Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
4.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEC for rats (203 mg/m³) was converted to a modified dose descriptor starting point for worker exposure using the correction factors described in Appendix R.8-2 in ECHA guidance R.8 (203 mg/m³ × 6h/8h x 6.7 m³/10 m³).

AF for dose response relationship:
1
Justification:
A default factor of 1 is used, in accordance with Table R.8-6 in ECHA guidance R.8, as the substance is of low toxicity and there are no effects of concern.
AF for differences in duration of exposure:
2
Justification:
In accordance with Table R.8-6 in ECHA guidance R.8, a default factor of 2 is used for the long-term DNEL (use of a sub-chronic study).
AF for interspecies differences (allometric scaling):
1
Justification:
A factor for allometric scaling is not required when setting a DNEL based on an inhalation animal study (ECHA guidance R.8, Table R.8-6).
AF for other interspecies differences:
2.5
Justification:
Default factor of 2.5 is used as described in Table R.8-6 in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
AF for the quality of the whole database:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Value:
7 mg/m³
AF for dose response relationship:
1
Justification:
A default factor of 1 is used, in accordance with Table R.8-6 in ECHA guidance R.8.
AF for differences in duration of exposure:
2
Justification:
A default factor of 2 is used the long-term DNEL (use of a sub-chronic study) in accordance with Table R.8-6 in ECHA guidance R.8.
AF for interspecies differences (allometric scaling):
1
Justification:
The effects seen in the available 90-day inhalation study in rats are predominantly local irritating effects. Allometric scaling is not applicable for local effects and an overall factor of 1 is used for local effects, as described in Table R.8-6 in ECHA guidance R.8.
AF for other interspecies differences:
1
Justification:
The effects seen in the available 90-day inhalation study in rats are predominantly local irritating effects and not related to metabolism. Following ECHA guidance chapter R8, Table R8-6, the assessment factor for other interspecies differences is therefore set to 1.
AF for intraspecies differences:
5
Justification:
The default factor of 5 is used, in accordance with Table R.8-6 in ECHA guidance R.8.
AF for the quality of the whole database:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.02 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEC
Value:
1.02 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.02 mg/kg bw/day
AF for dose response relationship:
1
Justification:
A default factor of 1 is used, in accordance with Table R.8-6 in ECHA guidance R.8.)
AF for differences in duration of exposure:
2
Justification:
In accordance with Table R.8-6 in ECHA guidance R.8, a default factor of 2 is used for the long-term DNEL (use of a sub-chronic study).
AF for interspecies differences (allometric scaling):
4
Justification:
The ECHA default factor is used for allometric scaling as described in table Table R.8-3 in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
Default factor of 2.5 in accordance with Table R.8-6 in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
A default factor of 5 is used, in accordance with Table R.8-6 in ECHA guidance R.8.
AF for the quality of the whole database:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
Default factor is used as described in Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Summary of toxicity

Toxicokinetics

A theoretical assessment of the toxicokinetics of e-caprolactone indicates that the substance will be rapidly chemically or enzymatically hydrolysed under physiological conditions (i.e. in the stomach or following absorption into the bloodstream) with the subsequent production of 6 -hydroxyhexanoic acid. The half-life of e-caprolactone in the stomach is approximately 0.4 hours (pH 1.2, temperature 37 °C). Human serum paraoxonase (PON1) isozymes Q and R are able to hydrolyse lactone substances including e-caprolactone; half-lives of less than one minute are reported for structurally similar substances. The hydrolysis product is water soluble and expected to be distributed throughout the body and excreted rapidly in the urine. Bioaccumulation is not predicted; however, the hydrolysis product may be incorporated to some extent in metabolic pathways due to its structural similarity to endogenous fatty acids.

 

Acute toxicity

The substance is of low acute toxicity by the oral route (LD50 values reported are > 2000–4290 mg/kg bw) and also by the dermal route (LD50 = 6400 mg/kg bw). A waiver is proposed for acute inhalation toxicity 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 (Smythet 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. These local effects are consistent with the findings of the 90-day inhalation toxicity study, in which local irritation of the respiratory tract but no systemic toxicity was seen. Findings are also consistent with the known potential of the substance to be an eye irritant. 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.

 

Irritation

e-Caprolactone was not irritating to the skin of rabbits but was found to be an eye irritant in a rabbit study and should be classified as such under CLP.

 

Sensitisation

No evidence of skin sensitisation potential was seen in a modern LLNA. There is no indication of skin or respiratory sensitisation potential from experience of worker exposure.

