Registration Dossier

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
DNEL related information
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
180
Dose descriptor starting point:
other: LOAEL

Workers - Hazard for the eyes

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. In the present case, DNELs have been derived according to the ECETOC guidance (ECETOC, Technical Report No. 86, 2003). In case no substance specific data were available, read-across from an appropriate read-across candidate alpha-iso-methylionone (EC name:3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one) was used (analogue approach). An additional assessment factor of 3 has been applied in such cases to account for possible uncertainties related to the use of read-across.

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No toxicokinetic studies on delta-damascone were available. Therefore, the assessment of its toxicokinetic behaviour was based on the general description of the whole group of ionones and damascones presented in Belsito et al. (2007). The available evidence indicates that absorption of delta-damascone after oral, dermal and inhalation exposure is significant and after absorption in vivo the substance is metabolised extensively by pathways involving oxidation, reduction and conjugation. No quantitative figures could be derived for oral, dermal and inhalation absorption.Therefore, in the current risk assessment performed under REACH, the default factors for route-to-route extrapolation as presented in Chapter R.8 of REACH Guidance for information requirements and chemical safety assessment were used.

Acute toxicity

Delta-damascone is classified for acute toxicity as Harmful if swallowed (Xn, R22 or Acute oral toxicity Cat. 4 - H302). Therefore a DNEL for acute toxicity needs to be derived in case peak exposures occur. However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure via the oral route therefore does not occur for delta-damascone. Thus no DNEL has been derived for the oral route of exposure.

Delta-damascone is not classified for acute dermal or acute inhalation toxicity. Therefore no dermal or inhalation DNELacute for systemic effects have been derived.

Regarding the inhalation route of exposure, available data indicate that inhalation exposure is not likely because delta-damascone has a low vapour pressure and the dermal exposure by far exceeds the inhalation exposure. Therefore no DNELacutehas been derived for this route of exposure. 

Delta-damascone is classified as irritating to skin (Xi, R38 or Skin Irritant Cat. 2, H315); however, it is not possible to derive a DNEL on the basis of the available data. It is necessary to stipulate risk management measures that prevent the occurrence of skin irritation (see chapter 9 and 10 of the CSR). The substance is not irritating to eyes.

Delta-damascone is classified as sensitising to skin (R43 or Skin sensitisation, Cat. 1, H317). Therefore a DNEL for skin sensitisation has been derived.

Long-term toxicity.

No repeated dose studies with delta-damascone are available. Based on the read-across from a structural analogue of delta-damascone, alpha-iso-methylionone, a NOAEL of 30 mg/kg bw/day was established for delta-damascone based on several adverse effects at the next dose level, including increase in creatinine and absolute and relative increase in kidney and spleen weight, and follicular cell hypertrophy in the thyroid. This value has been used as a point of departure for DNEL derivation. As no data on systemic toxicity by long-term inhalation and dermal route of exposure are available, a route-to-route extrapolation will be performed for DNEL calculation.

Delta-damascone is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

No data on developmental and reproductive toxicity are available for delta-damascone. However, based on the oral developmental toxicity study with rats on a structural analogue of delta-damascone, alpha-isomethylionone, the substance does not show adverse effects on development at least up to the dose level of 30 mg/kg bw/day (the highest tested dose), which is equal to the established NOAEL for systemic toxicity by long-term exposure. Therefore no separate risk characterisation will be performed for this endpoint.

DNEL derivation:

Long-term – inhalation, systemic effects (based on 90-day oral (gavage) study in rats with alpha-iso-methylionone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 30 mg/kg/day

Based on several adverse effects observed at the level of 500 mg/kg bw/day, including an increase in creatinine levels and absolute and relative increase in kidney and spleen weight, and follicular cell hpertrophy in the thyroid.

Step 2) Modification of starting point

2

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

The REACH guidance prescribes a default factor of 2 in case of oral to inhalation extrapolation.

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).).

