Carbamic acid, [(1S)-2-[(2-aminoethyl)amino]-1-[(4-ethoxyphenyl)methyl]ethyl]-, phenylmethyl ester, dihydrochloride

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from February 2004 to April 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

24 February 1987

Deviations:

yes

Remarks:

- 3 instead of 5 animals/sex used

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

impurity 1

Reference substance name:

n.a.

Molecular formula:

n.a.

IUPAC Name:

n.a.

impurity 2

impurity 3

Reference substance name:

Carbamic acid [(1S)-,2-[(2-aminoethyl)amino]-1-[(4-ethoxyphenyl)methyl]ethyl]-,phenylmethyl ester, dihydrochloride (9Cl)

IUPAC Name:

Carbamic acid [(1S)-,2-[(2-aminoethyl)amino]-1-[(4-ethoxyphenyl)methyl]ethyl]-,phenylmethyl ester, dihydrochloride (9Cl)

Constituent 1

Reference substance name:

benzyl[(2S)-1-[(2-aminoethyl)amino]-3-(4-ethoxyphenyl)propan-2-yl]carbamate dihydrochlorid

EC Number:

606-946-6

Cas Number:

221640-14-8

Molecular formula:

C21 H29 N3 O3 . 2 Cl H

IUPAC Name:

benzyl[(2S)-1-[(2-aminoethyl)amino]-3-(4-ethoxyphenyl)propan-2-yl]carbamate dihydrochlorid

Test material form:

solid

Test animals

Species:

rat

Strain:

other: HAN: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG, Germany
- Mean weight at study initiation: 287-314 g (males) or 198-205 g (females)
- Housing: 1 animal per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: >= 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23
- rel. Humidity (%): 48 - 57
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: 9 mg NaCl ad 1 mL aqua p.i.

Details on dermal exposure:

TEST SITE
- Area of exposure: The test substance was applied on a piece of gauze covering approximately 10% (4 x 9 cm) of the animal body surface under occlusive conditions for 24 hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washing


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): A paste consisting the original compound (group 2: 79.2-125.8 mg, group 3: 400.0-590.2 mg) and 0.9% (w/v) sodium chloride (group 2: 0.05-0.075 mL, group 3: 0.30-0.35 mL)
was administered.
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.05 mL to 0.35 mL

Duration of exposure:

24 hours

Doses:

400, 2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
General findings:
All alterations of the baseline condition of the animals were recorded. All animals were checked four times on administration day and once daily on the following days up to day 14 of the test.
Local findings:
All alterations of the skin at the administration sites of all animals were recorded according to the scoring system recommended by the EU (Amendment of the Directive 67/548/EEC, Annex V, B.4. Acute toxicity (Skin irritation) in the version of the Directive 92/69/EEC, dated 31 Jul 1992.). The application sites were evaluated 1, 24, 48 and 72 h after removal of the patches and then once daily until day 14 of the test.
Body weight
Body weight was determined at the start (day 1), on day 8 and at the end of the study (day 14).

- Necropsy of survivors performed: yes; the animals were sacrificed 14 days post administration by inhalation of carbon dioxide and after occurrence of death a complete postmortem examination was performed on each animal.
- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All treated animals survived at both doses.

Clinical signs:

other: no clinical findings at both doses.

Gross pathology:

Autopsy revealed no compound-related findings.

Any other information on results incl. tables

 

 

Dose [mg/kg]

Sex

Findings

Numberof animals with findings/number of surviving animals

Days after administration(hours after removal of the patches)

2 (1)

3 (24)

4 (48)

5 (72)

6

7

8

9

10

11

12

13

14

400

M

without findings

3/3

3/3

3/3

3/3

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

F

without findings

3/3

3/3

3/3

3/3

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

M

Pustules spotty

2/3

Pustules, plain

1/3

Scab formation, spotty

1/3

1/3

1/3

1/3

2/3

2/3

1/3

1/3

1/3

1/3

Scab formation, plain

1/3

1/3

1/3

1/3

1/3

1/3

1/3

1/3

2000

Scab formation, total treated area

2/3

2/3

1/3

1/3

without findings

3/3

0/3

0/3

0/3

0/3

0/3

0/3

1/3

1/3

1/3

1/3

3/3

3/3

F

Reddening. sporadic, punctiform

3/3

3/3

3/3

3/3

2/3

2/3

1/3

1/3

1/3

1/3

1/3

Scab formation, spotty

2/3

2/3

2/3

1/3

1/3

1/3

1/3

Skin defect -only outside of the treated area

2/3

2/3

2/3

1/3

2/3

without findings

0/3

0/3

0/3

0/3

1/3

1/3

2/3

0/3

0/3

0/3

1/3

1/3

3/3

M = male

F = female

n.d. = not detected

 

 

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

A single dermal administration of the test substance to male and female rats at 400 mg/kg and 2000 mg/kg was tolerated without mortalities, compound-related clinical findings, sustained effects on body weight gain and gross pathological findings. According to OECD TG 402 the dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

Executive summary:

In an acute dermal toxicity study similar to OECD TG 402 (adopted 24 February 1987), groups of young adult Wistar rats (3/sex) were dermally exposed to Z-Triamine Dihydrochloride in physiological saline for 24 hours at doses of 400 and 2000 mg/kg bw. Animals then were observed for 14 days.

 

Dermal LD50 Combined = > 2000 mg/kg bw

The test item is of low Toxicity based on the combined LD50 value of > 2000 mg/kg bw.

The treatment was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. Local effects were observed only for the 2000 mg/kg bw treatment group.