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Toxicological information

Acute Toxicity: dermal

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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.

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.