Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.687 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
54.41 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
37.5
Modified dose descriptor starting point:
NOAEC

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:
0.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

The DNEL for worker acute inhalation exposure is derived as follows:

Step 1)

Description: Relevant dose-descriptor

Value: NOAEL: 451 ppm = 451 ppm X 165.0883 (MW) = 74454.8233 / 24.45 = 3045.18705 mg/m3

Remark: This is the concentration where no mortality was produced in a 4-hour LC50 rat inhalation study. Effects at this level included clinical observations that resolved within 2-4 days.

Step 2)

Description: Modification of starting point for differences in respiratory volumes

Value: 0.67 (6.7 m3/10 m3)

Remark: A modification was applied to account for the increased respiratory volumes in active workers as compared to individuals at rest per REACH guidance R.8.4.2.  

Step 3)

Description: Assessment Factor: Route–to-route extrapolation

Value: 1

Remark: A factor of 1 is appropriate per REACH guidance R.8.4.2 (inhalation to inhalation).

Description: Assessment Factor: Animal-to-man scaling factor (Allometric scaling)

Value: 1

Remark: A factor of 1 is appropriate since the adjusted start point was via mg/m3(inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.

Description: Assessment factor - Interspecies

Value: 2.5

Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

Description: Assessment factor – Intraspecies

Value: 5

Remark: This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.

Description: Assessment factor – Exposure duration

Value: 1

Remark: Acute to acute.

Description: Assessment factor – Dose response

Value: 3

Remark: A factor of 3 s appropriate since the dose descriptor is a concentration at which reversible clinical observations were produced.

Description: Assessment factor – Quality of database

Value: 1

Remark: A factor of 1 is appropriate because the database is considered to be adequately robust.

Description: DNEL worker acute inhalation

Value: 54.41 mg/m3

Remark: 3045.18705 x 0.67 = 2040.27532/ (1 x 1 x 2.5 x 5 x 1 x 3 x 1) = 54.41 mg/m3

 

The DNEL for worker long-term dermal exposure is derived as follows:

Step 1)

Description: Relevant dose-descriptor

Value: NOAEL: 15.2 ppm = 15.2 ppm X 165.0883 (MW) = 2509.3422 / 24.45 = 102.6 mg/m3

Remark: This is the concentration where no significant adverse effects were seen in a 28-day rat inhalation study.

  

Step 2)

Description: Modification of starting point for rat respiratory volume (Allometric scaling)

Value: 0.38 m3/kg bw (rat 8-hour respiratory volume)

Remark: A modification of starting point for rat respiratory volume was applied per REACH guidance R.8.4.2.

 

Step 3)

Description: Assessment Factor: Route–to-route extrapolation

Value: 1

Remark: A factor of 1 is appropriate per REACH guidance R.8.4.2 (inhalation to dermal). 

Description: Assessment Factor: Animal-to-man scaling factor (Allometric scaling)

Value: 4

Remark: A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance R.8.4.3.1.

 

Description: Assessment factor - Interspecies

Value: 2.5

Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1. 

Description: Assessment factor – Intraspecies

Value: 5

Remark: This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.

Description: Assessment factor – Exposure duration

Value: 6

Remark: This is a default assessment factor for a sub-acute study per REACH Guidance R.8.4.3.1.

Description: Assessment factor – Dose response

Value: 1

Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

Description: Assessment factor – Quality of database

Value: 1

Remark: A factor of 1 is appropriate because the database is considered to be adequately robust. 

Description: DNEL worker long term dermal

Value: 0.9 mg/kg

Remark: 102.6 x 0.38 / (1 x 4 x 2.5 x 5 x 6 x 1 x 1) = 0.13 mg/kg

 

The DNEL for worker long-term inhalation exposure is derived as follows:

Step 1)

Description: Relevant dose-descriptor

Value: NOAEL: 15.2 ppm = 15.2 ppm X 165.0883 (MW) = 2509.3422 / 24.45 = 102.6 mg/m3

Remark: This is the concentration where no significant adverse effects were seen in a 28-day rat inhalation study. 

  

Step 2)

Description: Modification of starting point for worker exposure time

Value: 0.75 (6-hr/8-hr) 

Remark: A modification of starting point for worker exposure time as compared to animals exposure time was applied per REACH guidance R.8.4.2.

