Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2nd December 1988 to 20th January 198

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate

EC Number:

404-520-2

EC Name:

Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate

Cas Number:

139893-43-9

Molecular formula:

C25 H43 O6 N

IUPAC Name:

ammonium 7-{8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5-dihydroxyheptanoate

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Composition:
99.2% L-654,969, 0.2% lovastatin ammonium salt, 0.2% triol

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were sourced from Charles River France, weight range 138 - 155g and 4 - 6 weeks old. The animals were acclimatised to the laboratory conditions for 15 days prior to the test. The rats were allocated to cages within the treatment groups in Building R14 Room 6. They were housed in groups of up to 5 rats of the same sex in metal cages. Each animal was identified by cage number and ear punching.
Temperature: 20-22oC
Humidity: 66%
Light sequence: 12 hour light / 12 hour dark
Food: Standard Rodent diet (Labsure LAD 1)
Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

20 ml/kg

Doses:

1260, 2000, 2500, 3200 mg/kg

No. of animals per sex per dose:

5 x males, 5 x females

Control animals:

not specified

Details on study design:

Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1 (6 hours), On subsequent days the animals were observed once in the morning and once at the end of the experimental day. Clinical signs were recorded at each observation.
Animals surviving treatment were observed for 5 and 14 days after dosing. Time of death, clinical observations and body weights were recorded. All animals were subject to gross necroscopy.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 2 400 mg/kg bw

Based on:

test mat.

95% CL:

> 2 100 - <= 2 700

Remarks on result:

other: Slope of the mortality curve: 13.8

Mortality:

Male: 1260 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 1
Male: 2500 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 3200 mg/kg bw; Number of animals: 5; Number of deaths: 5
Female: 1260 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 1
Female: 2500 mg/kg bw; Number of animals: 5; Number of deaths: 5
Female: 3200 mg/kg bw; Number of animals: 5; Number of deaths: 5

Clinical signs:

other: Signs of toxicity related to dose levels: Deaths occurred from within 2 hours of dosing until day 10. Pilo-erection was observed in all animals within 10 minutes of dosing, accompanied by: hunched posture, increased salivation, pallor of the extremities,

Gross pathology:

Congested blood vessels of the stomach were observed postmortem in one female dosed at 2.0g/kg, two females dosed at 2.5 g/kg and two males and one female dosed at 3.2 g/kg. Autoposy of rats that died revealed no macroscopic abnormalities.

Terminal autopsy findings were normal.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

It is notable that deaths in this test occurred over a prolonged period and that the clinical symtoms persisted, indicating that the substance has a rather prolonged toxic action in the rat. However, since the LD50 is greater than 2000mg/kg, the substance does not require labelling with risk phrase R22 "Harmful if swallowed".

Executive summary:

Objective
The study was performed to assess the acute oral toxicity of the test substance following a single oral dose.  The method met OECD Guidelines for the Testing of Chemicals - Acute Oral Toxicity (401). 

Method
A preliminary test was carried out to establish a dosing regime for the main study. Groups of two male and 2 female rats were dosed at 1000 and 2500 mg/kg. Based on the results, further groups of 5 male and 5 female rats were dosed at 1260, 2000, 2500 and 3200 mg/kg. Clinical observations and body weights were monitored during the study. All animals were subject to gross necroscopy.

There were deaths amongst male rats dosed at 2000 and 3200 mg /kg and amongst females dosed at 2000mg /kg and above. Deaths occured from within 2 hours of dosing until Day 10.  

Conclusions: Since the LD50 is greater than 2000mg/kg, the substance does not require labelling with risk phrase R22 "Harmful if swallowed".