Trimethylamine

Endpoint summary

Description of key information

Oral:
BASF AG, 1979. Bericht ueber die Gewerbetoxikologische Grundpruefung. Report Nr. 77/361; rats, gavage, 215, 316, 464, 681 and 1000 mg/kg bw
Nagata, Toxicity Testing Reports of Environmental Chemicals, v. 8 (1), p 41-43, Crj: CD(SD)IGS rats, gavage, 125, 200, 320, 512, 820 and 1310 mg/kg bw
Huntingdon Research Centre plc, Acute oral toxicity to rats of trimethylamine hydrochloride salt 58 % solution, HC/CFY (Remote Sprague-Dawley) rats, gavage, 2.0 g/kg bw

Inhalation:

Kinney, L. A. ; Burgess, B. A. ; Chen, H. C. ; Kennedy, G. L., 1990: Inhalation Toxicology of Trimethylamine

BASF AG, 1979. Bericht über die Bestimmung der akuten Inhalationstoxizitaet LC50 von Trimethylamin als Gas bei 4stuendiger Exposition an Sprague-Dawley-Ratten, Report Nr. 77/361a, rats, whole body, 6.23 mg/L (analytical: 5.91 mg/L).

E. I. du Pont de Nemours & Company (1983). Subacute inhalation toxicity of anhydrous trimethylamine.

Koch et al., 1980

BASF AG, 1979. Industrial Hygiene orienting investigation, Report Nr. 77/361; rats, inhalation vapour, 3 min, 545 mg/L

International Research and Developmental Corporation, 1992, Acute inhalation toxicity evaluation on trimethylamine in rats, rats, whole body, 6 min exposure: 18,600 ppm, 10 min exposure: 18,100 ppm, 20 min exposure were conducted at concentrations of 11,200; 12,700; 12,700; 14,100; 16,200 and 18,200 ppm, 60 min exposure were conducted at concentrations of 6,150; 7,100; 7,680; 7,720 and 8,170 ppm
Gagnaire., et al (1989). Nasal Irritation and Pulmonary Toxicity of Aliphatic Amines in Mice. JOURNAL OF APPLIED TOXICOLOGY, VOL. 9(5), 301-304 (1989), nose only, 15 min, no lethal effect at the highest test concentration (169 mg/m3).

Dermal:
BASF AG, 1979. Industrial hygiene orientating investigation, Report Nr. 77/361; rats, occlusive, 5000 , 2000 or 400 mg/kg bw.
BASF AG, 1979. Report Nr. 77/361, rats occlusive, 2000, 5000 mg/kg bw, 24 h

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

Study period:

22. Aug 1978 - 11. Oct 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented report which meets basic scientific principles.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

BASF-Test: The study was conducted according to an internal BASF method which in principle is comparable to the OECD Guideline 401.
A test group consisting of 5 animals/sex was treated by single gavage application with an aqueous solution of the test substance. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 7 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy.

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: WIGA
- Weight at study initiation: male: 220 g (mean); female: 178 g (mean)
- Fasting period before study: 15 - 20 h before application
- Diet: Herlian MRH; Eggermann; Germany, ad libitum
- Water: tap water ad libitum

Route of administration:

oral: gavage

Vehicle:

water

Doses:

215, 316, 464, 681 and 1000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: days 2-4, 7 and 13
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Animals were weighed before the experiment, and then on days 2-4, 7 and 13 of the experiment. Food was withheld from animals for a period of 15-20 hours before the application of the test substance, but water was available.  

Statistics:

A probit analysis was used to determine the LD50 value.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

766 mg/kg bw

95% CL:

654 - 901

Mortality:

No animals died in the three lowest groups, but 3/10 and 9/10 died in the two highest dose groups. No animals died in the first hour after administration of the test substance, but animals did die within the first 24 hours.

Clinical signs:

other: Animals of the two highest doses showed dyspnoea, apathy, aggressiveness, staggering, tremor, spastic gait, ruffled fur, diarrhoea, exsiccosis, agglutinated snouts and poor general state.

Gross pathology:

Animals that died:
Heart: acute dilatation and congestive hyperemia;
Lung: slight acute swelling;
Liver: peripheral lobule marking;
Stomach: corroded mucous membranes of glandular stomach, bloody content;
Intestine: atonic, corroded mucous membranes, slight hydrothorax

Mortality:

Dose (mg/kg bw)	1 h		24 h		48 h		7 days		14 days
	male	female	male	female	male	female	male	female	male	female
1000	0/5	0/5	4/5	4/5	4/5	5/5	4/5	5/5	4/5	5/5
681	0/5	0/5	0/5	1/5	0/5	1/5	1/5	2/5	1/5	2/5
464	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5
316	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5
215	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5

Mean weight (g):

Dose (mg/kg)	gender	day 0	day 2 - 4	day 7	day 13
1000	male	260	212	269	324
	female	190	-	-	-
681	male	190	170	217	259
	female	170	160	188	208
464	male	190	198	245	279
	female	170	185	201	210
316	male	190	211	249	254
	female	170	189	203	214
215	male	270	272	320	340
	female	190	199	214	222

The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependend manner.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependend manner.