 

Repeated dose toxicity

A 90-day rat inhalation study demonstrates local irritation (as indicated by effects on the eyes and nose) in the absence of any systemic toxicity at an exposure concentration of 45 ppm (203 mg/m³). A NOAEC of 15 ppm (70 mg/m³) is derived for this study. Waivers are proposed according to Column 2 of Annex VIII and IX of the REACH Regulation for dermal and oral exposure; the toxicity of the substance by a relevant route of exposure (inhalation) has been adequately investigated. Additional studies are therefore not scientifically justified and cannot be supported on animal welfare grounds

 

Genetic toxicity

Negative results are reported in vitro in three Ames tests and in studies of mutagenicity and clastogenicity in mammalian cells. An additional study of clastogenicity with the read-across substance adipic acid also gives negative results. In vivo, negative results are reported in a rat bone marrow cytogenicity assay and in a rat dominant lethal assay, both performed with the read-across substance adipic acid.

 

Reproductive and developmental toxicity

No studies are available with regard to reproduction and developmental toxicity of e-caprolactone. However, a well conducted 90-day inhalation study showed no macroscopic and histopathological effects on reproductive organs and also other systemic effects were not found during this study. The lack of systemic effects can be explained by the rapid hydrolysis in stomach and blood, resulting in the formation of 6-hydroxyhexanoic acid. No reproductive toxicity is expected for this simple aliphatic carboxylic acid.

A rabbit developmental toxicity study performed with the read-across substance adipic acid reports a NOAEL for maternal and developmental toxicity of 250 mg/kg bw/day, the highest dose level tested.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.02 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEC
Value:
1.02 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
1.02 mg/m³
Explanation for the modification of the dose descriptor starting point:

The inhalation NOAEC corresponds to a corrected inhalation NOAEC of 50.75 mg/m³ for general public exposure (203 × 6h/24h). 

AF for dose response relationship:
1
Justification:
A default factor of 1 is used as the substance is of low toxicity and there are no effects of concern, in accordance with REACH guidance (Chapter R.8).
AF for differences in duration of exposure:
2
Justification:
The ECHA default factor 2 is used for the long-term DNEL (use of a sub-chronic study), according to REACH guidance (Chapter R.8).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not required using a NOAEC based on inhalation, as described in the REACH guidance (Chapter R.8).
AF for other interspecies differences:
2.5
Justification:
The ECHA default factor of 2.5 is used for interspecies differences, in accordance with REACH guidance (Chapter R.8).
AF for intraspecies differences:
10
Justification:
The ECHA default factor of 10 is used for interspecies differences, in accordance with REACH guidance (Chapter R.8).
AF for the quality of the whole database:
1
Justification:
The ECHA default factor iof 1 s used as described in Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
The ECHA default factor iof 1 s used as described in Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor:
NOAEC
Value:
3.5 mg/m³
AF for dose response relationship:
1
Justification:
A default factor of 1 is used as the substance is of low toxicity and there are no effects of concern.
AF for differences in duration of exposure:
2
Justification:
The ECHA default factor of 2 is used for the long-term DNEL (use of a sub-chronic study) in accordance to Table R.8-6 in ECHA guidance R.8.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applicable for local effects, as described in Table R.8-6 in ECHA guidance R.8.
AF for other interspecies differences:
1
Justification:
The overall factor of 1 is used for local effects, as described in Table R.8-6 in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 is used, in accordance to Table R.8-6 in ECHA guidance R.8.
AF for the quality of the whole database:
1
Justification:
The ECHA default factor of 1 is used, in accordance to Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
The ECHA default factor of 1 is used, in accordance to Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEC
Value:
0.25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The corrected inhalation NOEC of 50.75 mg/m³ (NOAEL from the available 90-day inhalation study in rat, corrected for exposure duration 6 h (rat)/24 h (general population)) is used as basis for the DNEL calculations, in accordance with the ECHA guidance document chapter R.8.

AF for dose response relationship:
1
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8.
AF for differences in duration of exposure:
2
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8 (use of a sub-chronic study).
AF for interspecies differences (allometric scaling):
4
Justification:
The ECHA default factor is used for allometric scaling as described in table Table R.8-3 in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8.
AF for the quality of the whole database:
1
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8.
AF for remaining uncertainties:
1
Justification:
The ECHA default assessment factor is used, according to Table R.8-6 in ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEC
Value:
0.3 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting from the available NOAEC (203 mg/m³) in rat from the 90-day inhalation study and correcting for differences in duration (6 h exposure /day in the study compared to 24 h/day for general public) gives the following corrected NOAEC = 203 × 6/24 = 50.8 mg/m³. When going from an inhalation value to an oral value the standard breathing volume of 20 m³/day is used for the general public (as described in ECHA guidance R.8). Also the standard bodyweight of 60 kg is used to convert from mg/m3 to mg/kg bw/day. The corrected NOAEC is therefore generating an oral NOAEL of 14.7 mg/kg bw/day (= 50.8 × 20/60). The calculated oral NOAEL of 16.9 mg/kg bw/day is therefore used as basis for the DNEL calculations, in combinations with the overall assessment factor of 50.

