(6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol hydrochloride (1:1)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: FDA’s Department of Health and Human Services Revised Guidance for Single Dose Acute Toxicity Testing for Pharmaceuticals (Federal Register, Volume 61, No. 166, issued 26 Aug 1996; 61 FR 43934)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

dd 15.4.2005

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-, (6S)-

EC Number:

619-458-3

Cas Number:

99755-59-6

IUPAC Name:

1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-, (6S)-

Test material form:

solid: particulate/powder

Details on test material:

- Appearance: Off white powder
- Storage conditions: in tight containers, temperature not above 25°C

Test animals

Species:

rat

Strain:

other: CD® / Crl: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 49 days (males), 59 days (females)
- Weight at study initiation: 245-272 g (males), 196-229 g (females)
- Fasting period before study: yes, feeding was discontinued approx. 16 hours before administration
- Housing: During the 14-day observation period the animals were kept in groups of 3 animals per sex in MAKROLON cages (type III)
- Diet: Ssniff® R/M-H V1530, ad libitum except approx. 16 hours before administration
- Water: tap water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 (maximum range)
- Humidity (%): 55 ± 15 (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 February 2006 To: 01 March 2006

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: hydroxypropylmethylcellulose gel

Remarks:

(0.8%)

Details on oral exposure:

VEHICLE
- Amount of vehicle: 20 mL/kg bw
- Batch no.: Methocel, batch no. 0403A093, Synopharm GmbH, D-22885 Barsbüttel

DOSAGE PREPARATION: The aqueous solutions were prepared freshly on the day of administration.

Doses:

Dose range finding study: 50, 100, 200, 300, 500 and 1000 mg/kg bw
Main study: 215, 464, 1000, 1470 mg/kg bw

No. of animals per sex per dose:

3 (main study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration and at least daily thereafter.
- Frequency of weighing: before administration of the test item and thereafter in weekly intervals up to the end of the study and at death.
- Necropsy of survivors performed: yes

Statistics:

The approximate LD50 was calculated according to FINNEY by regression analysis. The mortality rates at 24 hours and 14 days were used.

Results and discussion

Preliminary study:

No signs of toxicity were observed up to and including the dose level of 200 mg/kg bw. Dose levels of 300 and 500 mg/kg bw caused slight signs of toxicity, the dose level of 1000 mg/kg bw caused severe signs of toxicity and death.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Remarks:

14 days

Effect level:

ca. 1 231 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was seen at 215 and 464 mg/kg bw. At 1000 mg/kg bw one male and one female died, both within 30 minutes after exposure. At 1470 mg/kg bw one male and one female died within 15 minutes after exposure, one additional male died within 24 hours and one additional female died in the second week after exposure (day 9).

Clinical signs:

other: Starting at a dose level of 464 mg/kg bw slightly reduced motility, slight ataxia, slight dyspnea and stereotypy in all 3 of 3 male and 3 of 3 female rats were noted. At 1000 mg/kg bw, in addition, slight tremor was observed in all 3 of 3 male and 3 of 3

Gross pathology:

No macroscopical changes were noted.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the outcome of an acute oral toxicity test with male and female rats, performed according to EU guideline and GLP principles, the LD50 of SPM 962 was found to be appr. 1231 mg/kg bw.

Executive summary:

An acute oral toxicity test was performed with SPM 962, according to EU guideline and GLP principles. Rats (3/sex/dose) were exposed to 215, 464, 1000 or 1470 mg/kg bw. At the dose level of 1000 mg/kg bw, one male and one female died within 30 minutes. At 1470 mg/kg bw, one male and one female died within 15 minutes, another male within one day and a second females within 9 days after administration. Clinical signs noted at 464 mg/kg bw and above included reduced motility, ataxia, tremor, dyspnea, clonic convulsions, myosis and stereotypy.

Based on these results, the LD50 of SPM 962 was found to be appr. 1231 mg/kg bw. As a result, the test substance is classified cat. 4 for acute oral toxicity according to Regulation (EC) No 1272/2008.