Executive summary:

An acute toxicity study was performed by BASF AG in 1979 comparable to the OECD Guideline 401. A test group consisting of 5 rats (strain: Sprague-Dawley)/sex was treated by single gavage application with an aqueous solution of the test substance trimethylamine. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 7 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 215, 316, 464, 681, and 1000 mg/kg bw. As effect level LD50 was 766 mg/kg bw. No animals died in the three lowest groups, but 3/10 and 9/10 died in the two highest dose groups. No animals died in the first hour after administration of the test substance, but animals did die within the first 24 hours. Animals of the two highest doses showed dyspnoea, apathy, aggressiveness, staggering, tremor, spastic gait, ruffled fur, diarrhoea, exsiccosis, agglutinated snouts and poor general state. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependend manner.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

766 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: well-documented publication, which meets basic scientific principles

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

The need to more accurately determine both the qualitative and quantitative response to inhaled TMA prompted this investigation, in which they looked at the response of rats to inhaled TMA following both single and repeated exposures. No details on the principle of method used is given.

GLP compliance:

not specified

Specific details on test material used for the study:

Trimethylamine (TMA, CAS no. 75-50-3)

Species:

rat

Strain:

Crj: CD(SD)

Remarks:

male Crl:CD(SD)BR rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS - male Crl:CD(SD)BR rats
- Source: Charles River Breeding Laboratory, Kingston, N.Y.
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 7-8 wk old
- Weight at study initiation: weighing between 234 and 293 g
- Fasting period before study: not specified
- Housing: in 8 x 14 x 8 in. suspended, steel-mesh cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow 5002 ab libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: quarantined for 1 wk prior to testing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 50 ± 10%
- Air changes (per hr): nto specified
- Photoperiod (hrs dark / hrs light): timer-controlled 12/12-h light/dark cycle.

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Remarks:

Animals were placed in cylindrical stainless-steel holders equipped with conical nose pieces. The restrainers were inserted into face plates on the exposure chambers such that the nose of each rat protruded into the chamber.

Vehicle:

air

Details on inhalation exposure:

Animals were placed in cylindrical stainless-steel holders equipped with conical nose pieces. The restrainers were inserted into face plates on the exposure chambers such that the nose of each rat protruded into the chamber.
Atmosphere Generation: Caseous atmospheres of TMA were generated by dilution of pure TMA with air. Polyethylene gas sample bags were filled with TMA, and the gases were subsequently metered into a three-neck mixing flask with FMI (Fluid Metering Inc., Oyster Bay, N.Y) metering pumps. The pumps were chosen with capacities sufficient to produce the design concentrations of 75, 250, and 750 ppm when mixed with 15 L/min of dilution air. The diluted gases were directed into 20-L cylindrical glass exposure chambers.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Analyical verification in 30-min intervals during the exposures, by pumping air continuously into Miran model 1A infrared spectrometers at a flow rate of 5 L/min and analysis at 3.3 µm and comparison freshly prepared TMA standards.

Duration of exposure:

4 h

Concentrations:

2000 ppm
3500 ppm

No. of animals per sex per dose:

6 males per group

Details on study design:

- Duration of observation period following administration: 14 days (The rats were observed and weighed daily for 14 d, at which time the surviving rats were sacrificed (without pathologic examination).
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

8.6 mg/L air

Exp. duration:

4 h

Remarks on result:

other: given in original study as 3500 ppm

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

3 500 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: 3 of 6 rats exposed to 3500 ppm died during the exposure period

Remarks:

.

Sex:

male

Dose descriptor:

LC0

Effect level:

2 000 ppm

Remarks on result:

other: No death occurred following a 4-h exposure to 2000 ppm TMA

Remarks:

.

Mortality:

No deaths occurred following a 4-h exposure to 2000 ppm TMA;
3 of 6 rats exposed to 3500 ppm died during the exposure period

Clinical signs:

other: During exposure, all rats showed labored breathing, nasal and oral discharges, and neither moved nor responded to sound. Rats exposed to 3500 ppm also had dry red nasal and ocular discharge during the early stages of the postexposure period.

