Hexan-6-olide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17th September to 1st October 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Proprietary study conducted according to guidelines and GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Hexan-6-olide

EC Number:

207-938-1

EC Name:

Hexan-6-olide

Cas Number:

502-44-3

Molecular formula:

C6H10O2

IUPAC Name:

oxepan-2-one

Details on test material:

e-Caprolactone, batch number WA 2809/0792. Supplier: Solvay S.A., Brussels. Purity: >99%.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

SPF-derived Hsd/Cpb:WU Wistar rats, obtained from Harlan/CPB, Zeist, The Netherlands. Male rats weighed 175-200g, and females weighed 150-175g on arrival. The rats were housed continuously in Macrolon cages with 2-3 animals per cage. The rats had free access to standard laboratory diet, except for a period of 18 hours prior to dosing until 6 hours after dosing. Water was provided ad libitum. The acclimatisation period was 5 days. The temperature of the housing room was maintained at 21-22oC, relative humidity was 50-70%, artificial light was provided betwenn 7am and 7pm, radio-sound was played 24 hours per day, and there were approximately 16 air changes per hour. The rats were individually identified by means of a dye marking system on the fur.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: tragacanth solution in distilled water

Details on oral exposure:

The test material was suspended in a 1.25% tragacanth solution in distilled water. The final concentration was 0.2g/ml. 10ml/kg aliquots were taken from the test material suspension, equivalent to 2000 mg/kg. Aliquots were administered by stomach tube to fasted rats.

Doses:

2000 mg/kg bodyweight

No. of animals per sex per dose:

5 males and 5 females all received one dose of 2000 mg/kg.

Control animals:

no

Details on study design:

The rats were observed from 0-0.5 hour and at 1.5, 3, 6 and 26.5 hours after treatment, and thereafter on each day until the end of the experiment. The total observation period was 14 days. Rats were weighed one day before dosing, the day of dosing prior to treatment, and at 2, 7 and 14 days after treatment. At the end of the observation period rats were killed by ether inhalation and an autopsy performed that included inspection of the external appearance, the cevical area, the thoracic and abdominal cavities.

Statistics:

No statistics were performed.

Results and discussion

Preliminary study:

No information available

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 20% mortality at the limit dose

Mortality:

Two female rats died between 26.5 and 48 hours after treatment. The thoracic and abdominal cavities were too autolytic to detect abnormalities. One of the females was found dead with an arched back and alopecia of flank and forelimbs.

Clinical signs:

other: Symptoms noted were: animals scattered in cage, decreased locomotor activity, apathy (males only), twitches (1 male), exophthalmia (1 male), decreased respiratory rate, respiratory difficulties, decreased alertness (in 2 males and 1 female this was precee

Gross pathology:

1 male rat showed a slightly swollen liver, no other abnormalities were noted. Of the three surviving females, one had slightly darkened adrenals, one had a slightly swollen uterus and one had alopecia of the forelimbs.

Other findings:

The following signs were observed in the two females that died between 26.5 and 48 hours after dosing: animals scattered in cage, decreased locomotor activity, apathy, decreased respiratory rate, respiratory difficulties, decreased alertness, decreased startle response, loss of righting reflex, abnormal gait and posture, total gait incapacity, pilo-erection (1 female), loss of cornea reflex, loss of pinna reflex, decreased body and limb tone, reduced dermal bloodflow, ptosis, retracted lower lip (1 female), hypothermia.

Any other information on results incl. tables

The signs seen at autopsy were reported to be frequently seen in Wistar rats at the authors laboratory when treated with unrelated substances or vehicles. Dilation of the uterus is considered to be a physiological process within the oestrus cycle, and routinely noticed in approximately 1 out of 5 females. Therefore, none of the autopsy findings were considered to be treatment related.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

2 out of 5 females rats died within 2 days of dosing, but no male rats died. Therefore the acute oral LD50 of the substance is >2000 mg/kg bw in rats.

Executive summary:

The 14 day oral LD50 of e-Caprolactone was determined in Wistar rats. A single dose of 2000 mg/kg bw was administered to the rats via a stomach tube, observations were made for 14 days and autopsy was performed at the end of the observation period. Two out of 5 females rats died within 2 days of dosing, but no male rats died. The clinical signs observed were mostly indicative of effects on motor coordination, muscle tone, autonomic nervous system, and central nervous system. Signs appeared within 30 minutes after dosing and disappeared within 3 days. Autopsy did not reveal any macroscopic abnormality that was thought to be treatment related. A sex difference with respect to toxic effects was observed, with female rats being more affected than males. The acute oral LD50 of the substance was determined to be >2000 mg/kg bw in rats, under the conditions of this study.