Modified dose-descriptor

30 / 2 / 0.38 x (6.7/10) = 26.45 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

Assessment factor for allometric scaling

Intraspecies

3

Default assessment factor

Exposure duration

2

Extrapolation for sub-acute to chronic study

Dose response

1

 

Quality of database

3

Assessment factor for differences because of read-across study

DNEL

Value

 

26.45 / (1 x 3 x 2 x 1 x 3) = 1.5 mg/m3

 

 

Long-term – dermal, systemic effects(based on 90-day oral (gavage) study in rats (with alpha-iso-methylionone).

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 30 mg/kg/day

Based on several adverse effects observed at the level of 500 mg/kg bw/day, including an increase in creatinine levels and absolute and relative increase in kidney and spleen weight, and follicular cell hpertrophy in the thyroid.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation

Modified dose-descriptor

30 x 1 = 30 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

3

Default assessment factor

Exposure duration

2

Extrapolation for sub-chronic to chronic study

Dose response

1

 

Quality of database

3

Assessment factor for differences because of read-across study

DNEL

Value

 

30 / (4 x 3 x 2 x 1 x 3) = 0.4 mg/kg bw/day

 


DNEL for sensitisation(based on Local Lymph Node Assay in mice with delta-damascone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

EC3 = 9.6%

 

Step 2) Modification of starting point

269μg/cm2/%

Based on a dose volume of 25μl, an estimated application area of 1 cm2and a density of 0.931

Modified dose-descriptor

LOAEL for induction: 9.6% x 269 [μg/cm2/%]= 2582 μg/cm2

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

3

Default assessment factor

Vehicle or matrix effects

1

No assessment factor needed since the matrix used in the test (diethylphthalate / ethanol = 3:1) is similar to the matrix in the product (ethanol) or worse-case for the situation that no vehicle is added to the substance

Different Exposure conditions

5

Assessment factor for difference in the experimental set up and actual human exposure conditions.

Dose response

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NAEL

Quality of database

1

 

DNEL

Value

 

2582 / (4 x 3 x 1 x 5 x 3 x 1) =14 μg/cm2/day

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
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal 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
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.6 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
300
Dose descriptor starting point:
other: LOAEL

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
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

According to the REACHGuidance on information requirements and chemical safety assessment, a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. In the present case, DNELs have been derived according to the ECETOC guidance (ECETOC, Technical Report No. 86, 2003). In case no substance specific data were available, read-across from an appropriate read-across candidate alpha-iso-methylionone (EC name:3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one) was used (analogue approach). An additional assessment factor of 3 has been applied in such cases to account for possible uncertainties related to the use of read-across.

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No toxicokinetic studies on delta-damascone were available. Therefore, the assessment of its toxicokinetic behaviour was based on the general description of the whole group of ionones and damascones presented in Belsito et al. (2007). The available evidence indicates that absorption of delta-damascone after oral, dermal and inhalation exposure is significant and after absorption in vivo the substance is metabolised extensively by pathways involving oxidation, reduction and conjugation. No quantitative figures could be derived for oral, dermal and inhalation absorption.Therefore, in the current risk assessment performed under REACH, the default factors for route-to-route extrapolation as presented in Chapter R.8 of REACH Guidance for information requirements and chemical safety assessment were used.

Acute toxicity

Delta-damascone is classified for acute toxicity as Harmful if swallowed (Xn, R22 or Acute oral toxicity Cat. 4 - H302). Therefore a DNEL for acute oral toxicity needs to be derived in case peak exposures occur. However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure via the oral route therefore does not occur for delta-damascone. Thus no DNEL has been derived for the oral route of exposure.

Delta-damascone is not classified for acute dermal or acute inhalation toxicity. Therefore no dermal or inhalation DNELacute for systemic effects have been derived.

Regarding the inhalation route of exposure, available data indicate that inhalation exposure is not likely because delta-damascone has a low vapour pressure and the dermal exposure by far exceeds the inhalation exposure. Therefore no DNELacute has been derived for this route of exposure. 

Delta-damascone is classified as irritating to skin (Xi, R38 or Skin Irritant Cat. 2, H315); however, it is not possible to derive a DNEL on the basis of the available data. It is necessary to stipulate risk management measures that prevent the occurrence of skin irritation (see chapter 9 and 10). The substance is not irritating to eyes.

Delta-damascone is classified as sensitising to skin (R43 or Skin sensitisation, Cat. 1, H317). Therefore a DNEL for skin sensitisation has been derived.

