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:
1.5 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):
18
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
26.45 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. Route-to route extrapolation can be done because there is adequate oral toxicity data, the critical effect is systemic rather than the site of contact. Also there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the inhalation route, the absorption via the inhalation route is chosen twice as high as the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012).

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8 (November, 2010). In the route to route extrapolation for the inhalation route a correction for respiratory volume is applied. The respiratory volume of rats (0.38 m3/kg bw) is multiplied by the respiratory volume of human (6.7 m3/person) and corrected for the respiratory volume for light activity to address the workers (10 m3/person). Therefore, the modified dose descriptor is calculated as follows: e.g. 30mg/kg bw NOAEL / 2 (oral versus inhalation) / 0.38 x (6.7/10) = 26.45 mg/m3.

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 was derived in the study similar to OECD 408 (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012)
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 NOEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
3
Justification:
An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
3
Justification:
An assessment factor of 3 has been used to account for the use of a 90-day oral repeated dose study with a structural analogue (Alpha-isomethylionone) for the derivation of the DNEL of Delta-damascone. According to ECHA Guidance R8 Appendix 8.8 (November 2012), if the starting point has been derived by using read-across from one or more structural analogues, the additional uncertainty deriving from using these data may be addressed by selecting an additional assessment factor. The addition of an assessment factor of 3 is considered to be sufficient, because Belsito et al (2007), demonstrated that the group of ionones and rose ketones has similar (toxicological) characteristics and the use of the NOAEL of 10 mg/kg bw/day would be sufficient for the risk assessment purposes for the whole group. In addition, in a 28-day oral repeated dose study with Delta-damascone, a NOAEL of 85 mg/kg bw has been derived. Taking the exposure duration into account and extrapolating this NOAEL from the sub-acute study to a sub-chronic study (ECHA, Guidance R8), the NOAEL would be 28 mg/kg bw. The latter NOAEL value is well above 10 mg/kg bw/day and thus further supports that an additional assessment factor of 3 is sufficient to account for the uncertainty associated with the use of read-across data.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
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):
72
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. Route-to-route extrapolation can be done because there is adequate oral toxicity data, the critical effect is systemic rather than at the site of contact and there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. Delta-damascone is expected to be absorbed to high extent via the oral route in view of its physico-chemical properties and structural properties but the default value of 50% as proposed in ECHA guidance, Chapter R.8.4.2 (November, 2012) will be used. The systemic dose via the dermal route is expected to be lower than the oral route in view of the physico-chemical properties, the dermal reactivity and supporting information on the systemic dermal absorption of methylionone. Therefore it will be assumed that the oral absorption will exceed dermal absorption with a factor of 5; e.g. 30 mg/kg bw/day * 5 = 150 mg/kg bw/day.

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 OECD 408 study was derived (ECHA’s guidance, R.8.4.3.1, November 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012.
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data. ECETOC (TR110, 2010), after a review of the scientific literature, concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans.
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
3
Justification:
An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
3
Justification:
An assessment factor of 3 has been used to account for the use of a 90-day oral repeated dose study with a structural analogue (alpha-isomethylionone) for the derivation of the DNEL of delta-damascone. According to ECHA Guidance R8 Appendix 8.8 (November 2012), if the starting point has been derived by using read-across from one or more structural analogues, the additional uncertainty deriving from using these data may be addressed by selecting an additional assessment factor. The addition of an assessment factor of 3 is considered to be sufficient, because Belsito et al (2007), demonstrated that the group of ionones and rose ketones has similar (toxicological) characteristics and the use of the NOAEL of 10 mg/kg bw/day would be sufficient for the risk assessment purposes for the whole group. In addition, in a 28-day oral repeated dose study with delta-damascone, a NOAEL of 85 mg/kg bw has been derived. Taking the exposure duration into account and extrapolating this NOAEL from the sub-acute study to a sub-chronic study (ECHA, Guidance R8), the NOAEL would be 28 mg/kg bw. The latter NOAEL value is well above 10 mg/kg bw/day and thus further supports that an additional assessment factor of 3 is sufficient to account for the uncertainty associated with the use of read-across data.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
116 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
For the LLNA study an assessment factor of 1 is applicable, because 1) the NOAEL is used as a starting point; 2) the doses were well separated with a factor of 2 (0.25, 0.5, 2.5, and 5.0 %) and; 3) the dose response was shallow (stimulation index was 1.3, 1.8, 3.2, and 6.3, respectively).
AF for differences in duration of exposure:
1
Justification:
An assessment factor of 1 is applicable, because the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction specific DNEL, page 125, 1st par). In addition, the presence of skin sensitization potential is similar in LLNA and HRIPT as presented at justification and comments.
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not needed because metabolic rates differences between mouse and human are not expected to be important for the skin sensitization of this substance, because the parent substance is causing the effect.
AF for other interspecies differences:
1
Justification:
An assessment factor for interspecies differences is not needed because a well conducted HRIPT test is also available showing similar sensitisation potency compared to the LLNA considering concentrations 155 ug/cm2 and 116 ug/cm2, respectively. The DNEL will be based on the NOAEL derived from the LLNA test, because this presents a real NOAEL and is the lower value, thus being a more conservative value for the risk characterization.
AF for intraspecies differences:
1
Justification:
An assessment factor of 1 can be used for intraspecies differences for workers. This is because 54 healthy subjects in the HRIPT are considered to be a similar sensitive population as the working population and therefore the intraspecies sensitivity is sufficiently covered.
AF for the quality of the whole database:
1
Justification:
An assessment factor for the quality of the database is not needed because two well-conducted LLNA guideline studies and a well-conducted HRIPT study are available.
AF for remaining uncertainties:
1
Justification:
Assessment factor for remaining uncertainties is not needed. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed. In addition, the lower DNEL of the two studies is used for risk characterisation but it is shown that the DNEL based on the LLNA is similar to the one based on the HRIPT.
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

