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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from February to April 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

24 April 2002

Deviations:

yes

Remarks:

- exposure time 24 hrs instead of 4 hrs; number of animals 6 instead of 3 animals

Principles of method if other than guideline:

A combined study on acute dermal toxicity and on local tolerance was used to assess skin irritation/corrosion. The study design and reporting deviates from the current OECD TG 404, however, the study is considered sufficient for assessment of this endpoint.

GLP compliance:

yes

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)

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

Test system

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

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

Controls:

other: the untreated skin served as control

Amount / concentration applied:

79.2 - 125.8 mg (= 400 mg/kg bw doese group animals)
400.0-590.2 mg/animal (= 2000 mg/kg bw dose group animals)

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

3 males and 3 females

Details on study design:

TEST SITE
- Area of exposure: 4 x 9 cm (approximately 10% of the body surface area of a rat)
- % coverage: 10%

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no removal


OBSERVATION TIME POINTS
(indicate if minutes, hours or days) 1, 24, 48, and 72h; total observation period 14 days

SCORING SYSTEM: According to 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.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal: #1-#6

Time point:

24/48/72 h

Score:

3.5

Max. score:

4

Reversibility:

fully reversible within: 14 days

Results 2

Irritation parameter:

edema score

Basis:

animal: #1- #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Any other information on results incl. tables

At the dose of 2000 mg/kg the animals showed primary and secondary efflorescences.

		Animal number and sex
Location (finding)	Time-point after end of exposure	27M	28M	29M	30F	31F	32F
Reddening and scrab formation	1 h	0	0	0	1	1	1
	24 h	4	4	4	1	4	4
	48 h	4	4	4	1	4	4
	72 h	4	4	4	1	4	4
Individual mean values:		4	4	4	1	4	4
Mean value of all animals							3.5
Swellings	1 h	0	0	0	0	0	0
	24 h	0	0	0	0	0	0
	48 h	0	0	0	0	0	0
	72 h	0	0	0	0	0	0
Individual mean values:		0	0	0	0	0	0
Mean value of all animals							0

 

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

A combined study on acute dermal toxicity and on local tolerance was conducted . The study design and reporting deviates from the current OECD TG 404, however, the study was considered sufficient for assessment of skin irritation/corrosion. After a single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg local irritation was described for 6/6 animals. Following grading at 24, 48 and 72 hours after patch removal a mean value of 3.5 for erythema/eschar was calculated. All animals were without local findings within 14 days.

Executive summary:

In a primary dermal irritation study similar to OECD TG 404, young adult Wistar rats, female and male (3/sex) were dermally exposed to 79.2 - 125.8 mg or 400.0-590.2 mg/ animal of Z-Triamine Dihydrochloride in physiological saline for 24 hours. Animals then were observed for 14 days. Irritation was scored by the method according to 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..

 

At the dose of 2000 mg/kg the animals showed primary and secondary efflorescences.. These irritations lasted 14 days. In this study, the test item is considered a dermal irritant.