Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.41 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR 110 (2010)
Overall assessment factor (AF):
28.44
Dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
182.38 mg/m³
Explanation for the modification of the dose descriptor starting point:

-       Route-to-route: 0.5 IGHRC Guidelines. April 2006 and ECHA 2012. Ch R.8. p19 In the absence of route-specific information on the starting route a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) is included in the case of oral-to inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption and 100% for inhalation.

-       Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral exposure to test substance

-       Bioavailability differences between test and target substances: 1 Not applicable

-       Modification for exposure (experiment in animal and human): 2.63 ECHA Ch R.8. 2012: Modification for exposure for workers - 8 h exposure /day = 1/sRV rat (8h)= 1/0.38 m3/kg/d.  

-       Modification for the respiratory volume: 0.67 ECHA Ch R.8. 2012. p 20: Respiratory volume light activity. Standard conditions for worker - 8 hour (sRV human = 6.7 m3/kg/d) with relevant duration of 8 h - respiratory volume / exposure of 10 m3 (wRV). Applicable worker = 6.7/10

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the 28-day/reproscreening study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
3
Justification:
There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Cedarwood Virginia oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The study used is highly reliable.
AF for remaining uncertainties:
1.58
Justification:
In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. ECETOC guidance taking the worst-case AF is followed.
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:
6.58 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR 110 (2010)
Overall assessment factor (AF):
227.52
Dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 497.83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

-      Route-to-route: 7.24 Oral-Dermal; On the assumption that, in general, dermal absorption will not be higher than oral absorption, no factor should be introduced when performing oral-to-dermal extrapolation. With SkinPerm it was determined that for the constituents  in the UVCB a weighed dermal absorption of 6.91% can be used for this substance.Therefore a factor 50/

6.91 = 7.24 will be applied.

-       Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral  exposure to the test substance

-       Bioavailability differences between test and target substances: 1 Not applicable

-       Modification for exposure (experiment in animal and human): 1 Not applicable

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. ECHA, 2012, Chapter R8.
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents). (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation from Rats to Humans.
AF for other interspecies differences:
1
Justification:
ECETOC (TR No. 110 (2010)) supports the inclusion of the factor for allometry, but considers that routine application of the factor of 2.5 is unjustified as a default factor. For interspecies extrapolation for systemic effects of Cedarwood Virginia oil, both toxicokinetic and toxicodynamic aspects should be considered. Toxicokinetics are covered by the principle of allometric scaling, with a factor of 4 for rats to humans, as the default approach. Allometry is generally accepted in the scientific community when the parent chemical or a stable metabolite is the toxic entity that is metabolically detoxified and when renal excretion is the predominant route of elimination. Therefore, for the derivation for the DNEL for Cedarwood Virginia oil the factor 2.5 for remaining differences including toxicodynamics is considered unnecessary.
AF for intraspecies differences:
3
Justification:
There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, for the evaluation of the substance the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
3.16
Justification:
An additional assessment factor of 1 is considered appropriate. The study used is highly reliable. In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. An additional assessment factor of 2 is considered appropriate as modelling (SkinPerm) has been used for dermal absorption estimation.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium 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 Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.9 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR 110 (2010)
Overall assessment factor (AF):
47.4
Dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
90.05 mg/m³
Explanation for the modification of the dose descriptor starting point:

-       Route-to-route: 0.5 IGHRC Guidelines. April 2006 and ECHA 2012. Ch R.8. p19 in the absence of route-specific information on the starting route. to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption. and 100% for inhalation.

-       Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral exposure to test substance

-       Bioavailability differences between test and target substances: 1 Not applicable

-       Modification for exposure (experiment in animal and human): 0.87 ECHA Ch R.8. 2012: Applicable general population = 1/1.15

-       Modification for the respiratory volume: 1

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the 28-day/reproscreening study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
5
Justification:
There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Cedarwood Virginia oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1.58
Justification:
In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. ECETOC guidance taking the worst-case AF is followed.
AF for remaining uncertainties:
1
Justification:
No additional uncertainties.
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:
3.95 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR 110 (2010)
Overall assessment factor (AF):
379.2
Dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 497.83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to-route: 7.24 "Oral-Dermal; On the assumption that, in general, dermal absorption will not be higher than oral absorption, no

factor should be introduced when performing oral-to-dermal extrapolation. With SkinPerm it was determined that for the constituents  in the UVCB a weighed dermal absorption of 6.91% can be used for this substance."

Bioavailability differences between  human and animal species: 1 No evidence for a difference between species for oral  exposure to testsubstance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure (experiment in animal and human): 1 Not applicable

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. ECHA, 2012, Chapter R8
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation from Rats to Humans.
AF for other interspecies differences:
1
Justification:
ECETOC (TR No. 110 (2010)) supports the inclusion of the factor for allometry, but considers that routine application of the factor of 2.5 is unjustified as a default factor. For interspecies extrapolation for systemic effects of Cedarwood Virginia oil, both toxicokinetic and toxicodynamic aspects should be considered. Toxicokinetics are covered by the principle of allometric scaling, with a factor of 4 for rats to humans, as the default approach. Allometry is generally accepted in the scientific community when the parent chemical or a stable metabolite is the toxic entity that is metabolically detoxified and when renal excretion is the predominant route of elimination. Therefore, for the derivation for the DNEL for Cedarwood Virginia oil the factor 2.5 for remaining differences including toxicodynamics is considered unnecessary.
AF for intraspecies differences:
5
Justification:
There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, for the evaluation of the substance the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
3.16
Justification:
An additional assessment factor of 1 is considered appropriate. The study used is highly reliable. In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. An additional assessment factor of 2 is considered appropriate as modelling (SkinPerm) has been used for dermal absorption estimation.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium 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:
1.09 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR 110 (2010)
Overall assessment factor (AF):
189.6
Dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
207 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

-       Route-to-route: 1 No factor needs to be introduced as the original route of exposure was Oral

-       Bioavailability differences between  human and animal species: 1 No evidence for a difference between species for oral exposure to the test substance.

-       Bioavailability differences between test and target substances: 1 Not applicable

-       Modification for exposure (experiment in animal and human): 1 Not applicable

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. ECHA, 2012, Chapter R8.
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation from Rats to Humans.
AF for other interspecies differences:
1
Justification:
ECETOC (TR No. 110 (2010)) supports the inclusion of the factor for allometry, but considers that routine application of the factor of 2.5 is unjustified as a default factor. For interspecies extrapolation for systemic effects of Cedarwood Virginia oil, both toxicokinetic and toxicodynamic aspects should be considered. Toxicokinetics are covered by the principle of allometric scaling, with a factor of 4 for rats to humans, as the default approach. Allometry is generally accepted in the scientific community when the parent chemical or a stable metabolite is the toxic entity that is metabolically detoxified and when renal excretion is the predominant route of elimination. Therefore, for the derivation for the DNEL for Cedarwood Virginia oil the factor 2.5 for remaining differences including toxicodynamics is considered unnecessary.
AF for intraspecies differences:
5
Justification:
There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, for the evaluation of the substance the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1.58
Justification:
In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. ECETOC guidance taking the worst-case AF is followed.
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population