N,N,N',N'-tetramethyltrimethylenediamine

Acute Toxicity: dermal

Administrative data

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)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

N,N,N',N'-tetramethyltrimethylenediamine

EC Number:

203-818-8

EC Name:

N,N,N',N'-tetramethyltrimethylenediamine

Cas Number:

110-95-2

Molecular formula:

C7H18N2

IUPAC Name:

N,N,N',N'-tetramethyltrimethylenediamine

Details on test material:

- Name of test material (as cited in study report): Tetramethylpropandiamin-1,3
- Analytical purity: 99%
- Physical state: liquid

Test animals

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

Administration / exposure

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

Results and discussion

Effect levels

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.

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.