δ-valerolactone

Toxicological Summary

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:

102 mg/m³

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required since a repeated dose inhalation toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose-response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

The dose descriptor from the underlying animal study (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle. No additional factor is required.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The qualitiy of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

The dose-response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

When comparing subchronic to chronic exposure duration, irritation responses are considered to be mostly concentration dependent; no duration-based difference between subchronic and chronic exposure is assumed.

AF for interspecies differences (allometric scaling):

1

Justification:

The dose descriptor from the underlying animal study (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle. No additional factor is required.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The qualitiy of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by the dermal route available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

The DNELs for Workers - Hazard via inhalation route were calculated with NOAECs obtained in a 90 days inhalation toxicity study in rats (OECD 413) performed with Epsilon-Caprolactone (read across, CAS 502-44-3, Bushy Run Research Centre, 1992). The following DNELs were calculated from a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) performed with Delta-Valerolactone (CAS 542-28-9, BASF SE, 2013) and compared with the above DNELs in order to justify their selection on the basis of the most conservative approach. No additional read-across assessment factors were used for the derivation of the DNELs for worker - Hazard via inhalation route with Epsilon-Caprolactone.

Workers - Hazard via inhalation route, derived from the OECD 422 study (BASF SE, 2013)

Systemic effects

Long term exposure

Hazard assessment conclusion: DNEL (Derived No Effect Level) = 11.8 mg/m³

Most sensitive endpoint: repeated dose toxicity (OECD 422); Route of original study: Oral

DNEL releated information

DNEL derivation method: ECHA REACH Guidance

Overall assessment factor (AF): 75

Dose descriptor starting point (after route to route extrapolation): NOAEC: 881.6 mg/m³

AF for dose response relationship: 1

Justification: The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure: 6

Justification: The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scalling): 1

Justification: Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences: 2.5

Justification: Recommended AF for other interspecies differences.

AF for intraspecies differences: 5

Justification: The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database: 1

Justification: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties: 1

Justification: The approach of the DNEL derivation is conservative. No further assessment factors are required.

Justification and comments: The worker-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 1000 mg/kg bw/day, obtained in the key subacute oral repeated dose study (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) in Wistar rats. The NOAECcorr is calculated as follows: NOAECcorr = 1000 mg/kg bw/day*(1/0.38 m³/kg bw/d)*(0.5/1)*(6.7 m³ (8h)/10 m³ (8h)) = 881.6 mg/m³, with: 1000 mg/kg bw/day: NOAEL, (1/0.38 m³/kg bw/d): correction factor for sRVrat, (0.5/1): ABSoral-rat/ABSinh-human, (6.7 m³ (8h)/10 m³ (8h)): correction factor for physical activity.

Systemic effects

Acute/short term exposure

The DNEL (long-term inhalative exposure, local effects) is considered to ensure a sufficient level of protection for the systemic effects following acute/short term inhalative exposure.

To conclude, the DNEL for the inhalative route of exposure derived from the inhalative subchronic toxicity study with Epsilon-Caprolactone (read across, CAS 502-44-3, Bushy Run Research Centre, 1992) is the most conservative approach (4.1 mg/m3 vs 11.8 mg/m3), completely justifying this key study selection.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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

Modified dose descriptor starting point:

NOAEC

Value:

36.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required since a repeated dose inhalation toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

The dose descriptor from the underlying animal study (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle. No additional factor is required.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The qualitiy of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

When comparing subchronic to chronic exposure duration, irritation responses are considered to be mostly concentration dependent; no duration-based difference between subacute and chronic exposure is assumed.

AF for interspecies differences (allometric scaling):

1

Justification:

The dose descriptor from the underlying animal study (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle. No additional factor is required.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The qualitiy of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by the dermal route available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The DNELs for General population - Hazard via inhalation route were calculated with NOAECs obtained in a 90 days inhalation toxicity study (OECD 413) in rats performed with Epsilon-Caprolactone (read across, CAS 502-44-3, Bushy Run Research Centre, 1992). The following DNELs were calculated from a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) performed with Delta-Valerolactone (CAS 542-28-9, BASF SE, 2013) and compared with the above DNELs in order to justify their selection on the basis of the most conservative approach. No additional read-across assessment factors were used for the derivation of the DNELs for general population - Hazard via inhalation route with Epsilon-Caprolactone.

General Population - Hazard via inhalation route, derived from the OECD 422 study (BASF SE, 2013)

Systemic effects

Long term exposure

Hazard assessment conclusion: DNEL (Derived No Effect Level) = 2.9 mg/m³

Most sensitive endpoint: repeated dose toxicity (OECD 422); Route of original study: Oral

DNEL releated information

DNEL derivation method: ECHA REACH Guidance

Overall assessment factor (AF): 150

Dose descriptor starting point (after route to route extrapolation): NOAEC: 434.8 mg/m³

AF for dose response relationship: 1

Justification: The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure: 6

Justification: The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scalling): 1

Justification: Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences: 2.5

Justification: Recommended AF for other interspecies differences.

AF for intraspecies differences: 10

Justification: The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database: 1

Justification: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties: 1

Justification: The approach of the DNEL derivation is conservative. No further assessment factors are required.

Justification and comments: The general population-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 1000 mg/kg bw/day, obtained in the key subacute oral repeated dose study in (Combined Repeated Dose Toxicity Study with the Reproduction Developmental Toxicity Screening Test) Wistar rats (BASF SE,2013). The NOAECcorr is calculated as follows: NOAECcorr = 1000 mg/kg bw/day*(1/1.15 m³/kg bw/d)*(0.5/1) = 434.8 mg/m³, with: 1000 mg/kg bw/day: NOAEL, (1/1.15 m³/kg bw/d): correction factor for sRVrat, (0.5/1): ABSoral-rat/ABSinh-human.

Systemic effects

Acute/short term exposure

The DNEL (long-term inhalative exposure, local effects) is considered to ensure a sufficient level of protection for the systemic effects following acute/short term inhalative exposure.

To conclude, the DNEL for the inhalative route of exposure derived from the inhalative subchronic toxicity study with Epsilon-Caprolactone (read across, CAS 502-44-3, Bushy Run Research Centre, 1992) is the most conservative approach (0.7 mg/m3 vs 2.9 mg/m3), completely justifying this key study selection.