In deriving the DNELs for hazard identification for inhalation and the dermal route of exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors used have been adequately documented. For inter and intraspecies assessment factors have been used which were concluded to be scientifically sound by ECETOC (TR 110, 2010) and which are based on a thorough review of the scientific literature. Therefore the DNELs for all human health points relevant for workers are considered sufficiently conservative to be used in risk characterisation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 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):
30
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
13.04 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. In the route to route extrapolation for the inhalation route a correction for respiratory volume is applied. The oral rat study NOAEL is modified into a NOAEC for human inhalation for the General population using ECHA guidance: Starting point is the NOAEL of 30 mg/kg bw. A factor of 2 is applied for route-to-route extrapolation: oral to inhalation. In addition,

The respiratory volume of rats (1.15 m³/kg bw) is multiplied by the respiratory volume of human: 30 mg/kg bw / 2 (oral versus inhalation) / 1.15 m³/kg = 13.04 mg/m3.

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 OECD 408 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).
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 NOEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.
AF for the quality of the whole database:
3
Justification:
An assessment factor of 3 has been used to account for the use of a 90-day oral repeated dose study with a structural analogue (Alpha-isomethylionone) for the derivation of the DNEL of delta-damascone. According to ECHA Guidance R8 Appendix 8.8 (November 2012), if the starting point has been derived by using read-across from one or more structural analogues, the additional uncertainty deriving from using these data may be addressed by selecting an additional assessment factor. The addition of an assessment factor of 3 is considered to be sufficient, because Belsito et al (2007), demonstrated that the group of ionones and rose ketones has similar (toxicological) characteristics and the use of the NOAEL of 10 mg/kg bw/day would be sufficient for the risk assessment purposes for the whole group. In addition, in a 28-day oral repeated dose study with delta-damascone, a NOAEL of 85 mg/kg bw has been derived. Taking the exposure duration into account and extrapolating this NOAEL from the sub-acute study to a sub-chronic study (ECHA, Guidance R8), the NOAEL would be 28 mg/kg bw. The latter NOAEL value is well above 10 mg/kg bw/day and thus further supports that an additional assessment factor of 3 is sufficient to account for the uncertainty associated with the use of read-across data.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
1.25 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):
120
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. Route-to-route extrapolation can be done because there is adequate oral toxicity data, the critical effect is systemic rather than at the site of contact and there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. Delta-damascone is expected to be absorbed to high extent via the oral route in view of its physico-chemical properties and structural properties but the default value of 50% as proposed in ECHA guidance, Chapter R.8.4.2 (November, 2012) will be used. The systemic dose via the dermal route is expected to be lower than the oral route in view of the physico-chemical properties, the dermal reactivity and supporting information on the systemic dermal absorption of methylionone. Therefore it will be assumed that the oral absorption will exceeds dermal absorption with a factor of 5; e.g. 30 mg/kg bw/day * 5 = 150 mg/kg bw/day.

