Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.13 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
214 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
264.12 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:


NOAECcorr = NOAELoral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABSoral/ABSinh


NOAECcorr = 214 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:
1
Justification:
As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.
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:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is 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:
insufficient hazard data available (further information necessary)
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.99 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):
50
Dose descriptor starting point:
NOAEL
Value:
299.6 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
214 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:


NOAELcorr = NOAELoral x 7d/5d x ABSoral/ABSinh


NOAELcorr = 214 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:
1
Justification:
As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.
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. 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 chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is 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:
DNEL (Derived No Effect Level)
Value:
17.97 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.33
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: DNEL
Value:
5.99 mg/kg bw/day

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

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 214 mg/kg bw/day from a chronic oral rat (1 year feeding) study equivalent to OECD No. 452, 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 382 mg/m3 using the equation provided in the Guidance Document on Information Requirement, Chapter R8:


NOECcorr = NOAELoral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABSoral/ABSinh


Using assessment factors of (i) 2.5 for remaining species differences and (ii) 5 for intraspecies extrapolation, a DNEL of 21.13 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 (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral and dermal toxicity study and in in vivo skin irritation and eye irritation studies. Due to the physico-chemical properties of the substance (especially the moderately low volatility; vapour pressure =3.5 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item in rats by the oral and dermal route was more than 300 mg/kg bw and therefore 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 negative outcomes in in vivo skin irritation and eye irritation studies and further physico-chemical properties of the substance (especially the moderately low volatility; vapour pressure = 3.5 Pa), inhalation exposure is considered unlikely. Thus, long-term and acute local effects in the respiratory tract are not expected.


 


Systemic long-term DNEL for dermal exposure


The NOAEL of 214 mg/kg bw/day from a chronic oral rat (1 year feeding) study equivalent to OECD guideline 452 was 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 299.6 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:


NOAELcorr = NOAELdermal x 7d/5d


Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (ii) 2.5 for remaining interspecies differences and (iii) 5 for intraspecies extrapolation, a DNEL of 5.99 mg/kg bw/day for long-term, systemic dermal exposure was calculated.


 


Systemic acute DNEL for dermal exposure


In an acute dermal toxicity study, the NOAEL was >1600 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute oral toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 3.99 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).


dermal DNELacute = long-term DNEL x 1-5


To derive a dermal DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNELacute of 17.97 mg/kg bw/day was determined.


 


Local long-term and acute DNELs for dermal exposure


Hazards were identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived. A potency categorisation into medium hazard (> 60 % animals responding at > 1 % intradermal induction dose) applies according to ECHA (2016) Guidance on Information Requirements and Chemical Safety Assessment, Part E: Risk Characterisation for the neat substance or mixtures containing the substance in quantities of equal to or more than 1 %, taking into account the generic concentration limits that trigger classification of a mixture as given in Table 3.4.5 of Commission Regulation (EU) No 286/2011.


 


Hazard for the eyes


No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.7 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:
214 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
93 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:


NOAECcorr = NOAELoral x 1/1.15 m³/kg bw/day x ABSoral/ABSinh


NOAECcorr = 214 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:
1
Justification:
As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.
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 chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is 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:
insufficient hazard data available (further information necessary)
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 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:
214 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
214 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


Corrected NOAEL (dermal) for general population:


NOAELcorr = NOAELoral x ABSoral/ABSinh


NOAELcorr = 214 mg/kg bw/day 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:
1
Justification:
As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.
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. The recommended AF for other interspecies differences is applied.
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 chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is 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:
DNEL (Derived No Effect Level)
Value:
6.3 mg/kg bw/day
Most sensitive endpoint:
skin irritation/corrosion
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.33
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: DNEL
Value:
2.1 mg/kg bw/day

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 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:
214 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
214 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation was performed since the original application route for this study was oral.

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:
As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.
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. The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is 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:
DNEL (Derived No Effect Level)
Value:
6.3 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.33
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: DNEL
Value:
2.1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL

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 214 mg/kg bw/day from a chronic oral rat (1 year feeding) study equivalent to OECD No. 452, 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 135 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.


NOECcorr = NOAELoral x 1/1.15 m³/kg bw/day x ABSoral/ABSinh


Using assessment factors of (i) 2.5 for remaining species differences and (ii) 10 for intraspecies extrapolation, a DNEL of 3.7 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 (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral and dermal toxicity study and in in vivo skin irritation and eye irritation studies. Due to the physico-chemical properties of the substance (especially the moderately low volatility; vapour pressure = 3.5 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item in rats by the oral and dermal route was more than 300 mg/kg bw and therefore 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 negative outcomes in in vivo skin irritation and eye irritation studies and further physico-chemical properties of the substance (especially the moderately low volatility; vapour pressure = 3.5 Pa), inhalation exposure is considered unlikely. Thus, long-term and acute local effects in the respiratory tract are not expected.


 


Systemic long-term DNEL for dermal exposure


The NOAEL of 214 mg/kg bw/day from a chronic oral rat (1 year feeding) study equivalent to OECD No. 452 was used as POD. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8 as a similar absorption through the oral and dermal route is assumed.


Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 2.1 mg/kg bw/day for long-term, systemic dermal exposure of the general population was calculated.


 


Systemic acute DNEL for dermal exposure


In an acute dermal toxicity study, LD50 was >1600 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute oral toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 2.1 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).


dermal DNELacute = long-term DNEL x 1-5


To derive a dermal DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNELacute of 6.3 mg/kg bw/day was determined.


 


Local long-term and acute DNELs for dermal exposure


Hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived. A potency categorisation into medium hazard (> 60 % animals responding at > 1 % intradermal induction dose) applies for the neat substance or mixtures containing the substance in quantities of equal to or more than 1 %, taking into account the generic concentration limits that trigger classification of a mixture as given in Table 3.4.5 of Commission Regulation (EU) No 286/2011. However, the concentration of allyl 3-cyclohexylpropionate in fragranced end-products meant for end-use by the general public generally is below 1%. Therefore, no hazard with regard to skin sensitisation is assumed.


 


Systemic long-term DNEL for oral exposure


The NOAEL of 214 mg/kg bw/day from a chronic oral rat (1 year feeding) study equivalent to OECD No. 452 was used as POD. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8.


Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (ii) 2.5 for remaining interspecies differences and (iii) 10 for intraspecies extrapolation, a DNEL of 2.1 mg/kg bw/day for long-term, systemic oral exposure was calculated.


 


Systemic acute DNEL for oral exposure


In an acute oral toxicity study, the LD50 was 380 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute oral toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 3.99 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).


oral DNELacute = long-term DNEL x 1-5


To derive an oral DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNELacute of 17.97 mg/kg bw/day was determined.


 


Hazard for the eyes


No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely.