Cyclohexadecen-1-one

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

49.368 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 234.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m³

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 1000 mg/kg bw/day x 0.5 x 1/0.38 m³/kg bw/day x (6.7 m³/10 m³) x 1.4

= 1234.2 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:

2

Justification:

The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

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

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

14 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):

100

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.

There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected due to the physico- chemical properties of the test item.

Corrected NOAEL (dermal) for workers:

= 1000 mg/kg bw/day x 1.4

= 1400 mg/kg bw/day

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 exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

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

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure also an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected due to very low vapor pressure of 0.0092 Pa).

No repeated dose inhalation toxicity study with the test item is available. Therefore, long-term inhalation DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on an OECD TG 408 study with the test item, daily oral administration to Sprague Dawley rats revealed no adverse signs of toxicity up to the highest dose tested, i. e. 1000 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be >1000 mg/kg bw/day. This NOAEL is applied as Point of Departure for DNEL derivation.

Step 1: PoD: NOAEL = >1000 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 1000 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 1234.2 mg/m³

Step 3: Overall AF= 25

Intraspecies AF (worker): 5

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

Interspecies AF, remaining differences: 2.5

The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1

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

Exposure duration AF: 2

The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

Whole database AF: 1

AF for remaining uncertainties: 1

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

 

In conclusion, long term systemic inhalation DNEL, workers = 49.368 mg/m³

Acute, systemic DNEL- exposure via inhalation (workers)

There is no short-term or long-term toxicity study via inhalation route available for the test item. Due to its very low vapour pressure (< 1 Pa), high peak-inhalation exposure is not considered as relevant. The test item is unlikely to be available as a vapour to a large extent. Thus, the acute inhalation DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur. In addition, the test item is not classified as acutely toxic via oral or dermal route.

Long term & acute, local DNEL- exposure via inhalation (workers)

No data on respiratory irritation are available. The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled. Further, the test item is not expected to be available as a vapour due to its very low vapour pressure. Thus, the inhalation route is not considered relevant for humans

 

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation.

The NOAEL of >1000 mg/kg bw/day derived from an OECD TG 407 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL = >1000 mg/kg bw/day

Step 2: Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.

There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected due to the physico- chemical properties of the test item.

Corrected NOAEL (dermal) for workers:

= 1000 mg/kg bw/day x 1.4

= 1400 mg/kg bw/day

Step 3: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

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

 

Interspecies AF, remaining differences: 2.5

The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (worker): 5

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

 

Dose-response relationship AF: 1

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

 

Exposure duration AF: 2
The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

Whole database AF: 1

 

In conclusion, long term systemic dermal DNEL, workers = 14 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Long term & acute, local DNEL- dermal exposure (workers)

The test substance is classified for skin irritation. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. Thus, a qualitative risk assessment is applied and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

Hazard to the eye-local effects (worker)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP).

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.696 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Corrected NOAEC (inhalation) for general population:

= 1000 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 434.8 mg/m3

AF for dose response relationship:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

AF for differences in duration of exposure:

2

Justification:

The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

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

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

5 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification into a correct starting point:
Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population = 1

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 exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogeneous group "general population" is applied.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

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:

5 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No corrections of the PoD are required.

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 exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

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

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

In an acute oral toxicity study no mortality or signs of toxicity were observed up to the limit dose of 2000 mg/kg bw. Therefore the test item is not classified as acutely toxic via the oral route under Regulation (EC) No. 1272/2008 (CLP).

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General Population

Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

Using a conservative approach, a DNEL for general population (long-term inhalation exposure) is calculated. This long-term DNEL is considered to ensure also an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the test item is available. Therefore, long-term inhalation DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on an OECD TG 408 study with the test item, daily oral administration to Sprague Dawley rats revealed no adverse signs of toxicity up to the highest dose tested, i. e. 1000 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be >1000 mg/kg bw/day. This NOAEL is applied as Point of Departure for DNEL derivation.

Step 1: PoD: NOAEL = >1000 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Corrected NOAEC (inhalation) for general population:

= 1000 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 434.8 mg/m3

Step 3: Overall AF= 50

Intraspecies AF (General population): 10
The default value for the relatively heterogeneous group "general population" is used.

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

Exposure duration AF: 2
The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

Whole database AF: 1

In conclusion, long term systemic inhalation DNEL, general population = 8.696 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

There is no short-term or long-term toxicity study via inhalation route available for the test item. Due to its very low vapour pressure (< 1 Pa), high peak-inhalation exposure is not considered as relevant. The test item is unlikely to be available as a vapour to a large extent. Thus, the acute inhalation DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur. In addition, the test item is not classified as acutely toxic via oral or dermal route.

Long-term and short-term, local DNEL- exposure via inhalation (general population)

No data on respiratory irritation are available. The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled. Further, the test item is not expected to be available as a vapour due to its very low vapour pressure. Thus, the inhalation route is not considered relevant for humans.

 

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation. The NOAEL of 1000 mg/kg bw/day derived from an OECD TG 408 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL= >1000 mg/kg bw/day

Step 2: Modification into a correct starting point:
Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population = 1

Step 3: Overall AF= 200

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is applied

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 2
The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

Whole database AF: 1

In conclusion, long term systemic dermal DNEL, general population = 5 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

Long term & acute, local DNEL- dermal exposure (general population)

The test substance is classified for skin irritation. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. Thus, a qualitative risk assessment is applied and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

Long term, systemic DNEL- exposure by oral route (general population)

An oral repeated dose toxicity study according to OECD 408 with the test item is available. Based on this study, daily oral administration to Sprague Dawley rats revealed no adverse signs of toxicity up to the highest dose tested, i. e. 1000 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be 1000 mg/kg bw/day. This NOAEL is applied as Point of Departure for DNEL derivation.

Step 1: PoD: NOAEL = 1000 mg/kg bw/day

Step 2: Overall AF= 200

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is used.

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 2
The exposure duration of the OECD TG 408 study performed with the test item was 90 days. The default assessment factor for extrapolation from sub-chronic to chronic exposure is 2.

Whole database AF: 1

 

In conclusion, long term systemic oral DNEL, general population= 5 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

In an acute oral toxicity study no mortality or signs of toxicity were observed up to the limit dose of 2000 mg/kg bw. Therefore the test item is not classified as acutely toxic via the oral route under Regulation (EC) No. 1272/2008 (CLP).

 

Hazard to the eye-local effects (general population)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016