Heptanal, 2-(phenylmethylene)-, (2E)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.71 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):

75

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

278.05 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 60 mg/kg bw/day derived from OECD 414 was used. Even though the NOAEL from the 90 -day study was lower i.e. 30 mg/kg bw/day, this data quality was inadequate as the the effects  on liver and kidney was observed at the highest dose of  287.3 mg/kg bw/day (female) and 320.3 mg/kg bw/day (male) with the middle doses of 29.9 mg/kg bw and 34.9 mg/kg bw/day. The difference between the mid and high doses was considered too wide and further more the effects on the organ weights was not accompanied by any histopathological finding, it was therefore considered adoptive response not treatment effects.

Regarding absorption, 83% absorption for starting route (oral)  was used and the end route (inhalation), worst-case assumptions were made i.e. 100% was considered in line with  ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rabbit default respiratory volume in accordance with TGD (2003) an inhalation volume of 750ml/min has been used for the rabbit (3kg) resulting in a sRVrabbit of 250ml/min/kg.

For an exposure of 8h per day the following can be assumed:

sRVrabbit(8h) = 0.00025m3/min/kg * 60min * 8h = 0,12 m3/kg

Corrected Inhalatory NOAEC = [NOAEL] X (1/sRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

Therefore; 60 mg/kg bw/day * [1/0.12 m3/kg] * [83/100]*[6.7m3/10m3] = 278.05 mg/m3 NOAEC for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

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:

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:

1.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long-term dermal systemic DNEL values are derived from the systemic NOAEL of 125 mg/kg bw/d from a 90 -day rat dermal toxicity study; this approach is conservative as it is likely that the effects seen in this study are secondary to oral ingestion of the test material.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

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:

DNEL (Derived No Effect Level)

Value:

0.24 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

other: NOAEC

AF for dose response relationship:

1

Justification:

default value: use of a NOAEC

AF for differences in duration of exposure:

1

Justification:

value appropriate for sensitisation

AF for interspecies differences (allometric scaling):

1

Justification:

appropriate for local effects

AF for other interspecies differences:

1

Justification:

use of a human study

AF for intraspecies differences:

5

Justification:

default value (workers)

AF for the quality of the whole database:

1

Justification:

default value

AF for remaining uncertainties:

10

Justification:

additional sensitisation-specific factor to take into account uncertainties regarding the sensitivity of different skin areas and the potential for mixture effects on sensitisation

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.24 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

other: NOAEC

AF for dose response relationship:

1

Justification:

default value: use of a NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

appropriate for local effects

AF for other interspecies differences:

1

Justification:

use of a human study

AF for intraspecies differences:

5

Justification:

default value (workers)

AF for the quality of the whole database:

1

Justification:

default value

AF for remaining uncertainties:

10

Justification:

additional sensitisation-specific factor to take into account uncertainties regarding the sensitivity of different skin areas and the potential for mixture effects on sensitisation

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

DNEL values are derived using the approach recommended by ECHA and default assessment factors.

The long-term inhalation systemic DNEL value is derived from the systemic NOAEL of 30 mg/kg bw/d from an OECD 414 oral developmental study in rabbit and a corrected (inhalation) starting point of 278.05 mg/m3 derived taking into account breathing rate (1\0.38*0.67) and the extent of oral absorption (83%) and assumed inhalation absorption (100%).

A short-term inhalation systemic DNEL is not derived in the absence of any acute hazard.

Inhalation local dermal DNEL values are not derived in the absence of any indication of a hazard or relevant data.

A long-term dermal systemic DNEL value is derived from the systemic NOAEL of 125 mg/kg bw/d from a 90 -day rat dermal toxicity study; this approach is conservative as it is likely that the effects seen in this study are secondary to oral ingestion of the test material.

A short-term dermal systemic DNEL is not derived in the absence of any acute hazard.

Although a lower oral NOAEL of 30 mg/kg bw/d was identified in a rat from the 90 day oral toxicity study, this data quality was inadequate as the the effects  on liver and kidney was observed at the highest dose of  287.3 mg/kg bw/day (female) and 320.3 mg/kg bw/day (male) with the middle doses of 29.9 mg/kg bw and 34.9 mg/kg bw/day. The difference between the mid and high doses was considered too wide and furthermore the effects on the organ weights was not accompanied by any histopathological finding, it was therefore considered adoptive response not treatment effects.

Amyl cinnamic aldehyde ( 2-benzylideneheptanal; EC number :204-541-5; CAS Number: 122-40-7)is identified as a potential skin sensitizer in a mouse LLNA (EC3 = 7.6%; 1900 µg/cm2. A significant number of studies of skin sensitisation in human subjects are available; some studies report a low response incident, however the two most reliable HRIPT studies report a 0% incidence of sensitisation reactions in approximately 200 subjects. These studies used 0.3 mL of 20% amyl cinnamic aldehyde in a 25 mm diameters chamber; the amount of substance applied in these studies is therefore 0.06 mL (~60 mg) or approximately 12 mg/cm2. This is considered to be the NOAEC.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.922 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):

150

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

138.33 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 60 mg/kg bw/day derived from OECD 414 was used. Even though the NOAEL from the 90 -day study was lower i.e. 30 mg/kg bw/day, this data quality was inadequate as the the effects  on liver and kidney was observed at the highest dose of  287.3 mg/kg bw/day (female) and 320.3 mg/kg bw/day (male) with the middle doses of 29.9 mg/kg bw and 34.9 mg/kg bw/day. The difference between the mid and high doses was considered too wide and furthermore the effects on the organ weights was not accompanied by any histopathological finding, it was therefore considered adoptive response not treatment effects.

