Registration Dossier

Administrative data

Description of key information

The acute oral LD50 of N, N, N', N'-tetramethyltrimethylenediamine is 624 mg/kg in rats and the acute dermal LD50 is 1180 mg/kg in rat. The 4 hour-exposure LC50 is higher than 1000 ppm (5300 mg/m3) in rats.

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 (limited characterisation of test substance, reduced documentation of test animal welfare)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(limited documentation on test substance and test animals)
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.
Test groups 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 14 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: Gassner
- Mean weight at study initiation: 189 g (males); 164 g (females)
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 8 %

MAXIMUM DOSE VOLUME APPLIED: ca. 15 mL/kg bw

Doses:
400, 500, 640, 800, 1000, 1250 µL/kg bw (312, 390, 500, 624, 780, 975 mg/kg bw - based on the density d=0.78 g/cm³)
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 observation: daily
- Frequency of weighing: days 0, 3, 7 and 13
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
0.8 mL/kg bw
Sex:
male/female
Dose descriptor:
LD50
Effect level:
624 mg/kg bw
Based on:
test mat.
95% CL:
> 500 - < 780
Remarks on result:
other: based on the density d=0.78 g/cm³
Mortality:
975 mg/kg: 9/10 (2 males and 4 females died within 6 h post application. 3 further males died within 24 h post application.)
780 mg/kg: 7/10 (1 male and 2 females died within 24 h post application. 3 further males and 1 further female died within 7 days post application.)
624 mg/kg: 4/10 (1 female died within 24 h. 2 further females and 1 male died within 7 days.)
500 mg/kg: 1/10 (1 male died within 48 h.)
390 mg/kg: 1/10 (1 female died within 14 days.)
312 mg/kg: 1/10 (1 female died within 48 h.)
Clinical signs:
- 975 and 780 mg/kg: immediately after application: accelerated respiration; 1 h post application: abdominal position, mouth discharge, chewing reflex, in some animals dyspnoea; 3 h post application: red smeared snouts and ruffled fur; 2 days post application: crouched position, irregular gasping, agglutinated eyes and snouts, ruffled fur
- 624 and 500 mg/kg: in the first hours after application: accelerated respiration; 3 h post application: crouched position and ruffled fur; 3 days post application: crouched position, gasping, agglutinated eyes and snouts, ruffled fur
- 390 and 312 mg/kg: on day 1 post application: accelerated respiration and crouched position; 3 days post application: gasping and crouched position
Body weight:
Animals lost weight in the first 3 days post treatment but regained weight until the end of the observation period.
Gross pathology:
Animals that died during observation period: acute passive hyperemia; acute dilatation of the heart; glandular stomach reddened diffusely; isolated ulcerations; diarrhetic contents of the intestines; acinar pattern of the liver

Sacrificed animals: 975 mg/kg: 1x thickened forestomach-epithelium

Mortality:

 Dose: (mg/kg)

 Gender

 1 h

 24 h

 48 h

 day 7

 day 14

 975

 male

 0/5

 5/5

 5/5

 5/5

 5/5

 975

 female

 0/5

 4/5

 4/5

 4/5

 4/5

 780

 male

 0/5

 1/5

 3/5

 4/5

 4/5

780 

 female

 0/5

 2/5

 2/5

 3/5

 3/5

 624

 male

 0/5

 0/5

 0/5

 1/5

 1/5

 624

 female

 0/5

 1/5

 1/5

 3/5

 3/5

 500

 male

 0/5

0/5 

 1/5

 1/5

 1/5

 500

 female

 0/5

 0/5

 0/5

 0/5

 0/5

 390

 male

 0/5

 0/5

 0/5

 0/5

 0/5

 390

 female

 0/5

 0/5

 0/5

 0/5

 1/5

 312

 male

 0/5

 0/5

 0/5

 0/5

0/5 

 312

 female

 0/5

 0/5

 1/5

 1/5

 1/5

 

Weight (g):

Dose (mg/kg)

 Gender

 day 0

 day 3

 day 7

 day 13

 975

 male

 168

 -

 -

 -

 780

 male

 192

 171

 206

 246

 624

 male

 186

 164

 184

 211

 500

 male

 194

 175

 211

 231

 390

male 

 180

 174

207 

 210

 312

 male

 193

 200

 229

 236

 

 

 

 

 

 

 975

female 

 163

 143

 158

 159

 780

 female

 163

 149

 157

 172

 624

 female

 165

 154

 149

 231

 500

 female

 164

 147

 173

 173

 390

 female

 165

 146

 150

170 

 312

 female

 166

 178

 168

 181

Harmful if swallowed. There is indication that the test substance causes local irritation to exposed tissue.

