Registration Dossier

Diss Factsheets

Administrative data

Description of key information

An acute oral toxicity study is available for the read-across (analogue) substance 2-Oxepanone, polymer with 1,4-butanediol (CAPA 203, now known as CAPA 2043). A waiver is proposed for acute inhalation toxicity based on exposure considerations. A waiver is proposed for acute dermal toxicity based on the low acute oral toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16th September 1991 - 15th January 1992.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
CAPA 203 (2-oxepanone, polymer with 1,4-butanediol) now known as CAPA 2043
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan/CPB, Zeist, The Netherlands.
- Age at study initiation: No information provided.
- Weight at study initiation: Males: 175 - 200 g, Females:150 - 175 g
- Fasting period before study: Rats were fasted for 18.5 hours prior to start of the study.
- Housing: Housed continuously in Macrolon cages with two or three animals per cage.
- Diet (e.g. ad libitum): Free access to food which was a standard labortory diet RHM-TM, except during the fasting period.
- Water (e.g. ad libitum): Water was available as libitum.
- Acclimation period: Acclimatisation period was 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 22°C
- Humidity (%): 50 - 70%
- Air changes (per hr): No information provided
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Final concentration was 0.2 g/mL
- Amount of vehicle (if gavage): No information provided.
- Justification for choice of vehicle: No information provided.
- Lot/batch no. (if required): No information provided.
- Purity: No information provided.

MAXIMUM DOSE VOLUME APPLIED: Volumes of 10 ml/kg bw, equivalent to 2000 mg/kg bw were administered.

DOSAGE PREPARATION: The test material was suspended in a 1.25% tragacanth solution in distilled water.
Doses:
2000 mg/kg w
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed at 0-0.5hr and at 1.5, 3, 6 and 26.5 hours after application and on each day until the end of the study. Body weights were recorded the day prior to dosing, day of dosing (day 0) and at 2, 7 and 14 days after treatment.
- Necropsy of survivors performed: yes, including inspection of external appearance, the cervical area, the thoracic and abdominal cavities.
Statistics:
Not required
Preliminary study:
No information provided.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities following administration of a single oral dose of 2000 mg/kg bw CAPA 203.
Clinical signs:
Clinical signs observed in males included decreased respiratory rate, respiratory difficulties, decreased alertness, decreased startle response, and strech movements. Clinical signs in females included exophthalmia and increased body and limb tone. Other clinical signs observed also included decreased locomotor activity, abnormal gait and posture. The time of onset of the first signs was within 30 minutes in males and females. Signs were slight to moderate in intensity in both sexes. All signs had disappeared by 26.5 hours after treatment.
Body weight:
Fasting on the day prior to dosing caused a small weight loss in all animals. Oral administration of 2000 mg/kg bw CAPA 203 had no effect on mean body weights and weight-gains of male rats during the observation period. Female rats given the same treatment showed a reduced weight gain during the first week of the study. In the second week, body weight gains recovered.
Gross pathology:
2 males and 1 female rat had alopecia of the anterior body wall. Another male rat had a slightly swollen liver. No abnormalities were noted in the other animals.
Other findings:
No additional information provided.

Mean body weight-gain (g) of groups of five male and five female rats given a single oral dose of CAPA 203:

Sex

Dose (mg/kg bw)

Day-1 to 2

Day 2 to 7

Day 7 to 14

Day -1 to 14

Male

2000

12.0

28.0

35.8

75.8

Female

2000

0.6

2.4

9.4

12.4

The clinical signs were mostly indicative of effects on motor coordination, muscle tone and on the autonomic nervous system.

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Oral administration of a single dose of 2000 mg/kg bw CAPA 203 caused no mortalities among male and female rats during the 14 day observation period. Therefore, the acute oral LD50 is >2000 mg/kg bw in rats. CAPA 203 does not require classification for acute oral toxicity according to CLP criteria.
Executive summary:

An acute oral toxicity study was conducted in accordance with GLP and with EEC method B.1 to determine the acute oral toxicity of CAPA 203 in male and female rats. A single oral dose of 2000 mg/kg bw CAPA 203 (suspended in 1.25% aqueous tragacanth solution) was given by stomach tube to groups of five male and five female fasted Wistar rats. Rats were weighed one day before dosing, at the day of dosing and at Days 2, 7 and 14. There was no mortality during the study. Clinical signs observed were mostly indicative of effects on motor coordination (decreased locomotor activity, abnormal gait and posture), on muscle tone (increased body and limb tone) and on the autonomic nervous system (decreased respiratory rate and breathing difficulties). There was no effect on mean bodyweight gain by male rats, but reduced bodyweight gain was reported for females during the first week of the study. Gross necropsy did not reveal any findings considered to be treatment-related. The acute oral LD50 of CAPA 203 in the rat was therefore established to be >2000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
16th September 1991 - 15th January 1992.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
See attached justification
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan/CPB, Zeist, The Netherlands.
- Age at study initiation: No information provided.
- Weight at study initiation: Males: 175 - 200 g, Females:150 - 175 g
- Fasting period before study: Rats were fasted for 18.5 hours prior to start of the study.
- Housing: Housed continuously in Macrolon cages with two or three animals per cage.
- Diet (e.g. ad libitum): Free access to food which was a standard labortory diet RHM-TM, except during the fasting period.
- Water (e.g. ad libitum): Water was available as libitum.
- Acclimation period: Acclimatisation period was 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 22°C
- Humidity (%): 50 - 70%
- Air changes (per hr): No information provided
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Final concentration was 0.2 g/mL
- Amount of vehicle (if gavage): No information provided.
- Justification for choice of vehicle: No information provided.
- Lot/batch no. (if required): No information provided.
- Purity: No information provided.

