Benzenemethanamine, N,.alpha.,3-trimethyl-, hydrobromide (1:1), (.alpha.S)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 November 2013 - 30 November 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test method according to OECD Guideline 420. GLP study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[(1S)-1-(3-methoxyphenyl)ethyl](methyl)amine hydrobromide

EC Number:

940-296-7

Cas Number:

1688686-16-9

Molecular formula:

C10H15NO.BrH

IUPAC Name:

[(1S)-1-(3-methoxyphenyl)ethyl](methyl)amine hydrobromide

Details on test material:

- Name of test material (as cited in study report): [1-(3-Methoxy-phenyl)-ethyl]-methyl-amine Hydrobromide
- Physical state: white powder
- Analytical purity: 100.2% (Potentiometric assay)
- Lot/batch No.: I13015A

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Experimental Medicine Centre at the Medical University in Białystok
- Age at study initiation: 12 week-old
- Weight at study initiation: average body weight: 210.8 g
- Fasting period before study: about 19 hours before the administration of the test item, restored 3 hours after the administration
- Housing: plastic cages covered with wire bar lids, 58 x 37 x 21 cm, with UV-sterilized wood shavings as bedding.
- Diet (e.g. ad libitum): ad libitum, "Murigran" standard granulated laboratory food.
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23ºC
- Humidity (%): 32-55%
- Air changes (per hr): 16 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 60 mg/mL
- Amount of vehicle (if gavage): 1 mL

MAXIMUM DOSE VOLUME APPLIED: 0.5 mL/100 g bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The test item at a single dose of 300 mg/kg bw was administered to one animal. The starting dose for the sighting study was selected from the fixed dose levels of 5, 50, 300 and 2000 mg/kg bw as a dose expected to produce evident toxicity. Since no data was available, the sighting study commenced with the administration of the test item at a dose of 300 mg/kg bw to one female rat. Considering the fact that the evident toxicity was observed during the sighting study, the test item at a single dose of 300 mg/kg bw was administered to four animals. The animal from the sighting study which had received the dose of 300 mg/kg bw was included in the main study.

Doses:

Sighting study: 300 mg/kg bw
Main study: 300 mg/kg bw

No. of animals per sex per dose:

1 female in the sighting study.
4 females in the main study.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: on days 0 (directly before the administration of the test item), 7, and 14 (before euthanasia).
- Necropsy of survivors performed: yes
- Other examinations performed:
General condition: observation of all animals for morbidity and mortality: twice a day or once a day (on days off) during the 14-day experiment.
Detailed clinical observations: on the day of the test item administration (day 0), i.e. 10, 30, and 60 minutes after the administration and then at hourly intervals up to the 5th hour after the administration. From the 1st to the 14th day of the experiment, the detailed clinical observations were performed once a day.
Gross examinations: After the 14-day observation period, all animals were euthanized by intraperitoneal administration of morbital at a dose of 200 mg/kg bw and subjected to gross examinations. The detailed gross examinations comprised the observation of the external body surface, all natural apertures, and the cranial, thoracic, and abdominal cavities with their contents.

Results and discussion

Preliminary study:

Clinical signs: rounded back from the 30th minute to the 5th hour after the administration of the test item, wavering gait from the 30th minute to the 2nd hour, a distinct increase in locomotor activity from the 30th minute to the 2nd hour, a slight increase in locomotor activity from the 3rd to the 5th hour, seizures from the 30th minute to the 2nd hour, and tremors from the 3rd to the 5th hour after the administration of the test item. It was difficult to catch the animal. Furthermore, strong reactions to sound stimuli were observed from the 30th minute to the 5th hour after the administration of the test item. This signs of toxicity were observed only on the administration day. The animal survived the experiment.
Body weight: During the second week of the experiment, body weight gain was stated. After the 14-day experiment, body weight gain was stated too.
Gross examinations: necrosis of the cecum, congestion around necrosis in the cecum, and petechiae in the mesentery of the cecum. These changes were probably caused by the test item.

Effect levels

Sex:

female

Dose descriptor:

discriminating dose

Effect level:

300 mg/kg bw

Based on:

test mat.

Remarks on result:

other: (evident toxicity)

Mortality:

All animals survived the experiment.

Clinical signs:

other: The following changes were observed in all animals: rounded backs from the 30th minute to the 4th hour after the administration of the test item, a distinct increase in locomotor activity from the 10th to the 30th minute, a slight increase in locomotor ac

Gross pathology:

The animals did not exhibit any pathological changes.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Key study: OECD 420. GLP study. Based on the evident toxicity observed in rats after a single exposure of 300 mg/k bw by gavage, the substance is classified as category 4 according to CLP Regulation (EC) no. 1272/2008.

Executive summary:

The acute oral toxicity study based on a fixed dose method was performed according to OECD Guideline 420 (GLP study). The experiment commenced with a sighting study in which the test item at a single dose of 300 mg/kg bw was administered to one female rat. Considering the fact that the evident toxicity was found during the sighting study, four animals used in the main study were given the test item at a dose of 300 mg/kg bw. After the administration of the test item, the animals were observed for 14 days. General and detailed clinical observations were conducted daily during the entire experiment. Body weights of the animals were determined. After the 14-day observation period, the animals were euthanized and subjected to a necropsy and a detailed gross examination. Following single administration of the test item at a dose of 300 mg/kg bw to four animals used in the main study, rounded backs, distinct and slight increases in locomotor activity, strong reactions to sound stimuli, and accelerated respiration were stated in case of all animals. All animals were difficult to catch. Furthermore, a bristled coat, tremors, and seizures were noticed. This signs of toxicity were observed on the administration day and the first day after administration. All animals survived the experiment. During the first and the second weeks of the experiment, body weight gain was stated in all females used in the study. After the 14-day experiment, body weight gain was stated too. Gross examinations of rat no. 1 revealed necrosis of the cecum, congestion around necrosis in the cecum, and petechiae in the mesentery of the cecum. These changes were probably caused by the test item. The remaining animals did not exhibit any pathological changes. Considering the fact that the evident toxicity was stated at a dose 300 mg/kg bw the test item was classified to the categories 4 according to the CLP Regulation (EC) no 1272/2008.