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

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from February 2004 to April 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

17 December 2001

Deviations:

yes

Remarks:

- according to the replaced version (1996) of the OECD TG 423 both sexes and a starting dose of 200 mg/kg bw were used

GLP compliance:

yes

Test type:

acute toxic class 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:Charles River, Berlin - Buch, Germany
- Mean weight at study initiation: 104-106 g (males) or 94-106 g (females)
- Housing: 1 animal per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least >=7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 23
- rel. Humidity (%): 48 - 56
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 9 mg NaCl ad 1 ml Aqua p.i.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20 and 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

200 mg/kg bw and 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: Clinical observations were performed at five (200 mg/kg bw) or nine (2000 mg/kg bw) different time points on administration day and then once daily until day 14. Body weight was recorded weekly.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 300 - < 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The LD50 value was determined according to the replaced version (1996) of OECD test guideline 423. According to Regulation (EU) No. 1272/2008 the LD50 value is >300 and < 2000 mg/kg bw, corresponding to GHS Category 4

Mortality:

No mortality was observed after adiministration of 200 mg/kg bw in both sexes. After 2000 mg/kg bw all animals died between 4 hours after treatment and the following day of the study.

Clinical signs:

other: The main clinical findings after administration of 2000 mg/kg were increased sialorrhea and compulsive behavior five minutes after administration. Apathy, abnormal respiration and eyelid closure were also observed in the first hour after administration. L

Gross pathology:

Necropsy of the rats which died after administration of 2000 mg/kg revealed reddening or dark-red discoloration of the gastro-intestinal mucosa (small intestine). There were no abnormal necropsy findings in male and female rats dosed at 200 mg/kg bw.

Any other information on results incl. tables

clinical findings

Dose of test item

Sex

Findings

Numberof animals with findings/number of surviving animals

Day 1 (min after administration

5

15

30

60

120

180

210

240

p.m.

Day 2-14

200

M

Compulsive behaviour

2/3

Increased sialorrhea

3/3

Without findings

0/3

3/3

3/3

3/3

3/3

3/3

F

Compulsive behaviour

1/3

Increased sialorrhea

2/3

Without findings

1/3

3/3

3/3

3/3

3/3

3/3

2000

F

Increased sialorrhea

3/3

Apathy, slight

2/3

3/3

3/3

Apathy, moderate

3/3

3/3

1/3

1/2

Apathy, severe

2/3

1/2

1/1

Prone, lateral or supine position, conscious

1/3

Compulsive behaviour

3/3

1/3

Gait spastic

3/3

3/3

2/3

2/2

1/1

Respiration retarded

3/3

3/3

3/3

3/3

3/3

3/3

2/2

1/1

Abnormal breathing sounds

1/3

1/3

1/3

1/3

1/3

1/3

1/2

1/1

Eyelid closure

1/3

2/3

3/3

3/3

3/3

3/3

2/2

1/1

Secretion, serous

2/3

2/3

2/2

1/1

Fur ruffled

3/3

3/3

3/3

2/2

1/1

Discolouration of eyes, dark reddish

3/3

3/3

3/3

2/2

1/1

Discolouration of fore and hind limbs, bluish

3/3

2/2

1/1

Without findings

0/3

0/3

0/3

0/3

0/3

0/3

0/3

0/2

0/1

0/0

 

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral toxicity of the test item was moderate with an LD50 value of > 300 < 500 mg/kg bw in rats according to ANNEX 3b of OECD TG 423 (1996). All males and females dosed with 200 mg/kg bw survived. After 2000 mg/kg bw all animals died between 4 hours after treatment and the following day of the study. Clinical findings beyond 5 minutes after aopplication were limited to the 2000 mg/kg bw dose group. Body weight development was not affected. During autopsy reddening or dark-red discoloration of the gastro-intestinal mucosa (small intestine) were described for the animals which died after application of 2000 mg/kg

Executive summary:

In an acute oral toxicity study according to OECD guideline 423 (1996), groups of, adult male and female WST (SPF) rats (3/sex) were given a single oral dose of Z-Triamine Dihydrochloride in 900 mg NaCl + 85 mg Myrj 53 ad 100 ml bidist. water at doses 2000 (only female) and 200 mg/kg bw (female and male) and observed for 14 days.

 

Oral LD50 Combined = > 300 mg/kg bw and < 2000 mg/kg bw (according to Regulation (EU) No. 1272/2008 (CLP))

Oral LD50 Combined = > 300 mg/kg bw and < 500 mg/kg bw (according to OECD Test Guideline 423 Annex 3c (1996))

 

All females died after oral ingestion of 2000 mg/kg bw. All males and females dosed with 200 mg/kg bw survived. Clinical findings were limited to the 2000 mg/kg bw dose group. Body weight development was not affected. Autopsy revealed reddening of the glandular mucosa of the stomach in only one animal which died after application of 2000 mg/kg and no compound-related or suspected compound-related findings in the two other animals which died or in the animals which were sacrificed at the end of the study.

 

Z-Triamine Dihydrochloride is of low Toxicity based on the LD50 in WIST (SPF) rats. The substance is classified according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) as Category 4 ‘harmful if swallowed’.