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Toxicological information

Acute Toxicity: oral

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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:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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 preceeded by increased alertness at 30 minutes after dosing), decreased startle response (in 2 males this was preceeded by increased startle response at 30 minutes after dosing), loss of righting reflex (2 males), abnormal gait and posture, Straub-tail (1 female), pilo-erection (1 male), loss of cornea reflex (1 male), decreased body and limb tone, increased body and limb tone (2 females), vocalisation, retracted lower lip (1 male) and sneezing (1 male and 1 female). Time of onset of the first signs was between 0 and 30 minutes, signs were slight to severe in intensity and had disappeared by day 3. In females more signs were scored as being severe than in males.
Body weight:
e-Caprolactone administration had no effect on mean body weights and weight-gains of male rats during the observation period. Female rats however showed a reduced a weight-gain during the first week, in the second week body weight-gains recovered.
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.