7-azatridecane-1,13-diamine

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines /standards

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

similar to OECD Guideline 401, but no single animal data presented

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no single animal data presented

GLP compliance:

no

Remarks:

study performed before GLP statement

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: Oncins, IFFA CREDO, France
- Weight at study initiation: 130-160 g

ENVIRONMENTAL CONDITIONS
no further details

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 5 ml/kg

Doses:

390, 590, 890, 1330, and 2000 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; weighing was done only the dose group which produced less than 10% mortality - here 390 mg/kg bw)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs,

Statistics:

LD50 value was calculated using the method of Litchfield and Wilcoxon.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 170 mg/kg bw

Based on:

test mat.

95% CL:

740 - 1 850

Remarks on result:

other: Within the 14 days observation period 1/10, 3/10, 1/10, 5/10 and 9/10 animals died using 390, 590, 890, 1330, and 2000 mg/kg bw respectively.Deaths occurred within day 1 to day 5 post dosing.

Mortality:

390 mg/kg bw: 1/10 animals died, death occurred at day 7 after administration
590 mg/kg bw: 3/10 animals died, death occurred at day 2 after administration
890 mg/kg bw: 1/10 animals died, death occurred at day 5 after administration
1330 mg/kg bw: 5/10 animals died, death occurred within 1 day after administration
2000 mg/kg bw: 9/10 animals died, death occurred within 1 day after administration
All animals that died were dead within 1 to 5 days after administration

Clinical signs:

other: no clinical signs were observed

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

After single application of either 390, 590, 890, 1330, or 2000 mg test substance per kg into male and female rats lethality could be observed during the 14 day observation period, resulting in a LD50 of 1170 mg/kg bw.

Executive summary:

Acute oral toxicity was investigated using male and female Sprague-Dawley rats in a test similar to acute standard method (i.e. OECD TG 401, non GLP). The test substance was administered by gavage at doses of 390, 590, 890, 1330 or 2000 mg/kg bw to groups of 10 animals (5 animals/sex). Within the 14 days observation period 1/10, 3/10, 1/10, 5/10 and 9/10 animals died using 390, 590, 890, 1330, and 2000 mg/kg bw, respectively. Deaths occurred within 1 to 5 days post dosing. Having this results a median lethal dose (LD50) of approximately 1170 mg/kg bw (CI: 740 to 1850 mg/kg bw) was identified .

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

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:

comparable to guideline study with acceptable restrictions

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)

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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

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

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): 0.93 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

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 Dragstedt and Lang.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 1 200 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Within the 14 days observation period no animals died after single application of 740 mg/kg bw. 4/10, 10/10 and 10/10 animals died using 1110, 1670 and 2500 mg/kg bw respectively. Deaths occurred within 1 to 3 days post application.

Mortality:

740 mg/kg bw: 0 males and 0 females died
1110 mg/kg bw: 4/10 animals died, death occurred within 1 to 3 days after administration
1670 mg/kg bw: 10/10 animals died, death occurred within 1 to 3 days after administration
2500 mg/kg bw: 10/10 animals; death occurred with day 1 and 2 after administration
All animals that died were dead within 1 to 3 days after administration

Clinical signs:

other: 740 mg/kg bw: only squeeking of the animals at the time of administration was noted 1110 mg/kg bw: same symptoms as decribed in the higher dose groups 1670 mg/kg bw: same symptoms as described in the high dose group, in addition staggering gait was obser

Gross pathology:

- 1670 and 2500 mg/kg bw: thickening of the skin at the site of application
- 1110 mg/kg bw: In surviving animals thickening of the skin at the site of application was noted and on day 4 and 5 eschar formation was observed at these sites. Cicatrisation of this eschar was observed starting at day 10 and at the end of the observation period a wound slightly healed with thick crust was seen in these animals, except for one animal which presented deeper lesions that can be attributed to a mutilation.
- 740 mg/kg bw: Same observations as mentioned above, but the mutilation phenomena were observed up to three hours after the dressing was removed in three females. Healing of these wounds sarts on day 4. In the other animals (females and males) eschar formation was noted on day 10, which began to heal on day 14 after start of exposure.

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  142.5 +/-4.2 t = 0.26 n.s. 153.0 +/-10.3 t = 4.9 s.s.   186.3 +/-12.3 t = 1.6 n.s. 207.0 +/-21.0 t = 0.9 n.s.

n.s. difference to control group not statistically significant

s.s. difference to control group statistically significant

Interpretation of results:

Category 4 based on GHS criteria

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 approximately 1200 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 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. 4/10, 10/10 and 10/10 animals died using 1110, 1670 and 2500 mg/kg bw respectively. Deaths occurred within 1 to 3 days post application. Having this results a median lethal dose (LD50) of approximately 1200 mg/kg bw was identified for acute dermal toxicity.

Cross-reference 3

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines /standards

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

: one additional animal

Qualifier:

according to guideline

Guideline:

other: DRAIZE test published in "Appraisal of the safety of chemicals in foods and cosmetics" Association of Food and Drug Officials of the United States, published by the Editorial Committee, Baltimore (1959), p. 46

Deviations:

no

GLP compliance:

no

Remarks:

study performed before GLP statement

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2 to 2.6 kg

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g

Duration of treatment / exposure:

Substance application was performed once, without any washing subsequently.

