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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.98 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

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 vitroin 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 bwd, the highest dose level tested.

DNEL derivation

Local effects: dermal

Capa monomer is not a skin irritant, skin or respiratory sensitiser, but is an eye irritant. No dose-response data are available for this effect, therefore a dose descriptor is not available and a DNEL is not derived. Qualitative risk assessment is therefore relevant for local dermal effects and should focus on eliminating the potential for exposure by the use of engineering controls and personal protective equipment.

Local effects: inhalation

Some evidence of mild local irritant effects on the eye and nose were also seen in the 90 -day inhalation toxicity study, with a NOAEC for local effects of 15 ppm (70 mg/m3).

Assessment factors

The use of assessment factors is considered below:

Intraspecies differences: a factor of 1 is used for local effects

Interspecies differences: a default factor of 5 is used

Duration: a default factor of 1 is used for local (concentration-dependent) effects

Dose-response: A default factor of 1 is used

Database quality: A default factor of 1 is used

An overall assessment factor of 5 is therefore used for the long-term systemic inhalation DNEL

Application of the overall assessment factor 5 to the local inhalation NOAEC of 70 mg/m3gives a DNEL value of 14 mg/m3.

Systemic effects: inhalation

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed. The substance is of low toxicity. With the exception of the very high dose levels investigate in the acute toxicity studies, there is no evidence of systemic toxicity. The relevant dose descriptor is the NOAEC of 45 ppm (203 mg/m3) for systemic effects from the 90 -day inhalation toxicity study. The inhalation NOAEC corresponds to a corrected inhalation NOAEC of 104 mg/m3 for worker exposure (203 x 6h/8h x 6.7 m3/10 m3).

The use of assessment factors is considered below:

Intraspecies differences: a factor for allometric scaling is not required; a factor of 1 (for additional factors) is used

Interspecies differences: a default factor of 5 is used

Duration: a default factor of 2 is used for the long-term DNEL (use of a sub-chronic study)

Dose-response: A default factor of 1 is used as the substance is of low toxicity and there are no effects of concern

Database quality: a standard factor of 1 is used

An overall assessment factor of 10 is therefore used for the long-term systemic dermal and inhalation DNELs

Using the corrected inhalation NOAEC of 104 mg/m3, application of the assessment factor results in a a long-term DNEL of 10.4 mg/m3.

Systemic effects: dermal

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed.

The corrected inhalation NOEC of 104 mg/m3 is calculated to be equivalent to an dermal exposure of 14.9 mg/kg bw/d (assuming 70 kg bodyweight and inhalation of 10 m3/day). Following the default assumption that inhalation absorption is twice dermal absorption gives a corrected dermal NOAEL of 29.8 mg/kg bw/d. Applying the overall assessment factor of 10 to this value gives a dermal (systemic) DNEL value of 2.98 mg/kg bw/d.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
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
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.43 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.43 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNEL derivation

Local effects: dermal

E-caprolactone is not a skin irritant, skin or respiratory sensitiser, but is an eye irritant. No dose-response data are available for this effect, therefore a dose descriptor is not available and a DNEL is not derived. Qualitative risk assessment is therefore relevant for local dermal effects and should focus on eliminating the potential for exposure by the use of engineering controls and personal protective equipment

Local effects: inhalation

Some evidence of mild local irritant effects on the eye and nose were also seen in the 90-day inhalation toxicity study, with a NOAEC for local effects of 15 ppm (70 mg/m3).

Assessment factors

The use of assessment factors is considered below:

Intraspecies differences: a default factor of 1 is used for local effects

Interspecies differences: a default factor of 10 is used

Duration: a default factor of 1 is used for local (concentration-dependent) effects

Dose-response: A default factor of 1 is used

Database quality: A default factor of 1 is used

An overall assessment factor of 10 is therefore used for long-term systemic inhalation DNELs

Application of the assessment factor to the local inhalation NOAEC of 70 mg/m3gives a local DNEL value of 7 mg/m3.

Systemic effects: inhalation

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed. The effects relevant to acute exposure are local (site of contact), therefore the DNEL value derived for acute local effects is considered to be adequately protective of any systemic toxicity.

With the exception of the very high dose levels investigated in the acute toxicity studies, there is no evidence of systemic toxicity. The relevant dose descriptor is the NOAEC of 45 ppm (203 mg/m3) for systemic effects from the 90 -day inhalation toxicity study.

The inhalation NOAEC corresponds to a corrected inhalation NOAEC of 50.75 mg/m3for general public exposure (203 x 6h).

Assessment factors

The use of assessment factors according to REACH guidance (Chapter R8) is considered below:

Intraspecies differences: a factor for allometric scaling is not required, a factor to other differences of 1 is used

Interspecies differences: a default factor of 10 is used

Duration: a default factor of 2 is used for the long-term DNEL (use of a sub-chronic study)

Dose-response: A default factor of 1 is used as the substance is of low toxicity and there are no effects of concern

Database quality: A default factor of 1 is used

An overall assessment factor of 20 is therefore used for the long-term systemic dermal and inhalation DNELs

Using the corrected inhalation NOAEC of 50.75 mg/m3, application of the assessment factor of 20 results in a long-term DNEL of 2.5 mg/m3.

Systemic effects: dermal

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed.

The corrected inhalation NOEC of 50.75 mg/m3is calculated to be equivalent to a dermal exposure of 14.5 mg/kg bw/d (assuming 70 kg bodyweight and inhalation of 20 m3/day). Following the default assumption that inhalation absorption is twice dermal absorption gives a corrected dermal NOAEL of 29 mg/kg bw/d. Applying the overall assessment factor of 20 to this value gives a dermal (systemic) DNEL value of 1.43 mg/kg bw/d.

Systemic effects: oral

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed.

The corrected inhalation NOEC of 17 mg/m3 is calculated to be equivalent to an oral exposure of 14.5 mg/kg bw/d (assuming 70 kg bodyweight and inhalation of 20 m3/day). Following the default assumption that inhalation absorption is twice oral absorption gives a corrected oral NOAEL of 29 mg/kg bw/d. Applying the overall assessment factor of 20 to this value gives an oral (systemic) DNEL value of 1.43 mg/kg bw/d.