Bicyclo[2.2.1]heptane, 2-ethyl-5-methoxy-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

between 18 May and 8 June 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

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:

-

EC Number:

403-610-9

EC Name:

-

Cas Number:

122795-41-9

IUPAC Name:

1-ethyl-3-methoxytricyclo[2.2.1.0²,⁶]heptane; 2-ethyl-5-methoxybicyclo[2.2.1]heptane; 2-ethyl-6-methoxybicyclo[2.2.1]heptane

Test material form:

liquid

Test animals

Species:

rat

Strain:

other: Crl:CD (SD) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were in a weight range of 105 to 142 g prior to dosing and approximately four to six weeks of age. All the rats were acclimated to the experimental environment for a period of 7 days prior to the start of the main study.
The rats were allocated to cages within the treatment groups. They were housed in groups by sex in metal cages with wire mesh floors. A standard laboratory rodent diet (Labsure LAD 1) and water were provided ad libitum. The batch of diet used for the study was analysed for certain chemical and microbiological contaminants. Access to food only was prevented overnight prior to and approximately 4 hours after dosing.
The main daily minimum and maximum temperatures of the animal room were 20°C and 23°C respectively and the mean daily relative humidity value was 63%. The rate of air exchange was maintained at approximately 15 air changes/hour. Lighting was controlled by means of a time switch to provide 12 hours artificial light in each 24 hour period.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

Dose Dose Volume
1) 1.26 g/kg, 1.33ml/kg
2) 2.00g/kg, 2.11ml/kg
3) 3.20g/kg, 3.37ml/kg

No. of animals per sex per dose:

5 females and 5 males per dose

Control animals:

no

Details on study design:

Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1 (a period of five hours). On the subsequent days the animals were observed once in the morning and again at the end of the experimental day. Clinical signs were recorded at each observation.
Animals surviving treatment on the preliminary and main studies were observed for 5 and 14 days respectively, after dosing.
In the main study the following were recorded: approximate time of death of individual rats, nature, severity, approximate time of onset and duration of each toxic sign, individual bodyweights of rats on Days 1 (day of dosing), 8 and 15 and at death.
Surviving animals on the main study were killed on Day 15 by cervical dislocation. All animals died during the study and those killed on Day 15 were subjected to a macroscopic post mortem examination which consisted of opening the abdominal and thoracic cavities. The macroscopic appearance of abnormal organs when present was recorded.

Statistics:

The acute median lethal oral dose to male and female rats was calculated using the method of Finney (1971) probit analysis (3rd Edition) Cambridge University Press. Separate LD50 values for males and females were estimated by undertaking probit analysis on the mortality data by fitting two parallel lines on the data (males only and females only) using the technique described by Finney. A chi-squared test was carried out to check that the data did not contain any evidence for non-parallelism.

Results and discussion

Preliminary study:

A trial test was carried out by dosing two male and two female rats at 2.50 g/kg bodyweight.
The results of the preliminary study indicated that the acute median lethal oral dose to male and female rats of ethyl methoxy norbornane was less than 2.50 g/kg bodyweight.
Further groups of ten rats (five males and five females) were dosed at 1.26, 2.00, and 3.20 g/kg in order to determine the acute toxicity of the test substance more precisely.

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 100 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 700 - <= 2 700

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

2 300 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 700 - <= 3 300

Effect levels 3

Sex:

female

Dose descriptor:

LD50

Effect level:

1 900 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 300 - <= 2 700

Mortality:

There were deaths amngst rats of both sexes dosed at 2.00 g/kg and above. All deaths occurred on Day 2.
Autopsy of rats that died prior to scheduled termination revealed no macroscopic abnormalities.
Bodyweight losses (≤11g) were determined by comparison with Day 1 bodyweights for animals that died prior to the scheduled termination.

Clinical signs:

other: Signs of reaction to treatment observed in all rats from within three hours of dosing were pilo-erection, abnormal body carriage (hunched posture), abnormal gait (waddling), lethargy, pallor of the extremities and increased salivation. These clinical resp

Other findings:

Terminal autopsy findings were normal.

Applicant's summary and conclusion

Interpretation of results:

other: not acute harmful according to EU CLP (EC 1272/2008 and its amendments)

Conclusions:

The acute median lethal oral dose (LD50) and their 95% confidence limits to rats of Neoproxen were calculated to be:
Males & female combined: 2.1 g/kg bodyweight (1.7-2.7)
Males only: 2.3 g/kg bodyweight (1.7-3.3)
Females only: 1.9 g/kg bodyweight (1.3-2.7)

Executive summary:

Using OECD TG 401, the acute median lethal oral dose (LD50) and their 95% confidence limits to rats of Neoproxen was 2.1 g/kg bodyweight (1.7 -2.7): males and females combined.