 

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Executive summary:

The Acute oral toxicity of Tetramethylpropylendiamine (TMPDA) was evaluated in rats according an internal BASF method, which in principle is comparable to the OECD Guideline 401.

A test group consisting of 5 Sprague-Dawley rat/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 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 LD50 value was estimated on the basis of the observed mortalities.

At 975 mg/kg, 2 males and 4 females died within 6 h after treatment. 3 further males died within 24 after treatment.

At 780 mg/kg, 1 male and 2 females died within 24 h after treatment. 4 males and 3 females died within 7 days after treatment.

At 624 mg/kg, 1 female died within 24 h. 3 females and 1 male died within 7 days.

At 500 mg/kg, 1 male died within 48 h.

At 390 mg/kg, 1 female died within 14 days. 312 mg/kg: 1 female died within 48 h.

Under these experimental conditions, the oral LD50 of TMPDA is 624 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
624 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: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Six rats are exposed during 4hours to 1000ppm.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Carworth-Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing:no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: To:no data
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: no data
- Exposure chamber volume: no data
- Method of holding animals in test chamber: no data
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating particulates/aerosols:no data
- Method of particle size determination: no data
- Treatment of exhaust air:no data
- Temperature, humidity, pressure in air chamber: no data


TEST ATMOSPHERE
- Brief description of analytical method used: no
- Samples taken from breathing zone: no
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
ca. 4 h
Concentrations:
1000 ppm (5.32 mg/L)
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: no data
Sex:
male
Dose descriptor:
LC50
Effect level:
> 1 000 ppm
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
> 5.32 mg/L air
Exp. duration:
4 h
Mortality:
2/6
Clinical signs:
other: No data
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, the inhalation LC50 of TMPDA is higher than 1000 ppm (5.32 mg/l) in male.
Executive summary:

The Acute inhalation toxicity of Tetramethylpropylenediamine (TMPDA) was evaluated in one group of 6 rats. The 4-hour exposure at 1000 ppm caused death in 2/6rats.

Under these experimental conditions, the inhalation LC50 of TMPDA is higher than 1000 ppm (5.32 mg/l) in male.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5 300 mg/m³

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 (occlusive treatment)
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
(occlusive treatment)
GLP compliance:
not specified
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, Germany
- Age at study initiation: about 12 weeks
- Mean weight at study initiation: 212 g (males); 190 g (females)
- Housing: housing of individual animals during the exposure period (24 hours). lf there are no lesions afterward, the animals are kept in groups.
- Diet: Ssniff R; Ssniff Versuchstierdiaeten, Soest, Germany; ad libitum
- Water: fulIy demineralized water ad libitum each workday; tap water ad libitum on public holidays
- Acclimation period: at least 1 week.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26 °C
- Humidity (%): 45-75 %
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: 50 cm²

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 ml
- Concentration (if solution): 50%, 10% or 4.64%


Duration of exposure:
24 h
Doses:
2500, 1000 or 464 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: Recording of signs and symptoms <15min, 15min, 30min, 1h, 2h, 4h and 5h after test substance administration and then once each workday. Check for moribund and dead animals twice each workday and once daily at weekends and on public holidays.
- Frequency of weighing: day 0, 2, 7 and 13
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 1 180 mg/kg bw
Based on:
test mat.
95% CL:
> 1 000 - < 2 500
Remarks on result:
other: 3/10 animals died within 7 days in the 1000 mg/kg bw dose group; LD50 determined by interpolation
Mortality:
- 2500 mg/kg bw: all animals died within 24 h.
- 1000 mg/kg bw: 1 male and 1 female died within 48 h and 1 further female died within 7 days.
- 464 mg/kg bw: no animal died within the observation period.
Clinical signs:
Symptoms: dyspnoea, apathy, excitation, spastic gait, poor general state (see details in table in remarks on results)
Local findings: erythema, necrosis, ruptured necrosis, edema, scaling, anaemia, scar formation (see details in table in remarks on results).
Body weight:
The animals from all dose groups lost weight in the first days after treatment but regained weight after 7 days.
Gross pathology:
Animals that died: application site: severe hyperemia of muscles and subcutis; peritoneum blunt; general passive hyperemia.

Sacrificed animals: several animals with scabbed, extensive necroses at the margin of the application area; striated necroses in isolated animals.

