Registration Dossier

Administrative data

Description of key information

LD50 (oral gavage, rat) = 973 mg/kg bw (based on a data on trimethylamine)

LD50 (dermal, rat) > 5000 mg/kg bw (based on a data on trimethylamine)

LC50 (inhalation, rat, 4h) = ca. 3500 ppm.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

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.
Qualifier:
equivalent or similar to
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 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:
Animals of the two highest doses showed dyspnoea, apathy, aggressiveness, staggering, tremor, spastic gait, ruffled fur, diarrhea, exsiccosis, agglutinated snouts and poor general state.
Body weight:
See details in remarks on results.
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:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: not specified
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, diarrhea, exsiccosis, agglutinated snouts and poor general state. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependend manner.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached document in section 13 "Assessment reports" for justification and rationale for read across analogy approach.
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
972.82 mg/kg bw
95% CL:
> 834.39 - < 1 144.27
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the analogy approach with the trimethylamine (source substance), the LD50 value of the target substance for acute oral toxicity was defined at 972.82 mg/kg bw. Hence, according to CLP criteria, the target substance, trimethylamine N-oxide was classified as Acute Tox. 4 H302.
Executive summary:

An analogy approach was performed on the trimethylamine N-oxide (target substance) in order to assess the potential health toxicity. The analogy was made with the trimethylamine (source substance).Based on the current litterature, the trimethylamine was extensively metabolized in trimathylamine N-oxyde. This metabolic process takes place in the liver of human or rodent species (rat) by the FMO enzyme. Hence, the systemic toxicity of the trimethylamine can be attributed to its metabolite, the trimethylamine N-oxide.

Acute oral toxicity was in the range of applicability of the analogy approach. This endpoint covered systemic toxicity after oral acute exposure (gavage). The LD50 value obtained for the trimethylamine can be attributed to the target substance trimethylamine N-oxide.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
973 mg/kg bw
Quality of whole database:
Reliability 2 (reliable with restrictions)

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test:
2 groups of 6 male Crl:CD(SD)BR rats were exposed for single, 4h periods. The rats were observed and weighed daily for 14 d, at which time the surviving rats were sacrificed (without pathologic examination).
GLP compliance:
not specified
Test type:
fixed concentration procedure
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: supplied by the Chemicals and Pigments Department, E. I. du Pont de Nemours and Company, Inc., Belle, W.V.
- Impurities: 0.06% dimethylamine, 0.01 % monomethylamine, and 0.17% water
- Expiration date of the lot/batch: no data
- Purity test date: no data
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, N.Y.
- Age at study initiation: 7-8 wk old
- Weight at study initiation: between 234 and 293 g
- Fasting period before study: not specified
- Housing: in 8 x 14 x 8 in. suspended, steel-mesh cages
- Diet: Purina Certified Rodent Chow 5002 ad libitum
- Water: ad libitum
- Acclimation period: quarantined for 1 wk prior to testing

ENVIRONMENTAL CONDITIONS
- Temperature: 23 ± 2°C
- Humidity: 50 ± 10%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): timer-controlled 12/12-h light/dark cycle.

IN-LIFE DATES: no data
Route of administration:
inhalation: gas
Type of inhalation exposure:
not specified
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
no additional information

TEST ATMOSPHERE
no analysis
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
2000 ppm and 3500 ppm
No. of animals per sex per dose:
six males per group
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: no
Statistics:
not applicable
Sex:
male
Dose descriptor:
LC0
Effect level:
2 000 ppm
Based on:
test mat.
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
ca. 3 500 ppm
Based on:
test mat.
Exp. duration:
4 h
Mortality:
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.
Surviving rats showed 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 post exposure period.
Clinical signs:
other: During exposure, all rats showed labored breathing, nasal and oral discharges, and neither moved nor responded to sound.
Body weight:
Surviving rats showed moderate to severe weight losses 1-2 d post exposure.
Gross pathology:
not examined
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
A 4-hour LC50 (gas) of ca. 8.58 mg/L was determined (equivalent to 3500 ppm).
Executive summary:

In an acute inhalation study, 2 groups of 6 male Crl:CD(SD)BR rats were exposed for single, 4h periods. The tested concentrations were 2000 ppm and 3500 ppm The rats were observed and weighed daily for 14 d, at which time the surviving rats were sacrificed (without pathologic examination).

No deaths occurred following a 4h exposure to 2000 ppm TMA whereas 3 of 6 rats exposed to 3500 ppm died during the exposure period. During exposure, all rats showed labored 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.

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached document in section 13 "Assessment reports" for justification and rationale for read across analogy approach.
Reason / purpose:
read-across source
Sex:
male
Dose descriptor:
LC0
Effect level:
2 000 ppm
Based on:
test mat.
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
ca. 3 500 ppm
Based on:
test mat.
Exp. duration:
4 h
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
10 900 mg/m³
Quality of whole database:
Reliability 2 (reliable with restrictions)

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

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:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
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 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:
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.
Body weight:
no data
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).

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:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
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:
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:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached document in section 13 "Assessment reports" for justification and rationale for read across analogy approach.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Reliability 2 (reliable with restrictions)

Additional information

The data are obtained from the similar substance trimethylamine (TMA)

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 did die within the first 24 hours. Animals of the two highest doses showed dyspnoea, apathy, aggressiveness, staggering, tremor, spastic gait, ruffled fur, diarrhea, exsiccosis, agglutinated snouts and poor general state. The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependend manner.

Acute toxicity: dermal

BASF AG performed a test for acute toxicity by dermal application in 1979. TMA 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).

Acute toxicity: inhalation

In an acute inhalation study (Kinnley, 1990), 2 groups of 6 male Crl:CD(SD)BR rats were exposed for single, 4h periods. The tested concentrations were 2000 ppm and 3500 ppm The rats were observed and weighed daily for 14 d, at which time the surviving rats were sacrificed (without pathologic examination).

No deaths occurred following a 4h exposure to 2000 ppm TMA whereas 3 of 6 rats exposed to 3500 ppm died during the exposure period. During exposure, all rats showed labored 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.

Justification for classification or non-classification

A Klimisch-2-rated study on acute oral toxicity with the source substance TMA revealed a LD50 of 766 mg/kg bw, equivalent to 973 mg TMAO/kg bw. This value justifies a classification as Acute Tox. 4 - H302 Harmful if swallowed.

A Klimisch-2-rated study on acute dermal toxicity with the source substance TMA revealed a LD50 > 5000 mg/kg bw. No classification for acute dermal toxicity according to the CLP criteria is thus required.

A Klimisch-2-rated study on acute inhalation toxicity with the source substance TMA revealed a LC50 of 3500 ppm. This value justifies a classification as Acute Tox. 4 - H332 Harmful if inhaled.