Long-term toxicity.

No repeated dose studies with delta-damascone are available. Based on the read-across from a structural analogue of delta-damascone, alpha-iso-methylionone, a NOAEL of 30 mg/kg bw/day was established for delta-damascone based on several adverse effects at the next dose level, including increase in creatinine and absolute and relative increase in kidney and spleen weight, and follicular cell hypertrophy in the thyroid. This value will be used as a point of departure for DNEL derivation. As no data on systemic toxicity by long-term inhalation and dermal route of exposure are available, a route-to-route extrapolation will be performed for DNEL calculation.

Delta-damascone is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

No data on developmental and reproductive toxicity are available for delta-damascone. However, based on the oral developmental toxicity study with rats on a structural analogue of delta-damascone, alpha-iso-methylionone, the substance does not show adverse effects on development at least up to the dose level of 30 mg/kg bw/day (the highest tested dose), which is equal to the established NOAEL for systemic toxicity by long-term exposure. Therefore no separate risk characterisation will be performed for this endpoint.

DNEL derivation:

Long-term – oral, systemic effects (based on 90-day oral (gavage) study in rats with alpha-iso-methylionone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 30 mg/kg bw/day

Based on several adverse effects observed at the level of 500 mg/kg bw/day, including an increase in creatinine levels and absolute and relative increase in kidney and spleen weight, and follicular cell hpertrophy in the thyroid.

Step 2) Modification of starting point

-

 

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Exposure duration

2

Extrapolation for sub-chronic to chronic study

Dose response

1

 

Quality of database

3

Assessment factor for differences because of read-across study

DNEL

Value

 

30 / (4 x 5 x 2 x 1 x 3) = 0.25 mg/kg bw/day


Long-term – inhalation, systemic effects (based on 90-day oral (gavage) study in rats with alpha-iso-methylionone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 30 mg/kg/day

Based on several adverse effects observed at the level of 500 mg/kg bw/day, including an increase in creatinine levels and absolute and relative increase in kidney and spleen weight, and follicular cell hypertrophy in the thyroid.

Step 2) Modification of starting point

2

 

 

1.15 m3/kg bw

 

 

The REACH guidance prescribes a default factor of 2 in case of oral to inhalation extrapolation.

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

30 / 2 x (1/1.15) = 13.04 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Exposure duration

2

Extrapolation for sub-chronic to chronic study

Dose response

1

 

Quality of database

3

Assessment factor for differences because of read-across study

DNEL

Value

 

13.04 / (1 x 5 x 2 x 1 x 3) = 0.43 mg/m3

 

Long-term – dermal, systemic effects(based on 90-day oral (gavage) study in rats with Alpha-Isomethylionone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 30 mg/kg/day

Based on several adverse effects observed at the level of 500 mg/kg bw/day, including an increase in creatinine levels and absolute and relative increase in kidney and spleen weight, and follicular cell hpertrophy in the thyroid.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation

Modified dose-descriptor

30 x 1=30 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Exposure duration

2

Extrapolation for sub-chronic to chronic study

Dose response

1

 

Quality of database

3

Assessment factor for differences because of read-across study

DNEL

Value

 

30 / (4 x 5 x 2 x 1 x 3) = 0.25 mg/kg bw/day

 

DNEL for sensitisation (based on Local Lymph Node Assay in mice with delta-damascone)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

EC3 = 9.6%

 

Step 2) Modification of starting point

269μg/cm2/%

Based on a dose volume of 25μl, an estimated application area of 1 cm2and a density of 0.931

Modified dose-descriptor

LOAEL for induction: 9.6% x 269 [μg/cm2/%]= 2582μg/cm2

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Vehicle or matrix effects

1

No assessment factor needed since the matrix used in the test (diethylphthalate / ethanol = 3:1) is similar to the matrix in the product (ethanol)

Different Exposure conditions

5

Assessment factor for difference in the experimental set up and actual human exposure conditions.

Dose response

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NAEL

Quality of database

1

 

DNEL

Value

 

2582 / (4 x 5 x 1 x 5 x 3 x 1) = 8.6 μg/cm2/day