Observation period (in vivo):

7 days (Ocular reactions were observed at 1hour, 24, 48 and 72 hours after the instillation and then at days 7.)

Number of animals or in vitro replicates:

4

Details on study design:

SCORING SYSTEM: according to OECD TG 405 (Draize scale), reading at 1 h, 1, 2, 3, 4 and 7 days after removal of test item

The test item was instilled into the lower conjunctival sac of the left eye of each test animal.
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Remarks:

of animal #1, #2, and #3

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #4

Time point:

24/48/72 h

Score:

2.67

Max. score:

3

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3.3

Max. score:

4

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3.33

Max. score:

4

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

3.33

Max. score:

4

Reversibility:

not reversible

Remarks:

within 7 days post application

Irritant / corrosive response data:

Within 2 days post instillation the reading of all characteristics (i.e. corneal opacity, iris, conjunctivae redding, chemosis) in all animals resulted in maximum scores (see above), which were not reversible within 7 days post application.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Under the conditions tested the test item induced serious damage to eyes (corrosive).

Executive summary:

The primary eye irritation potential of the test item was investigated similar as described in OECD testing guideline no 405. The test item (0.1 g) was applied into the lower left conjunctival sac of the intact eye of four New Zealand White rabbits. Reading times were 1 h, 1, 2, 3, 4 and 7 days post instillation. Within 2 days post instillation the reading of all characteristics (i.e. corneal opacity, iris, conjunctivae redding, chemosis) in all animals resulted in maximum scores, which were not reversible within 7 days post application.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

prolonged exposure period, one additional animal; despite corrosiveness testing in all animals at the same time with long exposure period; additional application on scarified skin

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: DRAIZE test published in "Appraisal of the safety of chemicals in foods and cosmetics" Association of Food and Drug Officials of the United States, published by the Editorial Committee, Baltimore (1959), p. 46

Deviations:

no

GLP compliance:

no

Remarks:

study performed before GLP statement

Test material

Test material information

Constituent 1

Reference substance name:

7-azatridecane-1,13-diamine

EC Number:

205-593-1

EC Name:

7-azatridecane-1,13-diamine

Cas Number:

143-23-7

Molecular formula:

C12H29N3

IUPAC Name:

bis(6-aminohexyl)amine

Test material form:

solid

Details on test material:

The melting point of this sample is at 32-34°C.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.2 to 2.9 kg

Test system

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mg (solid test material humidified with a little bit of water)

Duration of treatment / exposure:

24 h

Observation period:

72 h

Number of animals:

4

Details on study design:

TEST SITE
- Area of exposure: two sites were shaved on the back of each animal, one of these was subsequntly sarified before the test item was applied


SCORING SYSTEM:
erythema scores similar to DRAIZE scoring system used in OECD 404
Erythema scores
0: none
1: very slight (barely perceptible)
2: slight (well perceptible)
3: moderate to severe
4: very severe erythema with slight eschar formation
8: very severe erythema and expanded eschar formation (over 50% of the apllication area)

Edema scores resemble those of OECD 404

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 24 h after start of exposure

Score:

2

Max. score:

8

Reversibility:

not reversible

Remarks:

within 72 hours

Remarks on result:

other: intact skin

Remarks:

all animals showed the same score

Results 2

Irritation parameter:

erythema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 72 hours after start of exposure

Score:

8

Max. score:

8

Reversibility:

no data

Remarks:

on reversibility as this was the final period of time investigated in the study

Remarks on result:

other: intact skin

Results 3

Irritation parameter:

edema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 24 hours after start of exposure

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hours

Remarks on result:

other: intact skin

Remarks:

all animals showed the same score

Results 4

Irritation parameter:

edema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 72 hours after start of exposure

Score:

4

Max. score:

4

Reversibility:

no data

Remarks:

on reversibility as this was the final period of time investigated in the study

Remarks on result:

other: intact skin

Results 5

Irritation parameter:

erythema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 24 after start of exposure

Score:

4

Max. score:

8

Reversibility:

not reversible

Remarks:

within 72 hours

Remarks on result:

other: scarified skin

Remarks:

individual scores: 8, 2, 4, 2

Results 6

Irritation parameter:

erythema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 72 hours after start of exposure

Score:

8

Max. score:

8

Reversibility:

no data

Remarks:

on reversibility as this was the final period of time investigated in the study

Remarks on result:

other: scarified skin

Results 7

Irritation parameter:

edema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 24 hours after start of exposure

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hours

Remarks on result:

other: scarified skin

Remarks:

all animals showed the same score

Results 8

Irritation parameter:

edema score

Basis:

mean

Remarks:

(for 4 tested animals)

Time point:

other: 72 hours after start of exposure

Score:

4

Max. score:

4

Reversibility:

no data

Remarks:

on reversibility as this was the final period of time investigated in the study

Remarks on result:

other: scarified skin

Applicant's summary and conclusion

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Remarks:

study design does not allow to disciminate further into subcategories

Conclusions:

According to the authors of this study the test item was found to be extremely irritant to the skin of rabbits under the conditions tested.

Executive summary:

In order to test primary skin irritation 4 New Zealand White rabbits were treated the submission substance. 0.5 mg of solid test material (pasted with water) were applied onto the intact skin as well as on scarified skin of the animals and held in contact with skin for 24 h (occlusive conditions). Reading was performed 24 h and 72 h after start of the application. According to the authors of this study the test item was found to be extremely irritant to the skin of rabbits.