Description: Modification of starting point for differences in respiratory volumes

Value: 0.67 (6.7 m3/10 m3)

Remark: A modification was applied to account for the increased respiratory volumes in active workers as compared to individuals at rest per REACH guidance R.8.4.2.

Step 3)

Description: Assessment Factor: Route–to-route extrapolation

Value: 1

Remark: A factor of 1 is appropriate per REACH guidance R.8.4.2 (inhalation to inhalation).

Description: Assessment Factor: Animal-to-man scaling factor (Allometric scaling)

Value: 1

Remark: A factor of 1 is appropriate since the adjusted start point was via mg/m3 (inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.

Description: Assessment factor - Interspecies

Value: 2.5

Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

Description: Assessment factor – Intraspecies

Value: 5

Remark: This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.

Description: Assessment factor – Exposure duration

Value: 6

Remark: This is a default assessment factor for a sub-acute study per REACH Guidance R.8.4.3.1.

Description: Assessment factor – Dose response

Value: 1

Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

Description: Assessment factor – Quality of database

Value: 1

Remark: A factor of 1 is appropriate because the database is considered to be adequately robust.

Description: DNEL worker long term inhalation

Value: 0.687 mg/m3

Remark: 102.6 X 0.75 x 0.67 / (1 x 1 x 2.5 x 5 x 6 x 1 x 1) = 0.687 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
150
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

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The DNEL for general population long-term inhalation exposure is derived as follows:

Step 1)

Description: Relevant dose-descriptor

Value: NOAEL: 15.2 ppm = 15.2 ppm X 165.0883 (MW) = 2509.3422 / 24.45 = 102.6 mg/m3

Remark: This is the concentration where no significant adverse effects were seen in a 28-day rat inhalation study.  

 

Step 2)

Description: Modification of starting point for general population exposure time

Value: 0.25 (6-hr/24-hr) 

Remark: A modification of starting point for general population exposure time as compared to animals exposure time was applied per REACH guidance R.8.4.2. – p. 27

 

Step 3)

Description: Assessment Factor: Route–to-route extrapolation

Value: 1

Remark: A factor of 1 is appropriate per REACH guidance R.8.4.2 (inhalation to inhalation).

 

Description: Assessment Factor: Animal-to-man scaling factor (Allometric scaling)

Value: 1

Remark: A factor of 1 is appropriate since the adjusted start point was via mg/m3(inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.

 

Description: Assessment factor - Interspecies

Value: 2.5

Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

 

Description: Assessment factor – Intraspecies

Value: 10

Remark: This is a default assessment factor for general population per REACH Guidance R.8.4.3.1.

 

Description: Assessment factor – Exposure duration

Value: 6

Remark: This is a default assessment factor for a sub-acute study per REACH Guidance R.8.4.3.1.

 

Description: Assessment factor – Dose response

Value: 1

Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

 

Description: Assessment factor – Quality of database

Value: 1

Remark: A factor of 1 is appropriate because the database is considered to be adequately robust.

 

Description: DNEL general population long term inhalation

Value: 0.17 mg/m3

Remark:  102.6 x 0.25/ (1x1x2.5x10x6x1x1) = 0.17 mg/m3

 

The DNEL for general population long-term oral exposure is derived as follows:

Step 1)

Description: Relevant dose-descriptor

Value: NOAEL: 218.8 mg/kg/day

Remark: This is the concentration where no significant adverse effects were seen in a 90-day rat inhalation study.  

 

Step 2)

Description: Assessment Factor: Route–to-route extrapolation

Value: 1

Remark: A factor of 1 is appropriate per REACH guidance R.8.4.2 (oral to oral).

 

Description: Assessment Factor: Animal-to-man scaling factor (Allometric scaling)

Value: 4

Remark: A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance R.8.4.3.1.

 

Description: Assessment factor - Interspecies

Value: 2.5

Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

 

Description: Assessment factor – Intraspecies

Value: 10

Remark: This is a default assessment factor for general population per REACH Guidance R.8.4.3.1.

 

Description: Assessment factor – Exposure duration

Value: 2

Remark: This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.

 

Description: Assessment factor – Dose response

Value: 1

Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

 

Description: Assessment factor – Quality of database

Value: 1

Remark: A factor of 1 is appropriate because the database is considered to be adequately robust.

 

Description: DNEL general population long term oral

Value: 1.1 mg/kg

Remark:  218.8 / (1 x 4 x 2.5 x 10 x 2 x 1 x 1) = 218.8/200 = 1.1 mg/kg