Registration Dossier

Administrative data

Description of key information

The substance is of low acute toxicity by the oral roure (LD50 values reported are >2000-4290 mg/kg bw) and also by the dermal route (LD50 6400 mg/kg bw). Acute toxicity by inhalation is not investigated due to the low volatilty of the substance; this is not considered to be a relevant expousre route and a waiver is proposed according to Column 2 of Annex VIII of the REACH Regulation.

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:
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.
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
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.
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.
Preliminary study:
No information available
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.

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.

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 290 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Older published study and original report; guideline comparable with limited reporting details but sufficient for the assessment of toxicity and classification
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
The study was conducted according to the one-day cuff method of Draize et al (1944), and is generally similar to OECD 402.
GLP compliance:
no
Remarks:
older proprietary study; pre-dates GLP
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
The animals were male New Zealand giant albino rabbits, weighing 2.5 to 3.5 kg and 3 to 5 months of age..
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The fur of the entire trunk was closely clipped, and the substance was placed in contact with the skin so as to cover about 10% of the body surface. The substance was held in place with an occlusive impervious plastic film (polyethylene). After 24 hours exposure to the substance, the film and test substance was removed.
Duration of exposure:
24 hours
Doses:
Doses applied were 5000 and 10000 mg/kg bw.
No. of animals per sex per dose:
4 males/dose
Control animals:
no
Details on study design:
The rabbits were observed for 14 days after removal of the test substance. Necropsies were performed.
Statistics:
The LD50 with limits of ± 2 standard deviations (95% confidence limits) was calculated by the Thompson method
Preliminary study:
None
Sex:
male
Dose descriptor:
LD50
Effect level:
5.99 mL/kg bw
Based on:
test mat.
95% CL:
4.27 - 8.42
Remarks on result:
other: Equivalent to 6400 mg/kg bw using a relative density of 1.07
Mortality:
Deaths occurred at 10000 ml/kg bw (4/4) and at 5000 ml/kg bw (1/4) on Day 1 or 2.
Clinical signs:
Skin erythema was produced, which may or may not result in necrosis and desquamation.
Body weight:
One survivor at 5000 mg/kg bw lost weight (58 g; ~2.4% initial weight) over the study period.
Gross pathology:
Autopsies revealed congested haemorrhagic lungs, and extremely congested livers.
Other findings:
No other findings reported.

Dose level (ml/kg bw)

Deaths

Day of death

10000

4/4

1-2

5000

1/4

2

The acute dermal LD50 was calculated to be 5.99 ml/kg bw; this is equivalent to 6400 mg/kg bw using a relative density of 1.07.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 was 5.99 (4.27 -8.42) ml/kg bw; calculated to be equivalent to 6400 (4570 -9000) mg/kg bw.
Executive summary:

The acute dermal toxicity of ε-caprolactone was determined in male New Zealand White rabbits (4 per group). The test substance was applied to the clipped skin of the trunk, covering approximately 10% of the body surface. The test substance was held in place for 24 hours using an impervious plastic film. After removal of the dressing, the rabbits were observed for 14 days for mortality. Deaths occurred at 10000 ml/kg bw (4/4) and at 5000 ml/kg bw (1/4). Skin erythema was produced, and autopsies revealed congested haemorrhagic lungs, and extremely congested livers. The acute dermal LD50 was 5.99 (4.27 -8.42) ml/kg bw; calculated to be equivalent to 6400 (4570 -9000) mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
6 400 mg/kg bw

Additional information

Acute oral toxicity

The oral LD50 of ε-caprolactone was determined in Wistar rats in a GLP study according to EU Method B.1 (Snoeji & Buse-Pot, 1992). A single dose of 2000 mg/kg bw ε-caprolactone 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 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. The acute oral LD50 of the substance was therefore found to be >2000 mg/kg bw under the conditions of this study.

The acute oral toxicity of ε-caprolactone was determined in groups of 5 male Carworth-Wistar rats (Smyth et al, 1954; Carpenter, 1953). ε-caprolactone was administered orally by gavage as a 10% aqueous solution at doses of 2000, 4000 and 8000 mg/kg bw and animals observed for 14 days. Deaths occurred at the two highest dose levels. Signs of toxicity were apparent within 4 hours of dosing and included narcosis, prostration, ruffed coats and sluggishness. Autopsies of decedents revealed congestion of the lungs, mottling of livers, pale kidneys and gastrointestinal tract irritation. The LD50 was calculated to to be 4290 (3070 -5980) mg/kg bw under the conditions of this study.

Acute toxicity: inhalation

A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation. Inhalation exposure is unlikely as the vapour pressure of the substance is 0.81 Pa at 25°C. An older and non-standard study (Smyth et al,1954; Carpenter, 1953) indicates that the only treatment-related effects in rats following exposure to air saturated with the substance for 8 hours was slight skin irritation. No additional testing is proposed for reasons of animal welfare. Worker inhalation exposure is not likely to be significant given the low vapour pressure and the effects of exposure will be limited by local irritation.

Acute toxicity: dermal

The acute dermal toxicity of ε-caprolactone was determined in groups of 4 male New Zealand White rabbits (Smyth et al, 1954; Carpenter; 1953). The test substance was applied to the clipped skin of the trunk, covering approximately 10% of the body surface. The test substance was held in place for 24 hours using an impervious plastic film. After removal of the dressing, the rabbits were observed for 14 days for mortality. Deaths occurred at 10000 ml/kg bw (4/4) and at 5000 mL/kg bw (1/4). Skin erythema was produced, and autopsies revealed congested haemorrhagic lungs, and extremely congested livers. The acute dermal LD50 was 5.99 (4.27 -8.42) mL/kg bw; calculated to be equivalent to 6400 (4570 -9000) mg/kg bw.

Justification for classification or non-classification

The substance is shown to be of low acute toxicity by the oral and dermal routes of exposure; inhalation exposure is unlikely due to the low volatilty of the substance and no testing is proposed for this route of exposure. The available data do not indicate that the substance requires classification for acute toxicity according to Dircetive 67/548/EEC and Regulation (EC) No 1272/2008 (the CLP Regulation).