Allyl (cyclohexyloxy)acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.34 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:

67.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

83.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

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

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

Corrected NOAEC (inhalation) for workers:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

NOEC_corr = 67.6 mg/kg bw/day x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x 1/2

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:

Extrapolation from subchronic to chronic exposure.

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

Justification:

The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

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:

0.946 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:

67.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

94.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/1

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

Corrected NOAEL (dermal) for workers:

NOAEL_corr = NOAEL_oral x 7d/5d x ABS_oral/ABS_inh

NOAEL_corr = 67.6 mg/kg bw/day x 7d/5d x 1/1

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:

Extrapolation from subchronic to chronic exposure.

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

Justification:

The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 67.6 mg/kg bw/day from a subchronic oral rat study according to OECD guideline 408, considering an oral bioavailability of 100%. It was modified  using a human standard respiratory volume (sRVhuman) of 6.7 m³ for 8 hours per person (70 kg), a rat standard respiratory volume (sRVrat) of 0.38 m³/kg bw for 8 hours, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 83.4 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

Using assessment factors of (i) 2 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 5 for intraspecies extrapolation, a DNEL of 3.34 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study needs to be conducted if, taking into account the vapor pressure of the substance and/or the possibility of exposure to dust, mist or vapour of an inhalable size, human exposure is to be expected. An acute inhalation study does not need to be conducted if the oral and dermal routes are more relevant for exposure. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure=0.52 hPa at 20°C), high peak-inhalation exposure is not considered relevant. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure=0.52 hPa at 20°C), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin and eye irritation as well as skin sensitisation according to Regulation (EC) No 1272/2008 (CLP). Thus, acute and long-term local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 67.6 mg/kg bw/day from a subchronic oral toxicity study according to OECD guideline 408 is used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 94.6  mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NOAEL_dermal x 7d/5d

Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 5 for intraspecies extrapolation, a DNEL of 0.946 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

An acute dermal toxicity study is available which showed an LD50 of >2000 mg/kg bw. Furthermore, no adverse systemic effects were observed in an in vivo skin irritation, ex vivo eye irritation and an in vivo skin sensitisation study. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for dermal exposure

No adverse local effects were observed in an in vivo skin irritation, in an ex vivo eye irritation and in an in vivo skin sensitisation study. Furthermore, no local effects were observed in a dermal acute toxicity study up to the limit dose of 2000 mg/kg bw. Thus, no acute and long-term local effects are expected during use of the substance.

 

Hazard for the eyes

No adverse local effects were observed in an ex vivo eye irritation study. Thus, no hazard for the eyes is expected during use of the substance. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.588 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:

67.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

29.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

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

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

Corrected NOAEC (inhalation) for general population:

NOEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

NOEC_corr = 67.6 mg/kg bw/day x 0.87 m³/kg bw/day x 1/2

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:

Extrapolation from subchronic to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling 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 heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

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:

0.338 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:

67.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

67.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No corrections are needed as a similar absorption through the oral and dermal route is assumed.

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:

Extrapolation from subchronic to chronic exposure.

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 heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.338 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:

67.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

67.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification is needed as the same route of exposure is assessed and the same exposure period is assumed.

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:

Extrapolation from subchronic to chronic exposure.

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 heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

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:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 67.6 mg/kg bw/day from a subchronic oral rat study according to OECD guideline 408 and considering an oral bioavailability of 100%. It was modified  using a rat standard respiratory volume (sRVrat) of 1.15 m³/kg bw/day for 24 hours and the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) to 29.4 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.

NOEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

Using assessment factors of (i) 2 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 10 for intraspecies extrapolation, a DNEL of 0.588 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study needs to be conducted if, taking into account the vapor pressure of the substance and/or the possibility of exposure to dust, mist or vapor of an inhalable size, human exposure is to be expected. An acute inhalation study does not need to be conducted if the oral and dermal routes are more relevant for exposure. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure= 0.52 hPa at 20°C), high peak-inhalation exposure is not considered relevant. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure=0.52 hPa at 20°C), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin and eye irritation as well as skin sensitisation according to Regulation (EC) No 1272/2008 (CLP). Thus, acute and long-term local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 67.6 mg/kg bw/day from a subchronic oral toxicity study according to OECD guideline 408 is used as POD. No corrections are needed as a similar absorption through the oral and dermal route is assumed.

Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 0.338 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

An acute dermal toxicity study is available which showed an LD50 of >2000 mg/kg bw. Furthermore, no adverse systemic effects were observed in the acute oral toxicity study and in in vivo skin irritation, eye irritation and skin sensitisation studies. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for dermal exposure

No adverse local effects were observed in an in vivo skin irritation, in an ex vivo eye irritation and in an in vivo skin sensitisation study. Furthermore, no local effects were observed in a dermal acute toxicity study up to the limit dose of 2000 mg/kg bw. Thus, no acute and long-term local effects are expected during use of the substance.

 

Systemic long-term DNEL for oral exposure

The NOAEL of 67.6 mg/kg bw/day from a subchronic oral toxicity study according to OECD guideline 408 is used as POD considering a 100% oral absorption. It did not have to be modified according to Guidance Document on Information Requirement, Chapter R8

Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 0.338 mg/kg bw/day for long-term, systemic oral exposure was calculated.

 

Systemic acute DNEL for oral exposure

The substance is classified as Acute Tox. 4; H302. No oral acute toxicity DNEL was derived. The assessment of the hazard after short-term exposure is sufficiently covered by derivation of the DNEL for long-term exposure.

 

Hazard for the eyes

No adverse local effects were observed in an ex vivo eye irritation study. Thus, no hazard for the eyes is expected during use of the substance.