Body weight:

Surviving rats showed moderate to severe weight losses 1-2 d postexposure and lung noise from 1 to 9 d postexposure.

Gross pathology:

not performed

Acute Toxicity Study

In the acute experiment, no deaths occurred following a 4-h exposure to 2000 ppm TMA whereas 3 of 6 rats exposed to 3500 ppm died during the exposure period. During exposure, all rats showed laboured breathing, nasal and oral discharges, and neither moved nor responded to sound. Surviving rats showed moderate to severe weight losses 1-2 d postexposure and lung noise from 1 to 9 d postexposure. Rats exposed to 3500 ppm also had dry red nasal and ocular discharge during the early stages of the postexposure period.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

A LC50 (4 hours) of ca. 8.6 mg/L was determined (equivalent to 3500 ppm).

Executive summary:

Trimethylamine (TMA) is a pungent gas that occurs in nature and has many industrial applications, including use as an intermediate in the manufacture of many chemicals. The lowest lethal concentration following a single 4-h inhalation exposure was determined to be 3500 ppm. Croups of 10 male rats each were then exposed by nose-only inhalation 6 h/d, 5 d/wk for 2 wk to either 0 (control), 75, 250, or 750 ppm TMA. Rats were sacrificed either immediately following exposure or following a 14-d recovery period. Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to 750 ppm produced a decreased rate of weight gain in rats. Evidence of mild, reversible, polycytnemia was also seen in these rats. Effects of TMA were present in the nose, trachea, and lungs. Degenerative changes in the nose were reversible at 75 ppm, but not at 250 or 750 ppm. Mild emphysematous alveoli were seen in lungs of rats exposed to 750 ppm immediately following the exposures, but not after a recovery period. A no-observed-effect level for TMA under these test conditions was not determined, although the nasal effects seen at 75 nnm were minimal.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

8 600 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

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: Acceptable, well documented report which meets basic scientific principles. Similar to guideline study; not GLP, no information regarding gross necropsy

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

BASF test: The product was applied once for 24 hours to the clipped skin of the back and flank (area about 42 cm²) unchanged in a dose of 5000 , 2000 or 400 mg/kg bw. 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.

GLP compliance:

no

Test type:

standard acute method

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: 221 g (mean); female: 180 g (mean)
- Diet: Herlian MRH, ad libitum
- Water: tap water ad libitum

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE - Area of exposure: 42 cm
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Lutrol and Lutrol/water (1:1)
- Time after start of exposure: 24 h

Duration of exposure:

24 h

Doses:

400, 2000, 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: No mortalities occurred at highest dose.

Mortality:

No mortality occured

Clinical signs:

other: Systemic toxicity: irregular respiration, staggering, apathy, spastic gait. Local symptoms: after 24 h skin irritation was noted and after 14 days scaling of the skin was observed.

Gross pathology:

no abnormalities observed.

Interpretation of results:

GHS criteria not met

Conclusions:

No mortality occured at highest dose rate of 5000 mg/kg bw. Only clinical symptons were observed: irregular breathing, staggering, spastic gait and apathy. After 14 days animals were mostly free of clinical signs.

Executive summary:

BASF AG performed a test for acute toxicity by dermal application in 1979. Trimethylamine was applied once for 24 hours to the clipped skin of the back and flank (area about 42 cm²) unchanged in a dose of 5000 , 2000 or 400 mg/kg bw. 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. No mortality was observed, as well as no changes in body weight and no abnormalities in gross pathology. Clinical signs were differentiated in systemic (irregular respiration, staggering, apathy, and spastic gait) and local symptoms (skin irritation after 24 hours, scaling of the skin after 14 days).

Reference 2

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: Similar to guideline study; not GLP, no information regarding gross necropsy

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

BASF Internal Procedure

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

not specified

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

no details available

Duration of exposure:

24 hours

Doses:

2000, 5000 mg/kg bw

No. of animals per sex per dose:

3/sex/dose

Control animals:

not specified

Details on study design:

Animals were observed for 14 days after the application of the test substance to the shaved dorsal surface of the rat.
The average weight of the animals was 221 g (males) and 180 g (females).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: no further details available

Mortality:

No animals died.

Clinical signs:

other: Irregular breathing, staggering, spastic gait and apathy were observed. After 14 days animals were mostly free of clinical signs.

Interpretation of results:

GHS criteria not met

Conclusions:

Only clinical symptons were observed: irregular breathing, staggering, spastic gait and apathy. After 14 days animals were mostly free of clinical signs.