Regarding absorption, 83% absorption for starting route (oral)  was used and the end route (inhalation), worst-case assumptions were made i.e. 100% was considered in line with  ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rabbit default respiratory volume in accordance with TGD (2003) an inhalation volume of 750ml/min has been used for the rabbit (3kg) resulting in a sRVrabbit of 250ml/min/kg.

Corrected inhalatory NOAEC = Oral NOAEL * [1/sRVrabbit] * [ABSoral-rat/ABSinh-human]

For an exposure of 8h per day the following can be assumed:

sRVrabbit(24h) = 0.00025m3/min/kg * 60min * 24h = 0.36 m3/kg/day

Therefore; = 60 mg/kg bw/day * [1/0.36 m3/kg]* [83/100]*[6.7m3/10m3] = 138.33 mg/m3 NOAEC general population

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A NOAEL of 125 mg/kg bw/d for systemic effects was identified in a OECD 411 rats study.  Applying assessment factors of 1 (default value for dose-response relationship), 2 (for duration, to cover extrapolation from a sub-acute study to a chronic endpoint), 4 (for allometric differences), 2.5 (default for interspecies differences) and 10 (default for intraspecies differences), 1 ( for quality of database) and 1 (remaining uncertainties) results in a DNEL value of 0.625 mg/kg bw/d.

For more information refer to "Additional information - general population".

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

default value (general population)

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

DNEL (Derived No Effect Level)

Value:

0.12 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor:

other: NOAEC

AF for dose response relationship:

1

Justification:

default value: use of a NOAEC

AF for differences in duration of exposure:

1

Justification:

value appropriate for sensitisation

AF for interspecies differences (allometric scaling):

1

Justification:

appropriate for local effects

AF for other interspecies differences:

1

Justification:

use of a human study

AF for intraspecies differences:

10

Justification:

default value (workers)

AF for the quality of the whole database:

1

Justification:

default value

AF for remaining uncertainties:

10

Justification:

additional sensitisation-specific factor to take into account uncertainties regarding the sensitivity of different skin areas and the potential for mixture effects on sensitisation

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

other: NOAEC

AF for dose response relationship:

1

Justification:

default value: use of a NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

appropriate for local effects

AF for other interspecies differences:

1

Justification:

use of a human study

AF for intraspecies differences:

10

Justification:

default value (workers)

AF for the quality of the whole database:

1

Justification:

default value

AF for remaining uncertainties:

10

Justification:

additional sensitisation-specific factor to take into account uncertainties regarding the sensitivity of different skin areas and the potential for mixture effects on sensitisation

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.167 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):

360

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Results available from sub-acute rabbit oral toxicity study, no route-to-route extrapolation required

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

2.4

Justification:

Default allometric scaling factor for rabbits. Table R.8-4 ECHA REACH Guidance..

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

DNEL values are derived using the approach recommended by ECHA and default assessment factors.

The long-term inhalation systemic DNEL value is derived from the systemic NOAEL of 30 mg/kg bw/d from an OECD 414 oral developmental study in rabbit and a corrected (inhalation) starting point of 278.05 mg/m3 derived taking into account breathing rate (1\0.38*0.67) and the extent of oral absorption (83%) and assumed inhalation absorption (100%).

A short-term inhalation systemic DNEL is not derived in the absence of any acute hazard.

Inhalation local dermal DNEL values are not derived in the absence of any indication of a hazard or relevant data.

A long-term dermal systemic DNEL value is derived from the systemic NOAEL of 125 mg/kg bw/d from a 90 -day rat dermal toxicity study; this approach is conservative as it is likely that the effects seen in this study are secondary to oral ingestion of the test material.

A short-term dermal systemic DNEL is not derived in the absence of any acute hazard.

Although a lower oral NOAEL of 30 mg/kg bw/d was identified in a rat from the 90 day oral toxicity study, this data quality was inadequate as the the effects  on liver and kidney was observed at the highest dose of  287.3 mg/kg bw/day (female) and 320.3 mg/kg bw/day (male) with the middle doses of 29.9 mg/kg bw and 34.9 mg/kg bw/day. The difference between the mid and high doses was considered too wide and furthermore the effects on the organ weights was not accompanied by any histopathological finding, it was therefore considered adoptive response not treatment effects.

Amyl cinnamic aldehyde ( 2-benzylideneheptanal; EC number :204-541-5; CAS Number: 122-40-7)is identified as a potential skin sensitizer in a mouse LLNA (EC3 = 7.6%; 1900 µg/cm2. A significant number of studies of skin sensitisation in human subjects are available; some studies report a low response incident, however the two most reliable HRIPT studies report a 0% incidence of sensitisation reactions in approximately 200 subjects. These studies used 0.3 mL of 20% amyl cinnamic aldehyde in a 25 mm diameters chamber; the amount of substance applied in these studies is therefore 0.06 mL (~60 mg) or approximately 12 mg/cm2. This is considered to be the NOAEC.