the lowest groups, but 4/10 died in the dose group with 1000 mg/kg bw. All animals died in the 4 highest dose groups. Animals showed staggering, atony, spatic gait, exsiccosis, tremor, salivation, opisthotonus, poor general state, reduction in body weight, "morphinschwanz”. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependent manner.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 000 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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline followed, GLP, test method sufficiently described
Qualifier:
no guideline followed
Principles of method if other than guideline:
The acute toxicity by inhalation of dimethylamine with rats (strain: Charles River Crl:cd BR VAF/Plus; Sprague-Dawley derived). The route of exposure was inhalation by whole body exposure. The exposure times were 6 - 60 minutes with different concentrations (ranging from 4,620 to 19,900 ppm).
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 or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: approx. 49-63 days
- Weight at study initiation: males 208-292 and females 158-220 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:
not reported but figure 1 shows the schematic diagram of generation and exposure system, for more information see study trimethylamine



Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 min
Remarks on duration:
6, 20, 60 min
Concentrations:
6 min exposure: 13,700; 15,400; 17,400; 17,500 and 19,900 ppm
20 min exposure were conducted at concentrations of 4,620; 5,940; 7,860; 7,740 and 8,860 ppm
60 min exposure were conducted at concentrations of 4,900; 5,040; 5,080; 5,120; and 5,920 ppm
No. of animals per sex per dose:
5 male and 5 female albino rats
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:
Statistics:
no data
Sex:
not specified
Dose descriptor:
LC50
Effect level:
17 600 ppm
95% CL:
15 400 - 20 300
Exp. duration:
6 min
Sex:
not specified
Dose descriptor:
LC50
Effect level:
7 340 ppm
95% CL:
6 550 - 8 230
Exp. duration:
20 min
Sex:
not specified
Dose descriptor:
LC50
Effect level:
5 290 ppm
95% CL:
5 050 - 5 530
Exp. duration:
60 min
Mortality:
6 min exposure: concentrations of 13,700; 15,400; 17,400; 17,500; and 19,900 ppm resulted in deaths of 20, 40, 50, 50, 60 %, respectively
20 min exposure: concentrations of 4,620; 5,940; 7,740; 7,860; and 8,860 ppm resulted in deaths of 0, 40, 50, 50, 80 %, respectively
60 min exposure: concentrations of 4,900; 5,040; 5,080; 5,120; and 5,920 ppm resulted in deaths of 20, 10, 40, 70, 80 %, respectively
Clinical signs:
other: The significant pharmacotoxic signs noted either immediately after the exposures or during the 14 day post-exposure period were: death, laborated breathing, gasping, rales, and corneal opacities. Most deaths occured on post-exposure days 1 and 2, with one
Body weight:
For all three exposure durations body weight gain for surviving animals was generally depressed during the first post-exposure week, but recovered during the second post-exposure week.
Gross pathology:
At necropsy, eye abnormalities (usually corneal opacities) and lung congestion (red discoloration) were the significant macroscopic findings. There were no significant differences between three exposure durations.
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
H332: Harmful if inhaled,
H335: May cause respiratory irritation
Executive summary:

The International Research and Developmental Corporation tested in 1992 the acute toxicity by inhalation of dimethylamine with rats (strain: Charles River Crl:cd BR VAF/Plus; Sprague-Dawley derived). The route of exposure was inhalation by whole body exposure. The exposure times were 6 - 60 minutes with different concentrations (ranging from 4,620 to 19,900 ppm). Different clinical signs, changes in body weight and also mortality (20, 40, 50, 50, 60% deaths (6 min exposure), 0, 40, 50, 50, 80 % death (20 min exposure), or 20, 10, 40, 70 and 80 % death (60 min exposures)) was reporteThis

The one hour value (LC50 = 5290 ppm = 9753.51 mg/m³) needs to be converted to a value comparable to a 4 hour LC50. This can be done as described in ECHA Guidance on the application of the CLP criteria, v5.0, July 2017, footnote c to Table 1 3.1.1 of Annex I to the CLP Regulation and Section 3.1.2.2): by dividing it by a factor of 2. (LC50 for CLP = 2645 ppm = 4876.76 mg/m³. This value is then also reported in the endpoint summary as key value.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
4 876.76 mg/m³
Quality of whole database:
Remark on Key study: The one hour value given in the Key study (LC50 = 5290 ppm = 9753.51 mg/m³) needs to be converted to a value comparable to a 4 hour LC50. This can be done as described in ECHA Guidance on the application of the CLP criteria, v5.0, July 2017, footnote c to Table 1 3.1.1 of Annex I to the CLP Regulation and Section 3.1.2.2): by dividing it by a factor of 2. (LC50 for CLP = 2645 ppm = 4876.76 mg/m³. This value is then also reported in the endpoint summary as key value.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Method: other: dimethylamine was applied once for 24 hours to the clipped skin of the back and flank (area about 48 cm²) in a dose of 400, 2500, 3200, 4000 and 5000 mg/kg bw.
GLP compliance:
no
Test type:
other: no details given
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: WIga
- Weight at study initiation: male: 139 g (mean); female: 127 g (mean)