Executive summary:

According to an internal BASF procedure (1979), which is equivalent to OECD guideline 402 the acute dermal toxicity was investigated on 3 male and female rats each. As type of coverage occlusive was chosen, the exposure duration was 24 hours and the doses were 2000 and 5000 mg/kg bw. An LD50 greater than 5000 mg/kg bw was reported, due to the fact that no animal died at the highest dose concentration. Only clinical symptoms as irregular breathing, staggering, spatic gait and apathy were observed. After 14 days the animals were mostly free of these clinical signs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Additional information

Acute toxicity: oral

An acute toxicity study was performed by BASF AG in 1979 comparable to the OECD Guideline 401. A test group consisting of 5 rats (strain: Sprague-Dawley)/sex was treated by single gavage application with an aqueous solution of the test substance trimethylamine. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 7 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 215, 316, 464, 681, and 1000 mg/kg bw. As effect level LD50 was 766 mg/kg bw. No animals died in the three lowest groups, but 3/10 and 9/10 died in the two highest dose groups. No animals died in the first hour after administration of the test substance, but animals died within the first 24 hours. Animals of the two highest doses showed dyspnoea, apathy, aggressiveness, staggering, tremor, spastic gait, ruffled fur, diarrhoea, exsiccosis, agglutinated snouts and poor general state. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependent manner.

Nagata et.al. tested acute toxicity according to OECD guideline 401 with GLP. 5 male and female rats (strain: CD(SD)IGS) each were investigated with gavage concentration doses of 125, 200, 320, 512, 820, and 1310 mg/kg bw, whereby water was used as vehicle. The effect levels were reported with male as LD50 = 397 mg/kg bw and female as LD50 = 512 - 820 mg/kg bw.

Koch et al., tested the acute toxicity of trimethylamine in rats and found a LD50 of 460 mg/kg. However, were little details on the materials and methods used were available.

Data on the read across substance trimethylamine hydrochloride:

In 1984 the Huntingdon research corporation investigated the acute oral toxicity of trimethylamine hydrochloride in Crl:CD rats. At a concentration of 2 g/kg bw 3 of 10 rats died. The clinical signs were pilo-erection, lethargy, decreased respiratory rate and pallor of the extremities. The signs were accompanied by abnormal body carriage (hunched posture), abnormal gait (waddling) and ptosis amougst treated rats or body tremor and ataxia in the rats that subsequently died. In conclusion an approximate lethal concentration of anhydrous trimethylamine can be concluded to be around 2 g/kg bw.

Acute toxicity: inhalation

Exposure duration: 4 hours:

The acute inhalation toxicity of trimethylamine has been investigated in rats by Kinney et al., 1990. A LC50 (4 hours) of 8.6 mg/L was determined (a value of 8.6 mg/L corresponds to 8600 mg/m³ which is equivalent to 3557.25 ppm (taking into account the molecular mass of TMA of 59,1103 and the athmospheric pressure of 1013.25 mbar and a temperature of 25°C).

An inhalation acute toxicity test was performed by a dynamic inhalation method (comparable to OECD 403) 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. The concentration of the test substance was nominal 6.23 mg/L (analytical: 5.91 mg/L). A LC50 value greater than 5.9 mg/L air was determined for both sexes. No animal died. Clinical symptoms were during exposure gasping, nasal secretion and after exposure irregular respiration occurred. After 1 day all animals were without symptoms. The animals gained weight and no significant difference to historic controls was seen. Also no other abnormalities were reported.

The acute inhalation toxicity of trimethylamine was investigated in Crl:CD rats by E. I du Pont de Nemours & Company (1983). At a concentration of 3500 ppm 3 of 6 rats died. The clinical signs were gasping, laboured breathing, nasal and oral discharge, no movement, and no responses to sound. The rats exposed to 3500 ppm exhibited lacrimation and dry red nasal and ocular discharge. In conclusion an approximate lethal concentration of anhydrous trimethylamine can be set at 3500 ppm. According to Haskell Laboratory Acute toxicity Classification, this material is considered slightly toxic via inhalation exposure.

The acute inhalation toxicity of trimethylamine has been investigated in rats also by Kinney et al., 1990. A lowest lethal concentration (4 hours) of 8.6 mg/L was determined (a value of 8.6 mg/L corresponds to 8600 mg/m³ which is equivalent to 3557.25 ppm (taking into account the molecular mass of TMA of 59,1103 and the athmospheric pressure of 1013.25 mbar and a temperature of 25°C).

A publication of Koch et al., 1980 reports a LC50 (4 hours) value of 10.3 mg/L in mice.