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 xx-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (November, 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data. ECETOC (TR110, 2010), after a review of the scientific literature, 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 other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature.
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
3
Justification:
An assessment factor of 3 has been used to account for the use of a 90-day oral repeated dose study with a structural analogue (alpha-isomethylionone) for the derivation of the DNEL of delta-damascone. According to ECHA Guidance R8 Appendix 8.8 (November 2012), if the starting point has been derived by using read-across from one or more structural analogues, the additional uncertainty deriving from using these data may be addressed by selecting an additional assessment factor. The addition of an assessment factor of 3 is considered to be sufficient, because Belsito et al (2007), demonstrated that the group of ionones and rose ketones has similar (toxicological) characteristics and the use of the NOAEL of 10 mg/kg bw/day would be sufficient for the risk assessment purposes for the whole group. In addition, in a 28-day oral repeated dose study with delta-damascone, a NOAEL of 85 mg/kg bw has been derived. Taking the exposure duration into account and extrapolating this NOAEL from the sub-acute study to a sub-chronic study (ECHA, Guidance R8), the NOAEL would be 28 mg/kg bw. The latter NOAEL value is well above 10 mg/kg bw/day and thus further supports that an additional assessment factor of 3 is sufficient to account for the uncertainty associated with the use of read-across data.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1.7
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
For the LLNA study an assessment factor of 1 is applicable, because 1) the NOAEL is used as a starting point; 2) the doses were well separated with a factor of 2 (0.25, 0.5, 2.5, and 5.0 %) and; 3) the dose response was shallow (stimulation index was 1.3, 1.8, 3.2, and 6.3, respectively).
AF for differences in duration of exposure:
1
Justification:
An assessment factor of 1 is applicable, because the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction specific DNEL, page 125, 1st par). In addition, the presence of skin sensitization potential is similar in LLNA and HRIPT as presented at justification and comments.
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not needed because metabolic rates differences between mouse and human are not expected to be important for the skin sensitization of this substance, because the parent substance is causing the effect.
AF for other interspecies differences:
1
Justification:
An assessment factor for interspecies differences is not needed because a well conducted HRIPT test is also available showing similar sensitisation potency compared to the LLNA considering concentrations 155 ug/cm2 and 116 ug/cm2, respectively. The DNEL will be based on the NOAEL derived from the LLNA test, because this presents a real NOAEL and is the lower value, thus being a more conservative value for the risk characterization.
AF for intraspecies differences:
1.7
Justification:
An assessment factor of 1.67 will be used to account for the sensitivity of the general population which may be more vulnerable compared to healthy volunteers used in the HRIPT test. The AF of 1.67 is based on the differences in sensitivity between workers and general population as has been derived in the ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In this ECETOC report systemic effects are presented. In view of sensitisation being a repeated dose effect and sensitisation involves systemic exposure the AF for intraspecies of ECETOC has been used for this endpoint. For the general population a factor of 1.67 is used (5 for general population / 3 for workers).
AF for the quality of the whole database:
1
Justification:
An assessment factor for the quality of the database is not needed because two well-conducted LLNA guideline studies and a well-conducted HRIPT study are available.
AF for remaining uncertainties:
1
Justification:
AF for remaining uncertainties is not needed. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed. In addition, the lower DNEL of the two studies is used for risk characterisation but it is shown that the DNEL based on the LLNA is similar to the one based on the HRIPT.
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:
0.25 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):
120
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (November, 2012)
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data. ECETOC (TR110, 2010), after a review of the scientific literature, concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans.
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.
AF for the quality of the whole database:
3
Justification:
An assessment factor of 3 has been used to account for the use of a 90-day oral repeated dose study with a structural analogue (alpha-isomethylionone) for the derivation of the DNEL of delta-damascone. According to ECHA Guidance R8 Appendix 8.8 (November 2012), if the starting point has been derived by using read-across from one or more structural analogues, the additional uncertainty deriving from using these data may be addressed by selecting an additional assessment factor. The addition of an assessment factor of 3 is considered to be sufficient, because Belsito et al (2007), demonstrated that the group of ionones and rose ketones has similar (toxicological) characteristics and the use of the NOAEL of 10 mg/kg bw/day would be sufficient for the risk assessment purposes for the whole group. In addition, in a 28-day oral repeated dose study with delta-damascone, a NOAEL of 85 mg/kg bw has been derived. Taking the exposure duration into account and extrapolating this NOAEL from the sub-acute study to a sub-chronic study (ECHA, Guidance R8), the NOAEL would be 28 mg/kg bw. The latter NOAEL value is well above 10 mg/kg bw/day and thus further supports that an additional assessment factor of 3 is sufficient to account for the uncertainty associated with the use of read-across data.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

In deriving the DNELs for hazard identification for inhalation, dermal route and oral exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors have been adequately documented. Therefore the DNELs for all human health points relevant for the general population are considered sufficiently conservative to be used in risk characterisation.