Mortality:

 Dose (mg/kg)

 Gender

 Conc. (%)

 1 h

 24 h

 48 h

 day 7

 day 14

 2500

male 

 50

 0

 5

 5

 5

 5

 2500

female

 50

 0

 5

 5

 5

 5

 1000

male

 10

 0

 0

 1

 1

 1

 1000

female

 10

 0

 0

 1

 2

 2

 464

male

 4.64

 0

 0

 0

 0

 0

 464

female

 4.64

 0

 0

 0

 0

 0

 

Weight: (g)

 Dose (mg/kg)

 Gender

 day 0

 day 2

day 7 

 day 13

 2500

 male

 207

 -

 -

 -

 1000

 male

 215

 197

 223

 271

  464

 male

 214

 203

 241

 277

 2500

 female

 186

 -

 -

 -

 1000

female

 192

 181

 191

 217

  464

 female

 194

 186

 204

 216

Signs and symptoms:

 Symptoms:

 2500   mg/kg bw

 1000   mg/kg bw

 464   mg/kg bw

 

 male

 female

 male

 female

 male

 female

 Dyspnoea

 15 min - 4 h

 15 min - 4 h

 30 min - 6 d

30 min - 6 d 

 30 min - 5 d

 30 min - 5 d

 Apathy

 15 min - 4 h

 15 min - 4 h

 30 min - 6 d

 30 min - 6 d

 30 min - 5 d

 30 min - 5 d

 Excitation

 < 15 min

 < 15 min

  - 15 min

 - 15 min

  - 15 min

 - 15 min

 Spastic gait

 15 min - 4 h

 15 min - 4 h

 2 d

 2 d- 5 d

 2 d

 2 d

 Aggressiveness

 -

 -

 -

 2 d

 -

 -

 Poor general state

 < 15 min - 4 h

 < 15 min - 4 h

 30 min - 6 d

 15 min - 6 d

30 min - 5 d 

 30 min - 5 d

min: minutes; h: hours; d: day

Local findings:

 Dose (mg/kg)

 2500

 1000

 464

Erythema

 -

 7 d -13 d

 7 d - 13 d

Necrosis

 -

 1 d - 13 d

 1 d - 13 d

Ruptured necrosis

 -

 13 d

 -

Edema

 -

 1 d - 13 d

 1 d - 7 d

Scaling 

 -

 7 d - 13 d

 7 d

Anaemia

 -

 1 d

  1 d

Scar formation

 -

 -

 13 d

h: hours; d: day

Executive summary:

The acute dermal toxicity of N,N,N',N'-tetramethylpropane-1,3-diamine (TMPDA) was evaluated in rats according to OECD N° 402 guideline. TMPDA was applied to the skin of groups of 5 male and 5 female Wistar rats at doses of 464, 1000 and 2500 mg/kg under an occlusive dressing for 24 hours. The application area was then washed with warm water. Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14). At 2500 mg/kg, all animals died within 24 h. At 1000 mg/kg, 1 male and 1 female died within 48 h and 1 further female died within 7 days. Systemic clinical signs observed were: dyspnea, apathy, excitation, spastic gait, poor general state. Local effects observed were: erythema, necrosis, ruptured necrosis, edema, scaling, anemic, scar formation. Animals found dead showed severe hyperemia of muscles and subcutis, peritoneum blunt and general passive hyperemia at the application site. Sacrificed animals showed scabbed, extensive necroses at the margin of the application area, striated necroses in isolated animals. Under these experimental conditions, the dermal LD50 of TMPDA is 1180 mg/kg in male and female Wistar rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 180 mg/kg bw

Additional information

Acute oral

The Acute oral toxicity of N, N, N', N'-tetramethyltrimethylenediamine (TMPDA) was evaluated in rats according an internal BASF method, which in principle is comparable to the OECD Guideline 401 (BASF, 1974). A test group consisting of 5 Sprague-Dawley rat/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 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 LD50 value was estimated on the basis of the observed mortalities.

At 975 mg/kg, 2 males and 4 females died within 6 h after treatment. 3 further males died within 24 after treatment.

At 780 mg/kg, 1 male and 2 females died within 24 h after treatment. 4 males and 3 females died within 7 days after treatment.

At 624 mg/kg, 1 female died within 24 h. 3 females and 1 male died within 7 days.

At 500 mg/kg, 1 male died within 48 h.

At 390 mg/kg, 1 female died within 14 days. 312 mg/kg: 1 female died within 48 h.

Under these experimental conditions, the oral LD50 of TMPDA is 624 mg/kg in rats.

According to Smyth (1969), the oral LD50 of TMPDA is 0.41 ml/kg (0.31 -0.53) or 320 mg/kg (242-414mg/kg) in male Carworth-Wistar rats.