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure:
- % coverage: 48 cm²

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 h


Duration of exposure:
24 h
Doses:
400, 2500, 3200, 4000, 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Dose descriptor:
LD50
Effect level:
3 900 mg/kg bw
Mortality:
5000 mg/kg: 6 animals died after 24 hours
4000 mg/kg: 6 animals died after 24 hours, 1 animal after 48 hours
3200 mg/kg: 1 animal died after 1 hour; 2 animals died after 24 hours
2500 mg/kg: 1 animal died after 24 hours
400 mg/kg: no mortality occured
Clinical signs:
apathy, convulsions, crying
Body weight:
no data
Gross pathology:
Animals that died:
Heart: acute dilatation, congestive hyperemia
Liver: peripheral lobule marking
Lung: oedema

400 mg/kg after 24 hours: primary irritation

2500 - 500 mg/kg after 24 hours: necrosis, which remained unchanched after 14 days

Interpretation of results:
other: EU GHS criteria not met
Conclusions:
5000 mg/kg: 6 animals died after 24 hours
4000 mg/kg: 6 animals died after 24 hours, 1 animal after 48 hours
3200 mg/kg: 1 animal died after 1 hour; 2 animals died after 24 hours
2500 mg/kg: 1 animal died after 24 hours
400 mg/kg: no mortality occured
Executive summary:

In a study of BASF AG in 1980 rats were used for the occlusive administration of dimethylamine for a duration of 24 hours. The used concentrations were 400, 2500, 3200, 4000, and 5000 mg/kg bw. With the highest dosage 6 animals died after 24 hours, as well as with a dosage of 4000 mg/kg bw; whereby another animal died after 48 hours. By applicate dimethylamine in a concentration of 3200 mg/kg bw one animal died after 1 hour and two more animals after 24 hours. Just one animal died after 24 hours by the usage of 2500 mg/kg bw and no mortality occured by a dosage of 400 mg/kg bw. Apathy, convulsions, crying were the observed clinical symptons. In gross pathology acute dilation and congestive hyperemia of the heart was observed. The peripheral lobule of the liver was marked and oedema were observable in the lung.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 900 mg/kg bw

Additional information

In an oral acute toxicity study performed by BASF AG in 1980, DMA was administered to rats (test group consisting of 5 rats, strain: Sprague-Dawley/sex) by single gavage with an aqueous solution of the test substance. 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; animals that died during the observations period also were subjected to necropsy. The initial concentrations were 681, 1000, 1470, 2150, 3160 and 4640 mg/kg bw. As effect level the LD50 was considered to be around 1000 mg/kg bw. No animals died in the lowest groups, but 4/10 died in the dose group with 1000 mg/kg bw. All animals died in the 4 highest dose groups. Animals showed staggering, atony, spatic gait, exsiccosis, tremor, salivation, opisthotonus, poor general state, reduction in body weight, "morphinschwanz”. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependent manner.

The International Research and Developmental Corporation tested in 1992 the acute toxicity by inhalation of dimethylamine with rats (strain: Charles River Crl:cd BR VAF/Plus; Sprague-Dawley derived). The route of exposure was inhalation by whole body exposure. The exposure times were 6 - 60 minutes with different concentrations (ranging from 4,620 to 19,900 ppm). Different clinical signs, changes in body weight and also mortality (20, 40, 50, 50, 60 % deaths (6 min exposure), 0, 40, 50, 50, 80 % death (20 min exposure), or 20, 10, 40, 70 and 80 % death (60 min exposures)) was reported. So 3 different LC50 were determined: LC50(6min) = 17600 ppm (32.9 g/m³/6 min), LC50(20min) = 7340 ppm (13.7 g/m³/20 min) and LC50(60min) = 5290 ppm (9.9 g/m³/60 min).

The one hour value (LC50 = 5290 ppm = 9753.51 mg/m³) needs to be converted to a value comparable to a 4 hour LC50. This can be done as described in ECHAGuidance on the application of the CLP criteria, v5.0, July 2017, footnote c to Table 1 3.1.1 of Annex I to the CLP Regulation and Section 3.1.2.2): by dividing it by a factor of 2. (LC50 for CLP = 2645 ppm = 4876.76 mg/m³. This value is then also reported in the endpoint summary as key value.

An inhalation acute toxicity test was performed by a dynamic inhalation method by BASF AG (1979). Each 10 male and female rats (strain: Sprague-Dawley) were exposed to whole body gas inhalation within a time period of 4 hours. After the 4 h DMA exposure, the animals were observed for 14 days. The concentration of the test substance was nominal 7.23 mg/L (analytical: 5.87 mg/L). The LC50 value was determined to be greater than 5.9 mg/L air for both sexes. No animal died. Clinical symptoms occurring during exposure were: eye and nasal secretion, dyspnea, salivation, hunched posture, smeared fur, closed eyelid, high-stepping gait, snout wiping and flatulence.

