N,N,N',N'-tetramethyltrimethylenediamine

Endpoint summary

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

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 or test system 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:

other: - 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 applica

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 or test system 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 air

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

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 or test system 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:

other: 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 result

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).