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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions (mostly due to reduced reporting in times before GLP, e.g. no single animal data presented, results of preliminary test not reported, lacking information on animal husbandry, occlusive conditions)
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
mostly due to reduced reporting in times before GLP, e.g. no single animal data presented, results of preliminary test not reported, lacking information on animal husbandry, occlusive conditions
GLP compliance:
no
Remarks:
study performed before GLP statement
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine
EC Number:
907-605-7
Cas Number:
68815-47-4
Molecular formula:
C6H16N2 (HMD) C12H29N3 (BHT)
IUPAC Name:
Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine
Details on test material:
- Name of test material (as cited in study report): 22983 R.P. (produit technique); Bis Hexamethylene triamine, culot de distillation
- Physical state:solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Oncins, IFFA CREDO, France
- Weight at study initiation: 120-150 g

ENVIRONMENTAL CONDITIONS
no further details

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 6cm x 6cm
- Type of wrap if used: aluminium foil and adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with lukewarm soap water
- Time after start of exposure: 24 h (directly after patch removal)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.85 ml/kg
- Other: as the test material was solid at 24 °C as well as in between 32 and 34°C, the test material was heated to 37 °C, became fluid and was administered pure to the skin of test animals
TEST SITE
- Area of exposure:
- % coverage:
- Type of wrap if used:

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Constant volume or concentration used: yes/no
- For solids, paste formed: yes/no

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of exposure:
24 hours
Doses:
740, 1110, 1670, and 2500 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: one group of vehicle treated animals were kept in order to determine normal body weight development.
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: every 5th day (i.e. study day 0, 5, 10 and 15) for vehicle treated groups and animals treated with 740 mg/kg bw (which is the highest dose which did not produce deaths)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and gross pathology
Statistics:
LD50 value was calculated using the method of Litchfield and Wilcoxon.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 500 mg/kg bw
Based on:
test mat.
95% CL:
1 160 - 1 930
Remarks on result:
other: Within the 14 days observation period no animals died after single application of 740 mg/kg bw. 1/10, 8/10 and 9/10 animals died using 1110, 1670 and 2500 mg/kg bw respectively. Deaths occurred within 1 to 5 days post application.
Mortality:
740 mg/kg bw: 0 males and 0 females died
1110 mg/kg bw: 1/10 animals died, death occurred within 5 days after administration
1670 mg/kg bw: 8/10 animals died, death occurred within 2 to 5 days after administration
2500 mg/kg bw: 9/10 animals; death occurred 1 to 4 days after administration )
All animals that died were dead within 1 to 5 days after administration
Clinical signs:
740 and 1110 mg/kg bw: Less severe effects on motoric activity as described at the highest dose level.
1670 mg/kg bw: same symptoms as described in the high dose group with cachexia being obvious at treatment days 1 to 5 within the surviving animals.
2500 mg/kg bw: Agitation within the 1st hour post administration. One day after start of exposure animals displaying prostration with tremor and convulsions were seen. Moreover a decrease of body temperature and decline in breathing depth with ptosis was noted.
Body weight:
Treated animals showed slightly decreased body weight gains compared to untreated control animals. The difference being significant at 5 days post administration. However at the end of the study differences between treated and control animals were no more visible.
Gross pathology:
740 mg/kg bw: In 7 animals necrosis was obvious 7days after test item administration. In the other animals eschar formation was seen 7 days after dose administration and scarring began on day 14 after start of exposure.
1110 mg/kg bw: In 3 animals necrosis was obvious 2 hours after the patch removal. Eschar formation in the other animals started at day 7 after test item administration. Just before the end of the observation period scarring could be observed.
1670 mg/kg bw: in the surviviing animals (i.e. 2/10) beginning at three days after administration, necrosis was obvious. The edges were indured and persistet up until the end of the observation period.
2500 mg/kg bw: the only surviving animal showed induration of skin which began to recover from day 4 until the end of the observation period

Any other information on results incl. tables

  Bodyweight development: Bodyweights given as group mean [g]+/- standard deviation after "n" days in observation
 Dose level n=0   n= 5  n=10  n=15
 Control (untreated)  143 +/- 4.2 172 +/- 7.2   198.2 +/- 20.4  217 +/-27.8
 740 mg/kg bw of test item  143.5 +/-2.1 t = 0.34 n.s. 160.3 +/-7.3 t = 3.77 s.s.   194.5 +/-11.6 t = 0.49 n.s. 210.5 +/-19.5 t = 0.6 n.s. 

n.s. difference to control group not statistically significant

s.s. difference to control group statistically significant

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Acute toxicity category 4 Criteria used for interpretation of results: EU
Conclusions:
After single dermal application of either 740, 1110, 1670 or 2500 mg test substance per kg onto the skin of male and female rats lethality could be observed during the 14 day observation period, resulting in a LD50 of 1500 mg/kg bw.
Executive summary:

Acute dermal toxicity was investigated using male and female Sprague-Dawley rats in a test similar to acute standard method (i.e. OECD TG 402, non GLP). The test substance was administered to the skin for 24 hours under occlusive conditions at doses of 740, 1110, 1670 and 2500 mg/kg bw to 4 groups of 10 animals (5animals/sex).

Clinical signs (dyspnea, agitation, apathy, atonia (with tremor and convulsions), hypothermia, cachexia) were observed starting from the mid-dose group. Within the 14 days observation period no animals died after single application of 740 mg/kg bw. 1/10, 8/10 and 9/10 animals died using 1110, 1670 and 2500 mg/kg bw respectively. Deaths occurred within 1 to 5 days post application. Having this results a median lethal dose (LD50) of 1500 mg/kg bw was identified for acute dermal toxicity.