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REACH

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

EC number: 606-946-6 | CAS number: 221640-14-8

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

LD50 oral (rat):> 300 < 2000 mg/kg bw [report, Lewin 2005]
LD50 dermal (rat): > 2000 mg/kg bw [report, Lewin 2004]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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

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:

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

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:

Control animals:

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

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.

clinical findings

Dose of test item

Sex

Findings

Numberof animals with findings/number of surviving animals

Day 1 (min after administration

120

180

210

240

p.m.

Day 2-14

200

Compulsive behaviour

2/3

Increased sialorrhea

3/3

Without findings

0/3

3/3

Compulsive behaviour

1/3

Increased sialorrhea

2/3

Without findings

1/3

3/3

2000

Increased sialorrhea

3/3

Apathy, slight

2/3

3/3

Apathy, moderate

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

2/3

2/2

1/1

Respiration retarded

3/3

2/2

1/1

Abnormal breathing sounds

1/3

1/2

1/1

Eyelid closure

1/3

2/3

3/3

2/2

1/1

Secretion, serous

2/3

2/2

1/1

Fur ruffled

3/3

2/2

1/1

Discolouration of eyes, dark reddish

3/3

2/2

1/1

Discolouration of fore and hind limbs, bluish

3/3

2/2

1/1

Without findings

0/3

0/2

0/1

0/0

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’.

Endpoint conclusion

Endpoint conclusion:: adverse effect observed
Dose descriptor:: discriminating dose
Value:: 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:: no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

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

Reason / purpose for cross-reference:

reference to same study

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:

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

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:

Control animals:

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

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.

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)

400

without findings

3/3

n.d.

without findings

3/3

n.d.

Pustules spotty

2/3

Pustules, plain

1/3

Scab formation, spotty

1/3

2/3

1/3

Scab formation, plain

1/3

2000

Scab formation, total treated area

2/3

1/3

without findings

3/3

0/3

1/3

3/3

Reddening. sporadic, punctiform

3/3

2/3

1/3

Scab formation, spotty

2/3

1/3

Skin defect -only outside of the treated area

2/3

1/3

2/3

without findings

0/3

1/3

2/3

0/3

1/3

3/3

M = male

F = female

n.d. = not detected

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.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: discriminating dose
Value:: 2 000 mg/kg bw

Additional information

Acute toxicity: oral

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))

Acute dermal toxicity:

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.

Justification for classification or non-classification

Acute toxicity: oral

LD50: > 300 - < 2000 mg/kg bw (rat, female/male)

According to Regualtion EU-No.1272/2008 (CLP), Z-Triamin-Dihydrochlorid shall be classified as harmful if swallowed Category 4.

Acute toxicity: inhalation

No data available

Acute toxicity: dermal

LD50: > 2000 mg/kg bw (rat, female/male)

No classification required according to Regulation (EC) No 1272/2008, Annex I

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