Exposure duration: 3 min:

In addition, BASF AG (1979) performed an acute inhalation toxicity study in principle as OECD guideline 403. 6 male and female rats each were exposed to trimethylamine vapour in a limit test of 3 minutes duration and with a nominal concentration of 545 mg/L. All 12 animals died in the exposure time. Heavy escape attempts, reddish nasal secretion, gasping, intermittent respiration, cyanosis, and convulsions were observed as clinical symptoms. The hearts of the animals showed acute dilatation, acute congestive hyperemia, the lung was swelled to a moderate level.

Exposure duration: 1 -2 hours:

The International Research and Developmental Coorparation tested in 1992 the acute toxicity by inhalation of trimethylamine with albino rats (strain: 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 (6 min exposure: 18,600 ppm; 10 min exposure: 18,100 ppm ;20 min exposure were conducted at concentrations of 11,200; 12,700; 12,700; 14,100; 16,200 and 18,200 ppm; 60 min exposure were conducted at concentrations of 6,150; 7,100; 7,680; 7,720 and 8,170 ppm). Different clinical signs (6 min exposure: laboured breath, increased salivation and corneal opacity; 10 min exposure: death, gasping, rales, laboured breath, and corneal opacity; 20 min exposure: death, gasping, laboured breath, increased salivation and corneal opacity; 60 min exposure: death, gasping, laboured breath, rales and corneal opacity), changes in body weight (10 min exposure: body weight gain was depressed for males during post-exposure week 1 but had returned to a normal rate of gain for second post-exposure week. 20 min exposure: both males and females exposed to 11,200 and 12,700 ppm exhibited depressed weight gain during the first week post-exposure. Females continued to have depressed body weight at a normal rate. 60 min exposure: body weight gain during the first post exposure week was normal for females exposed to concentrations at or below 7,100 ppm while the males exhibited depressed weight at these exposure levels. At concentrations higher than 7,100 ppm, both males and females exhibited depressed body weight gain. At the second post-exposure week, all surviving animals exhibited normal body weight gain) and also mortality (20 min exposure: concentrations of 11,200; 12,700; 12,700; 14,100; 16,200 and 18,200 ppm resulted in deaths of 20, 60, 90, 90, 80, 100%, respectively 60 min exposure: concentrations of 6,150; 7,100; 7,680; 7,720 and 8,170 ppm resulted in deaths of 10, 30, 40, 30, and 70%, respectively. No mortality at 6 min exposure, 20 % death at single dose 10 min exposure) was observable.

Exposure duration: 15 min:

Gagnaire et.al. performed a RD50 test, based on depression of respiratory rate in nose-only exposed mice. 6 male mouse (Swiss OF1 (IFFA CREDO)) were exposed for 15 minutes to trimethylamine. As result a RD50 of 147 mg/m³ air was reported. No lethal effect was observed at the highest test concentration of 169 mg/m³.

Acute toxicity: dermal

BASF AG performed a test for acute toxicity by dermal application in 1979. Trimethylamine was applied once for 24 hours to the clipped skin of the back and flank (area about 42 cm²) unchanged in a dose of 5000 , 2000 or 400 mg/kg bw. 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. No mortality was observed, as well as no changes in body weight and no abnormalities in gross pathology. Clinical signs were differentiated in systemic (irregular respiration, staggering, apathy, and spastic gait) and local symptoms (skin irritation after 24 hours, scaling of the skin after 14 days).

According to an internal BASF procedure (1979), which is equivalent to OECD guideline 402 the acute dermal toxicity was investigated on 3 male and female rats each. As type of coverage occlusive was chosen, the exposure duration was 24 hours and the doses were 2000 and 5000 mg/kg bw. An LD50 greater than 5000 mg/kg bw was reported, due to the fact that no animal died at the highest dose concentration. Only clinical symptoms as irregular breathing, staggering, spatic gait and apathy were observed. After 14 days the animals were mostly free of these clinical signs.

Justification for classification or non-classification

Acute toxicity:

Classification and labelling for acute exposures is warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008:

GHS Classification & Labeling for Trimethylamine (aqueous solution): Acute tox. 4, H302: harmful if swallowed, H332: Harmful if inhaled.

The overall GHS Classification & Labeling for Trimethylamine (gaseous form) for acute inhalation is Acute tox. 4, H332: Harmful if inhaled. This is based on the evaluation of the available data, which shows that the LC50 is 8600 mg/m³.

Systemic target organ toxicity (single exposure):

TMA caused effects in treated animals which are inflammatory and irritating to respiratory tract. The effects occured at non-lethal dose levels. Therefore, classification and labelling for systemic organ toxicity after single exposure (STOT-SE) to TMA (aqueous and gaseous forms) is warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008:

STOT SE 3, H335: May cause respiratory irritation.