MAXIMUM DOSE VOLUME APPLIED: Volumes of 10 ml/kg bw, equivalent to 2000 mg/kg bw were administered.

DOSAGE PREPARATION: The test material was suspended in a 1.25% tragacanth solution in distilled water.
Doses:
2000 mg/kg w
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed at 0-0.5hr and at 1.5, 3, 6 and 26.5 hours after application and on each day until the end of the study. Body weights were recorded the day prior to dosing, day of dosing (day 0) and at 2, 7 and 14 days after treatment.
- Necropsy of survivors performed: yes, including inspection of external appearance, the cervical area, the thoracic and abdominal cavities.
Statistics:
Not required
Preliminary study:
No information provided.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities following administration of a single oral dose of 2000 mg/kg bw CAPA 203.
Clinical signs:
Clinical signs observed in males included decreased respiratory rate, respiratory difficulties, decreased alertness, decreased startle response, and strech movements. Clinical signs in females included exophthalmia and increased body and limb tone. Other clinical signs observed also included decreased locomotor activity, abnormal gait and posture. The time of onset of the first signs was within 30 minutes in males and females. Signs were slight to moderate in intensity in both sexes. All signs had disappeared by 26.5 hours after treatment.
Body weight:
Fasting on the day prior to dosing caused a small weight loss in all animals. Oral administration of 2000 mg/kg bw CAPA 203 had no effect on mean body weights and weight-gains of male rats during the observation period. Female rats given the same treatment showed a reduced weight gain during the first week of the study. In the second week, body weight gains recovered.
Gross pathology:
2 males and 1 female rat had alopecia of the anterior body wall. Another male rat had a slightly swollen liver. No abnormalities were noted in the other animals.
Other findings:
No additional information provided.

Mean body weight-gain (g) of groups of five male and five female rats given a single oral dose of CAPA 203:

Sex

Dose (mg/kg bw)

Day-1 to 2

Day 2 to 7

Day 7 to 14

Day -1 to 14

Male

2000

12.0

28.0

35.8

75.8

Female

2000

0.6

2.4

9.4

12.4

The clinical signs were mostly indicative of effects on motor coordination, muscle tone and on the autonomic nervous system.

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Oral administration of a single dose of 2000 mg/kg bw of the read-across substance CAPA 203 caused no mortalities among male and female rats during the 14 day observation period. Therefore, the acute oral LD50 is >2000 mg/kg bw in rats. Based on read-across, CAPA 2047A does not require classification for acute oral toxicity according to CLP criteria.
Executive summary:

An acute oral toxicity study was conducted in accordance with GLP and with EEC method B.1 to determine the acute oral toxicity of the read-across substance CAPA 203 in male and female rats. A single oral dose of 2000 mg/kg bw CAPA 203 (suspended in 1.25% aqueous tragacanth solution) was given by stomach tube to groups of five male and five female fasted Wistar rats. Rats were weighed one day before dosing, at the day of dosing and at Days 2, 7 and 14. There was no mortality during the study. Clinical signs observed were mostly indicative of effects on motor coordination (decreased locomotor activity, abnormal gait and posture), on muscle tone (increased body and limb tone) and on the autonomic nervous system (decreased respiratory rate and breathing difficulties). There was no effect on mean bodyweight gain by male rats, but reduced bodyweight gain was reported for females during the first week of the study. Gross necropsy did not reveal any findings considered to be treatment-related. The acute oral LD50 of CAPA 203 in the rat was therefore established to be >2000 mg/kg bw. Based on read-across, low acute oral toxicity is also predcited for CAPA 2047A.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
A modern, guideline- and GLP-compliant (K1) read-across study is available.

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

Studies of the acute toxicity of 2-oxepanone, polymer with 1,6 hexanediol are not available. An acute oral toxicity study is available for the read-across (analogue) substance 2 -oxepanone, polymer with 1,4-butanediol (CAPA 203, now known as CAPA 2043). A waiver is proposed for acute inhalation toxicity based on exposure considerations. A waiver is proposed for acute dermal toxicity based on the low acute oral toxicity.

Acute oral toxicity (read-across)

An acute oral toxicity study was conducted in accordance with GLP and with EEC method B.1 to determine the acute oral toxicity of CAPA 203 in male and female rats. A single oral dose of 2000 mg/kg bw CAPA 203 (suspended in 1.25% aqueous tragacanth solution) was given by stomach tube to groups of five male and five female fasted Wistar rats. Rats were weighed one day before dosing, at the day of dosing and at Days 2, 7 and 14. There was no mortality during the study. Clinical signs observed were mostly indicative of effects on motor coordination (decreased locomotor activity, abnormal gait and posture), on muscle tone (increased body and limb tone) and on the autonomic nervous system (decreased respiratory rate and breathing difficulties). There was no effect on mean bodyweight gain by male rats, but reduced bodyweight gain was reported for females during the first week of the study. Gross necropsy did not reveal any findings considered to be treatment-related. The acute oral LD50 of CAPA 203 in the rat was therefore established to be >2000 mg/kg bw.

Acute dermal toxicity

A waiver is proposed based on the low toxicity seen in the acute oral toxicity study.

Acute inhalation toxicity

A waiver is proposed for acute inhalation studies in accordance with Column 2 of Annex VIII of the REACH Regulation.  Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance. The substance is a non-volatile liquid and the use pattern indicates that significant inhalation exposure is unlikely.

Justification for classification or non-classification

Classification for acute oral toxicity is not required based on the results of a study with a read-across (analogue) substance. Low acute dermal toxicity is predicted. No data on acute inhalation toxicity are avaialable. The submission substance (2-oxepanone, polymer with 1,6 hexanediol) is therefore not classified for acute toxicity according to CLP criteria.