The effects of DMA on the respiratory tract were investigated by Gross and colleagues in 1987. The distribution of lesions found in this study indicates that there is possibly a high rate of deposition of DMA in the anterior nasal passage. Gross et al. (1987) concluded that DMA toxicity is primarily attributable to the irritant properties of the parent compound with a possible role for the metabolites of DMA. The direct cytolethal effects of DMA causing frank tissue damage are most likely due to the one or both of these mechanisms. It is of interest that despite severe tissue destruction in the anterior nose following a single 6-hr exposure, the nasal lesions exhibited very little evidence of progression, even after 2 years of exposure. These findings indicate a possible regional susceptibility to DMA toxicity or a degree of adaptation by the rat to continued DMA exposure. Effects of DMA on nasal mucociliary function were apparent after a single 6-hr exposure and they exhibited minimal progression throughout the acute study. DMA-induced effects included almost complete reversal of mucus flow and ciliary beat in one region of the lateral wall and clear modification of flow patterns to provide clearance around areas of turbinate and septal destruction. Mucus pooling, seen between and over the turbinates of DMA treated rats, indicates that while the mucociliary apparatus can respond to damage by altering mucus flow patterns, it may not function optimally under these conditions. DMA-induced alteration of mucus flow patterns and ciliary beat direction may provide a useful tool for studies of factors which control this complex clearance system in the nose. The vacuolation of epithelial cytoplasm, induced by acute DMA exposure, was very severe in affected areas and was seen in both ciliated and nonciliated epithelial cells and ducts of underlying glands of the respiratory mucosa, while in the olfactory epithelium this change was largely confined to sensory cells.

BASF AG performed a test for acute toxicity by dermal application in 1980. Dimethylamine was applied once for 24 hours to the clipped skin of the back and flank (area about 48 cm²) unchanged in a dose of 5000, 4000, 3200, 2500 or 400 mg/kg bw. The coverage of the treated area was creating occlusive conditions. The treated area of skin was then covered with an inert foil, which was secured in position with adhesive tape. The bandage was removed after an exposure period of 24 hours; subsequently, the test substance was washed off with warm water or a mixture of water/Lutrol and dried with cellulose. Mortality was observed as well as abnormalities in gross pathology. Clinical signs were systemic (apathy, convulsions, crying). With the highest dosage 6 animals died after 24 hours, as well as with a dosage of 4000 mg/kg bw; whereby another animal died after 48 hours. By application of dimethylamine in a concentration of 3200 mg/kg bw one animal died after 1 hour and two more animals after 24 hours. Just one animal died after 24 hours by the usage of 2500 mg/kg bw and no mortality occurred by a dosage of 400 mg/kg bw. Pathology performed revealed: acute dilatation of the heart, congestive hyperemia, peripheral lobule marking in the liver, and edema in the lung.

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during oronasal exposure to increasing concentrations of twenty aliphatic amines (Gagnaire et al., 1989). The breathing frequency was monitored before and during a 15-min exposure period. For each measurement, the maximum decrease in respiratory rate was recorded. Four to six different exposure concentrations were used, and six previously unexposed mice were used at each level. The airborne concentration resulting in a 50 % decrease in the respiratory rate of mice (RD50) was calculated for each test compound.

For DMA, the onset of action was very rapid, ca. 30 s to 1 min. 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. The different exposure concentrations produced a broad range of effects.

Previous studies with several chemicals have shown that the RD50 values can be used successfully to predict safe industrial exposure. At 0.1 RD50, humans would experience some slight discomfort and this should be the highest level permitted in industry. At 0.01 RD50 no sensory irritation is observed and a convenient threshold limit value (TLV) would be 0.3 RD50 the midpoint on a logarithmic scale between the 0.1 and 0.01 RD50. For dimethylamine, a TLV of 10 ppm seems too high and should be divided by a factor of two.

In conclusion, the experimental results indicate, that dimethylamine is of low acute toxicity in mammals: LD50rat (oral) > 1000 mg/kg bw/day, or - after concerion - a LC50rat (inhalative, originally 1 hour, converted to a value comparable to 4 hours) = 4876.76 mg/m³, LD50rat (dermal) > 3900 mg/kg bw/ day. The main symptoms following exposure were eye and nasal secretion, dyspnoea, salivation, hunched posture, smeared fur, closed eyelid, high-stepping gait, snout wiping, flatulence. The key study performed by the International Research and Development corporation, 1992, identified even 3 different LC50with unusual exposure durations. Still this study provides a lot of qualified and useful information. The result obtained from the experiments after 1 hour inhalation exposure were converted using a factor of 2 to obtain a value comparable to a 4 hour value. This fit really well to the results of BASF 1979, and the value will be used for Classification and Labelling.

Justification for classification or non-classification

Classification for acute toxicity is needed according to GHS:

DMA (aqueous solution) has been classified according to GHS:

- Acute Tox. 4 (H302: Harmful if swallowed)

- Acute Tox, 4 (H332: Harmful if inhaled)

- STOT -SE Cat 3 (H335: May cause respiratory irritation, Affected organs: respiratory tract, lungs)

DMA (gaseous) has been classified according to GHS:

- Acute Tox. 4 (H332: Harmful if inhaled);

- STOT - SE Cat 3 (H335: May cause respiratory irritation, Affected organs: respiratory tract, lungs).