Acute inhalation

The Acute inhalation toxicity of N, N, N', N'-tetramethyltrimethylenediamine (TMPDA) was evaluated in one group of 6 rats (Smyth 1969). The 4 hour-exposure at 1000 ppm caused death in 2/6 rats and allowed to determine an inhalation LC50 higher than 1000 ppm (5300 mg/m3).

The toxicity of an atmosphere saturated with vapour of TMPDA was evaluated at the temperature 20 °C (BASF, 1974). Groups of 6 male and female rats were exposed to the vapour, generated by bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 10 min or 30 min. The documentation of mortality and clinical signs was performed over a period of 8 days. One male died 1 hour after a 30-min exposure to 39 mg/L. During exposure at this concentration, escape attempts, gasping, clear partially bloody nose discharge were observed, immediately after exposure: animals showed imbalance, accelerated respiration and apathy, after 24 h, slight dyspnoea and apathy, bloody nose crusts were noted. All symptoms were reversible within 4 days. No animals died within the observation period after a 10 min exposure to 40.3 mg/L. During exposure at this concentration, escape attempts, clear partially bloody nose and eye discharge, and gasping were observed. All symptoms were reversible within 1 day. All animals gained weight. General venous passive hyperemia, slight pulmonary edema, and acute dilatation of the heart bilaterally were observed in animal that died. No abnormalities were observed in the sacrificed animals.

Acute dermal

The acute dermal toxicity of N, N, N', N'-tetramethyltrimethylenediamine (TMPDA) was evaluated in rats according to OECD N° 402 guideline (BASF, 1982). TMPDA was applied to the skin of groups of 5 male and 5 female Wistar rats at doses of 464, 1000 and 2500 mg/kg under an occlusive dressing for 24 hours. The application area was then washed with warm water. Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14). At 2500 mg/kg, all animals died within 24 h. At 1000 mg/kg, 1 male and 1 female died within 48 h and 1 further female died within 7 days. Systemic clinical signs observed were: dyspnea, apathy, excitation, spastic gait, poor general state. Local effects observed were: erythema, necrosis, ruptured necrosis, edema, scaling, anemic, scar formation. Animals found dead showed severe hyperemia of muscles and subcutis, peritoneum blunt and general passive hyperemia at the application site. Sacrificed animals showed scabbed, extensive necroses at the margin of the application area, striated necroses in isolated animals. Under these experimental conditions, the dermal LD50 of TMPDA is 1180 mg/kg in male and female Wistar rats.

The acute dermal toxicity of N, N, N', N'-tetramethyltrimethylenediamine (TMPDA) was evaluated in 4 male rabbits. Animals were immobilized during the 24-hour contact and then caged during the 14 day-observation period (Smyth et al., 1969). Under these experimental conditions, the dermal LD50 of TMPDA is 234 mg/kg (164 -328 mg/kg) in rabbits.


Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – inhalation endpoint
Key study

Justification for selection of acute toxicity – dermal endpoint
Key study

Justification for classification or non-classification

Acute oral toxicity:

The oral LD50of N, N, N', N'-tetramethyltrimethylenediamine was 624 mg/kg in rats. In accordance with Regulation (EC) No 1272/2008, TMPDA shall be classified as Acute Tox. 4 (Hazard statement: H302; Harmful if swallowed) and in accordance with Annex VI of Commission Directive 2001/59/EC, TMPDA shall be classified as being harmful if swallowed (R22).

Acute inhalation toxicity:

The LC50of N, N, N', N'-tetramethyltrimethylenediamine was higher than 5.3 mg/L in rats (but probably lower than 10 mg/L). On the basis of this study and in accordance with Regulation (EC) No 1272/2008 TMPDA shall be classified as Acute Tox. 3 (Hazard statement: H331; Toxic if inhaled) and in accordance with Annex VI of Commission Directive 2001/59/EC, N, N, N', N'-tetramethyltrimethylenediamine shall be classified as being harmful by inhalation (R20).

Acute dermal toxicity:

The percutaneous LD50 of N, N, N', N'-tetramethyltrimethylenediamine was 1180 mg/kg in rats. On the basis of this study and in accordance with Regulation (EC) No 1272/2008 TMPDA shall be classified as Acute Tox. 4 (Hazard statement: H312; Harmful by skin contact) and in accordance with Annex VI of Commission Directive 2001/59/EC, N, N, N', N'-tetramethyltrimethylenediamine shall be classified as being harmful by skin contact (R21).