Benzenepropanamine, 2-methoxy-5-methyl-N,N-bis(1-methylethyl)-.gamma.-phenyl-, hydrobromide (1:1)

Endpoint summary

Description of key information

Key study: Acute oral toxicity study: OECD guideline 420 and EU method B.1 bis. GLP study.
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline and EU method. GLP study.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

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:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK
- Age at study initiation: Approximately 8 to 12 weeks at stari of treatment
- Weight at study initiation: 154-177 g
- Fasting period before study: Food will be removed overnight prior to dosing and returned approximately three to four hours after dosing.
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Rodent 2014C Teklad Global Certified Diet, ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 ºC
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours of continuous artificial light in each twenty-four hour period

Route of administration:

oral: gavage

Vehicle:

arachis oil

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

Five animals at 300 mg/kg bw
One animal at 2000 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality: Morbidity and mortality checks were made twice daily.
Clinical Observations: At ½, 1, 2, and 4 hours after dosing and then daily for up to fourteen days.
Bodyweights: Recorded on Day 0 (prior to dosing), Day 7 and 14, or at death.
- Necropsy of survivors performed: yes
- Other examinations performed:
All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Sex:

female

Dose descriptor:

LD50

Effect level:

300 - 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Dose Level - 2000 mg/kg: The animal was killed for humane reasons, four hours after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit.

Dose Level - 300 mg/kg: There were no deaths.

Clinical signs:

other: Dose Level - 2000 mg/kg: Signs of systemic toxicity noted were body tremors, ataxia, increased lachrymation, pallor of the extremities and hypothermia. Dose Level - 300 mg/kg: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

Dose Level - 2000 mg/kg: Abnormalities noted at necropsy were abnormally red lungs, off white solid substance present in the stomach and epithelial sloughing of the gastric mucosa.

Dose Level - 300 mg/kg: No abnormalities were noted at necropsy.

Table 1: Mortality

Dose (mg/kg bw)	Mortality
300	0/5
2000	1/1

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight.

Executive summary:

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following:

-OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001)

- Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

Following a sighting test at dose levels of 2000 mg/kg and 300 mg/kg, a further group of four fasted females was given a single oral dose of test item, as a suspension in arachis oil BP, at a dose level of 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. The animal treated at a dose level of 2000 mg/kg was killed for humane reasons, four hours after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit. There were no deaths at a dose level of 300 mg/kg. Signs of systemic toxicity noted in the animal treated at a dose

level of 2000 mg/kg were body tremors, ataxia, increased lachrymation, pallor of the extremities and hypothermia. There were no signs of systemic toxicity noted at a dose level of 300 mg/kg. Surviving animals showed expected gains in bodyweight except for one

animal treated at a dose level of 300 mg/kg which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week. Abnormalities noted at necropsy of the animal treated at a dose level of 2000 mg/kg were abnormally red lungs, off white solid substance present in the stomach and epithelial sloughing of the gastric mucosa. No abnormalities were noted at necropsy animals treated at a dose level of 300 mg/kg. The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight (Globally Harmonised Classification System - Category 4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1. This study was carried out in accordance with internationally valid GLP principles.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Key study: Acute oral toxicity study: OECD guideline 420 and EU method B.1 bis. GLP study.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight.

Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for classification or non-classification

Based on the available data on the acute oral toxicity study, the substance is classified as Acute oral toxicity Category 4.