AF for dose response relationship:
1
Justification:
The ECHA default factor is used, according to REACH guidance (Chapter R8).
AF for differences in duration of exposure:
2
Justification:
In accordance to Table R.8-6 in ECHA guidance R.8, a default factor of 2 is used for the long-term DNEL (use of a sub-chronic study).
AF for interspecies differences (allometric scaling):
1
Justification:
The allometric differences are already considered when converting the NOAEC in rat to corresponding NOAEL in humans, as described in example R8-1 in in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
The ECHA default factor is used for other interspecies differences as described in table Table R.8-3 in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
The ECHA default factor of 10 is used, in accordance with Table R.8-6 in ECHA guidance R.8
AF for the quality of the whole database:
1
Justification:
The ECHA default factor is used, in accordance with Table R.8-6 in ECHA guidance R.8
AF for remaining uncertainties:
1
Justification:
The ECHA default factor is used, in accordance with Table R.8-6 in ECHA guidance R.8
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Summary of toxicity

Toxicokinetics

A theoretical assessment of the toxicokinetics of e-caprolactone indicates that the substance will be rapidly chemically or enzymatically hydrolysed under physiological conditions (i.e. in the stomach or following absorption into the bloodstream) with the subsequent production of 6 -hydroxyhexanoic acid. The half-life of e-caprolactone in the stomach is approximately 0.4 hours (pH 1.2, temperature 37 °C). Human serum paraoxonase (PON1) isozymes Q and R are able to hydrolyse lactone substances including e-caprolactone; half-lives of less than one minute are reported for structurally similar substances. The hydrolysis product is water soluble and expected to be distributed throughout the body and excreted rapidly in the urine. Bioaccumulation is not predicted; however, the hydrolysis product may be incorporated to some extent in metabolic pathways due to its structural similarity to endogenous fatty acids.

 

Acute toxicity

The substance is of low acute toxicity by the oral route (LD50 values reported are > 2000–4290 mg/kg bw) and also by the dermal route (LD50 = 6400 mg/kg bw). A waiver is proposed for acute inhalation toxicity 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 (Smythet 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. These local effects are consistent with the findings of the 90-day inhalation toxicity study, in which local irritation of the respiratory tract but no systemic toxicity was seen. Findings are also consistent with the known potential of the substance to be an eye irritant. 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.

 

Irritation

e-Caprolactone was not irritating to the skin of rabbits but was found to be an eye irritant in a rabbit study and should be classified as such under CLP.

 

Sensitisation

No evidence of skin sensitisation potential was seen in a modern LLNA. There is no indication of skin or respiratory sensitisation potential from experience of worker exposure.

 

Repeated dose toxicity

A 90-day rat inhalation study demonstrates local irritation (as indicated by effects on the eyes and nose) in the absence of any systemic toxicity at an exposure concentration of 45 ppm (203 mg/m³). A NOAEC of 15 ppm (70 mg/m³) is derived for this study. Waivers are proposed according to column 2 of Annex VIII and IX of the REACH Regulation for dermal and oral exposure; the toxicity of the substance by a relevant route of exposure (inhalation) has been adequately investigated. Additional studies are therefore not scientifically justified and cannot be supported on animal welfare grounds

 

Genetic toxicity

Negative results are reported in vitro in three Ames tests and in studies of mutagenicity and clastogenicity in mammalian cells. An additional study of clastogenicity with the read-across substance adipic acid also gives negative results. In vivo, negative results are reported in a rat bone marrow cytogenicity assay and in a rat dominant lethal assay, both performed with the read-across substance adipic acid.

 

Reproductive and developmental toxicity

No studies are available with regard to reproduction and developmental toxicity of e-caprolactone. However, a well conducted 90-day inhalation study showed no macroscopic and histopathological effects on reproductive organs and also other systemic effects were not found during this study. The lack of systemic effects can be explained by the rapid hydrolysis in stomach and blood, resulting in the formation of 6-hydroxyhexanoic acid. No reproductive toxicity is expected for this simple aliphatic carboxylic acid.

A rabbit developmental toxicity study performed with the read-across substance adipic acid reports a NOAEL for maternal and developmental toxicity of 250 mg/kg bw/day, the highest dose level tested.