Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEC
DNEL value:
249 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
125 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEC of 249 mg/m3 from the 28-day inhalation study is corrected for the duration of exposure (*6/8) and respiratory volume (*6.7/10), to give a corrected NOAEC of 125 mg/m3.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
6
Justification:
Extrapolation from a sub-acute study to long-term exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric factors are already accounted for in derivation of the corrected starting point.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Good quality database
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:
6.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
641 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 50 mg/kg bw/d from the 90-day rat study with isoamyl salicylate is corrected for the extent of oral absorption (100%) and dermal absorption of 7.8%.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Extrapolation from a sub-chronic study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point is a rat study.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Deafult value (workers)
AF for the quality of the whole database:
1
Justification:
Default value: good quality database
AF for remaining uncertainties:
1
Justification:
Default value: no significant 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:
885 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor:
other: The starting point is the Weight of Evidence No Expected Sensitisation Induction Level (NESIL) for hexyl salicylate of 35400 μg/cm2 from human data.
DNEL value:
354 000 mg/m³
AF for dose response relationship:
1
Justification:
Not applicable
AF for differences in duration of exposure:
1
Justification:
Not applicable
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
1
Justification:
Not required - starting point is a human study
AF for intraspecies differences:
5
Justification:
Default value (workers)
AF for the quality of the whole database:
2
Justification:
Default value
AF for remaining uncertainties:
2
Justification:
An additional assessment factor of 2 is applied to take into account potential matrix effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
885 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
other: The starting point is the Weight of Evidence No Expected Sensitisation Induction Level (NESIL) for hexyl salicylate of 35400 μg/cm2 from human data.
DNEL value:
354 000 mg/m³
AF for dose response relationship:
1
Justification:
Not applicable
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
1
Justification:
Not applicable
AF for intraspecies differences:
5
Justification:
Default value (workers)
AF for the quality of the whole database:
2
Justification:
Default value
AF for remaining uncertainties:
2
Justification:
An additional assessment factor of 2 is applied to take into account potential matrix effects.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL derivation: workers

 

Systemic inhalation DNEL values

The NOAEC of 249 mg/m3 from the 28-day inhalation study is corrected for the duration of exposure (*6/8) and respiratory volume (*6.7/10), to give a corrected NOAEC of 125 mg/m3. Individual assessment factors of 1 (for dose-response relationship), 6 (for duration of exposure), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) give an overall assessment factor of 75. Applying the AF to the corrected starting point gives a long-term DNEL of 1.7 mg/m3.

 

In the absence of any identified hazard, a short-term systemic inhalation DNEL is not derived.

 

Local inhalation DNEL values

No hazard is identified. No local effects were observed at any exposure level in a 28 -day inhalation study with hexyl salicylate. Local inhalation DNELs are therefore not derived.

 

Systemic dermal DNEL values

The NOAEL of 50 mg/kg bw/d from the 90-day rat study with isoamyl salicylate is corrected for the extent of oral absorption (100%) and dermal absorption of 7.8% to give a corrected starting point of 641 mg/kg bw/d. Individual assessment factors of 1 (for dose-response relationship), 2 (for duration of exposure), 4 (for allometric differences), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) give an overall assessment factor of 100. Applying the AF to the corrected starting point gives a DNEL of 6.4 mg/kg bw/d.

In the absence of any identified hazard, a short-term systemic demal DNEL is not derived.

Local dermal DNEL values

Hexyl salicylate is classified for skin sensitisation in Category 1B. The starting point is the Weight of Evidence No Expected Sensitisation Induction Level (NESIL) for hexyl salicylate of 35400 µg/cm2 from human data. Individual assessment factors of 1 (for duration), 2 (for data quality), 2 (for matrix effects), 2 (for conditions of exposure), 5 (for intraspecies differences) and 1 (for interspecies differences) results in an overall assessment factor of 40. Application of the overall assessment factor results in long-term local dermal DNEL values (short-term and long-term) of 885 µg/cm2.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEC
DNEL value:
249 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
62 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEC from the 28-day inhalation study is corrected for the duration of exposure (*6/24). Individual assessment factors of 1 (for dose-response relationship), 6 (for duration of exposure), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) give an overall assessment factor of 150. Applying the AF to the corrected starting point gives a DNEL of 0.4 mg/m3.

