10-methoxy-6-methylergoline-8β-methanol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2017-04-13 to 2017-05-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

yes

Remarks:

Three groups were dosed at 300 mg/kg instead of the required two groups.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

10-methoxy-6-methylergoline-8β-methanol

EC Number:

252-385-1

EC Name:

10-methoxy-6-methylergoline-8β-methanol

Cas Number:

35121-60-9

Molecular formula:

C17H22N2O2

IUPAC Name:

[(2S,4R,7R)-2-methoxy-6-methyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(16),9,12,14-tetraen-4-yl]methanol

Specific details on test material used for the study:

Batch:16052R23A
Purity: >= 95%

Test animals

Species:

rat

Strain:

other: Crl: WI(Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source: Charles River Deutschland, Sulzfeld, Germany.
Age at study initiation: Young adult animals (approximately 8-10 weeks old) were selected.
Weight at study initiation: 144 to 194 g
Housing: On arrival and following assignment to the study, animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages. containing sterilized sawdust as bedding material equipped with water bottles.
Diet: Pelleted rodent diet was provided ad libitum throughout the study, except during designated procedures.
Water: Municipal tap-water was freely available to each animal via water bottles.
Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
Temperature (°C): 18°C to 24°C (Target), 21 to 22°C (Actual)
Humidity (%): 40% to 70% (Target), 43 to 56% (Actual)
Air changes (per hr): Ten or greater
Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
Identification: Water (Elix)
Specific gravity: 1.0
Justification for choice of vehicle: Trial preparations were performed at the Test Facility to select the suitable vehicle and to establish a suitable formulation procedure.

CLASS METHOD
The dose levels are based on the OECD test guidelines and will be selected from the series 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. The starting dose level should be the one that is likely to produce mortality in at least some of the animals
and will be selected based on available toxicity data of the test item.

Doses:

300 and 2000 mg/kg body weight

No. of animals per sex per dose:

Three females per group

Control animals:

no

Details on study design:

Duration of observation period following administration: 14 days
Frequency of observations and weighing: Mortality/Viability: Twice daily. Body weights: Days 1 (predose), 8 and 15. Clinical signs: at periodic intervals on the day of dosing (at least three times) and once daily thereafter.
Necropsy of survivors performed: yes, at the end of observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy.
Other examinations performed: no.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, all animals were found dead on Day 1 or 2.
At 300 mg/kg, one out of nine animals was found dead on Day 1. No further mortality occurred.

Clinical signs:

other: At 2000 mg/kg, lethargy, lateral recumbency, flat posture, hunched posture, uncoordinated movements, shallow respiration, slow breathing, piloerection, pale appearance and/or ptosis were noted for all animals on Day 1. At 300 mg/kg, lethargy, lateral recu

Gross pathology:

At 2000 mg/kg, distention of the stomach with gas was found in the animal which was found dead on Day 2. At 300 mg/kg, watery-clear fluid in the stomach was found in the animal which was found dead on Day 1. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 value of test item in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

Executive summary:

According to the OECD 423 test guideline, initially, the test substacne was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure three additional groups of three females were dosed at 300 mg/kg body weight.

All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

At 2000 mg/kg, all animals were found dead on Day 1 or 2. At 300 mg/kg, one out of nine animals was found dead on Day 1. No further mortality occurred.

At 2000 mg/kg, lethargy, lateral recumbency, flat posture, hunched posture, uncoordinated movements, shallow respiration, slow breathing, piloerection, pale appearance and/or ptosis were noted for all animals on Day 1. At 300 mg/kg, lethargy, lateral recumbency, tremor, hunched posture, uncoordinated movements, shallow respiration, quick breathing, piloerection, salivation, ptosis and/or hypothermia were noted for all animals on Day 1. Additionally piloerection was noted for two animals on Day 2.

At 2000 mg/kg, distention of the stomach with gas was found in the animal which was found dead on Day 2. At 300 mg/kg, watery-clear fluid in the stomach was found in the animal which was found dead on Day 1. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

The oral LD50 value of test substance in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. The LD50 cut-off value was considered the LD50 cut-off value was considered to be 500 mg/kg body weight.