(Z)-tetrahydro-6-(2-pentenyl)-2H-pyran-2-one

Endpoint summary

Description of key information

The acute median lethal dose (LD50) in rats following single oral administration of Jasminlactone was greater than 4000 mg/kg in female or male rats.

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

Study period:

09 June 1992 - 23 June 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Ministry of Health and Welfare's "Regarding standards for conducting a safety study of medicine" (PAB Notification No.313, March 31, 1982),
"Regarding partial revision of standards for conducting a safety study of medicine" (PAB Notification No.776, October 1, 1983),
"Regarding revision of regulations about GLP and inspection for medicine" (PAB Notification No.870, October 5, 1988), and
"Regarding guidelines on a toxicity study for an application of manufacturing (import)

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot No.19001
- Purity: 95.0 %


STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Cool and dark place after replacement by N2
- Stability under test conditions: It is stable under test conditions.
- Solubility and stability of the test substance in the solvent/vehicle: It can dissolve in alcohol and resolve in water, alkali and alcohol

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4 weeks
- Fasting period before study: 18 hours
- Weight at study initiation: The male and female rats weighed 136 to 144 g and 110 to 119 g, respectively
- Housing: The animals were housed in room 5 of flat A (SPF facility), and each rat was in one stainless bracket cage for rats, SN-790-2 (260W x 380D x 180H mm).
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 46 to 65
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 hours

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

Preliminary test: 250, 500, 1000, 2000, and 4000 mg/kg
Definitive test: 0 mg/kg, 2000 mg/kg and 4000 mg/kg

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

General state of health.
We observed and checked any change in the general state of health and the number of death cases at 5, 15, and 30 minutes, and 1, 3, 6, and 24 hours after the administration and then twice daily until the 14th day.

Body weight
We measured body weight on the 0, 1, 2, 3, 7, 10, and 14 days after the administration.

Anatomical dissection
After the observation period was over, all the cases were bled to death under ether anesthesia, and we observed the body surface, inside the skull, thoracic cavity, and abdominal cavity with the naked eye.

Histopathological test
We did not conduct a histopathological test because no abnormal change was observed in the anatomical dissection.

Statistics:

Method for statistical analysis:
Concerning change in body weight, first we obtained an average value and standard deviation in each group. Then, if uniformity of dispersion was observed with F-test, we conducted the Student's t-test, otherwise we conducted Aspin-Welch's t-test, in order to compare the treatment groups to the control.

Preliminary study:

In the preliminary test conducted a dose of 250, 500, 1000, 2000, and 4000 mg/kg of the substance were administered to five groups respectively, each of which consisted of 2 male and 2 female animals. No death resulting from test item was observed. Therefore, the maximum doses of 2000 mg/kg and 4000 mg/kg) were chosen in the main study.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 000 mg/kg bw

Based on:

test mat.

Mortality:

One case of death was observed in the females assigned to the 4000 mg/kg group 3 hours after the administration.

Clinical signs:

other: 4000 mg/kg group: Salivation was observed in 2 or 3 females 5 minutes to 1 hour after the administration; salivation was observed in 2 male rats 3 hours after the administration. In addition, decreased activity was observed in 1 or 2 female and male rats

Gross pathology:

A noteworthy change was not observed in the fatal case of the female rat in the 4000 mg/kg group and in any surviving male or female rats in all groups.

Interpretation of results:

GHS criteria not met

Conclusions:

One death was observed in the 5 females in the 4000 mg/kg group while no case of death was observed in the males. No difference was observed in both general state of health and change in body weight between the females and the males. Therefore, LD50 of test item in this study was estimated to be greater than 4000 mg/kg in both female and male rats.

Executive summary:

A study was performed to assess the acute oral toxicity of the test item to Crj:CD(SD) rats. A single dose of test item at 0, 2000 and 4000 mg/kg were administered orally to three groups of Crj:CD(SD) rats, each of which consisted of 5 females or 5 males. After the administration, the rats were observed for 14 days for examination of signs of toxicity.

One death was observed in the 5 females in the 4000 mg/kg group. Transient salivation and decreased activity were observed in a few females and males in both groups in 5 minutes to 3 hours after administration. Significant restraint on increase of body weight was observed on the 1st day in both the females and the males in 4000 mg/kg group, however the condition started making a recovery on the 2nd day or later, and reached approximately same levels as the control group on the 7th day or later. At autopsy, no abnormal change was observed in any females and males in each group including the fatal case.

One death was observed in the 5 females in the 4000 mg/kg group. No difference was observed in both general state of health and change in body weight between the females and the males. Therefore, LD50 of test item in this study was estimated to be about 4000 mg/kg in both female and male rats

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 4 000 mg/kg bw

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

An acute oral toxicity study was conducted (Nippon Experimental Medical Research Institute, 1992, Study H-92032) to assess the toxicity of Jasminlactone following a single oral administration. The study was conducted in accordance with the Ministry of Health and Welfare's "Regarding standards for conducting a safety study of medicine" (PAB Notification No.313, March 31, 1982), "Regarding partial revision of standards for conducting a safety study of medicine" (PAB Notification No.776, October 1, 1983), "Regarding revision of regulations about GLP and inspection for medicine" (PAB Notification No.870, October 5, 1988), and "Regarding guidelines on a toxicity study for an application of manufacturing (import) approval for medicine" (PAB/ED Notification No.1-24, September 11, 1989) and in compliance with GLP.

In the preliminary test single doses of 250, 500, 1000, 2000, and 4000 mg/kg of Jasminlactone were administered via oral gavage to five groups each consisting of 2 male and 2 female Crj:CD(SD) rats. As no deaths were observed, the main test was carried out with the maximum doses from the preliminary test. A single dose of 0, 2000, 4000 mg/kg of Jasminlactone were administered to three groups each consisting of 5 female or 5 male rats. The animals were observed for 14 days.

One female rat assigned to the 4000 mg/kg group has died. Salivation and decreased activity were observed in male and female rats in both dose groups; however, these disappeared 3 - 6 hours after the administration. Therefore, they were considered to be a reflection of pharmacologic effect of Jasminlactone. In addition, loose stool, recumbent state, and lowered body temperature were observed in the case of dead animal. Significant restraint on increase of weight was observed on the 1st day after the administration in both the females and the males assigned to the 4000 mg/kg group, compared to the control group, however the animals started making a recovery on the 2nd day or later, and weights have reached the approximately same level as the control group on the 7th day or later. No changes resulting from the Jasminlactone were observed in anatomical dissection of any females and males in each group.

It was concluded that the acute median lethal dose in rats following single oral administration of Jasminlactone was greater than 4000 mg/kg in female or male rats.

 

No acute inhalation toxicity or acute dermal study was conducted.

Justification for classification or non-classification

The acute oral LD50 of Jasminlactone was determined to be greater than 4000 mg/kg. According to table 3.1.1 of CLP Regulation (Commission Regulation 1272/2008) Jasminlactone is not classified for acute oral toxicity.

No test data is available classify Jasminlactone for acute dermal or inhaled toxicity.