AF for dose response relationship:
1
Justification:
The starting point was a NOAEC
Justification:
Extrapolation from sub-acute study to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Not required: already accounted for
AF for other interspecies differences:
2.5
Justification:
Default value (starting point is a rat study)
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Good quality database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
AF for remaining uncertainties:
2

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:
3.2 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
641 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 50 mg/kg bw/d from the 90-day rat study with isoamyl salicylate is corrected for the extent of oral absorption (100%) and dermal absorption of 7.8% to give a corrected starting point of 641 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
The starting point used was an NOAEL
AF for differences in duration of exposure:
2
Justification:
Extrapolation from sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (starting point was a rat study)
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Good quality database
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:
442.5 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Dose descriptor:
other: NESIL
DNEL value:
354 000 mg/m³
AF for dose response relationship:
1
Justification:
Not required
AF for differences in duration of exposure:
1
Justification:
Not relevant
AF for interspecies differences (allometric scaling):
1
Justification:
Not relevant
AF for other interspecies differences:
1
Justification:
Not relevant
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
2
AF for remaining uncertainties:
2
Justification:
An additional assessment factor of 2 is applied to take into account potential matrix effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
442.5 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Dose descriptor starting point:
other: NESIL
DNEL value:
354 000 mg/m³
AF for dose response relationship:
1
Justification:
Not required
AF for interspecies differences (allometric scaling):
1
Justification:
Not required
AF for other interspecies differences:
1
Justification:
Not required
AF for intraspecies differences:
10
Justification:
Default value (geeral population)
AF for the quality of the whole database:
2
Justification:
Default value
AF for remaining uncertainties:
2
Justification:
An additional assessment factor of 2 is applied to take into account potential matrix effects.

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not required: the starting point is an oral study.
AF for dose response relationship:
1
Justification:
Default value: the starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Extrapolation from sub-chronic study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point is the rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population
AF for the quality of the whole database:
1
Justification:
Good quality database
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

DNEL derivation: general population

 

Systemic inhalation DNEL values

The NOAEC of 249 mg/m3 from the 28-day inhalation study is corrected for the duration of exposure (*6/24), to give a corrected NOAEC of 62 mg/m3. Individual assessment factors of 1 (for dose-response relationship), 6 (for duration of exposure), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) give an overall assessment factor of 150. Applying the AF to the corrected starting point gives a long-term DNEL of 0.4 mg/m3.

 

In the absence of any identified hazard, a short-term systemic inhalation DNEL is not derived.

 

Local inhalation DNEL values

No hazard is identified. No local effects were observed at any exposure level in a 28 -day inhalation study with hexyl salicylate. Local inhalation DNELs are therefore not derived.

 

Systemic dermal DNEL values

The NOAEL of 50 mg/kg bw/d from the 90-day rat study with isoamyl salicylate is corrected for the extent of oral absorption (100%) and dermal absorption of 7.8% to give a corrected starting point of 641 mg/kg bw/d. Individual assessment factors of 1 (for dose-response relationship), 2 (for duration of exposure), 4 (for allometric differences), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) give an overall assessment factor of 200. Applying the AF to the corrected starting point gives a DNEL of 3.2 mg/kg bw/d.

In the absence of any identified hazard, a short-term systemic demal DNEL is not derived.

Local dermal DNEL values

Hexyl salicylate is classified for skin sensitisation in Category 1B. The starting point is the Weight of Evidence No Expected Sensitisation Induction Level (NESIL) for hexyl salicylate of 35400 µg/cm2 from human data. Individual assessment factors of 1 (for duration), 2 (for data quality), 2 (for matrix effects), 2 (for conditions of exposure), 10 (for intraspecies differences) and 1 (for interspecies differences) results in an overall assessment factor of 40. Application of the overall assessment factor results in local (short-term an long-term) dermal DNELs of 442.5 µg/cm2.