Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
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:
100 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker:

Based on the available data no classification and labeling for toxicology endpoints is required for N,N''-(isobutylidene)diurea.

The primary routes of anticipated industrial and professional exposure are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 408 study (BASF, 2017) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for systemic toxicity was at 1000 mg/kg bw/day.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 1763 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8  

 - Intraspecies factor: 5

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 2

Standard factor as outlined in REACh Guidance document R.8

- Dose-response: 1

Total AF = 1 x 2.5 x 5 x 2 x 1 = 25

Based on this calculation the resulting DNEL is 70.5 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 408 study (BASF, 2017) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal uptake. The NOAEL for systemic toxicity was at 1000 mg/kg bw/day.

This point of departure was modified to get the corrected starting point for DNEL derivation. Estimations using Dermwin v2.02 show that the estimated Kp value is very low (0.0000414 cm/hour) and consequently also dermal uptake through the skin will be very low. Thus the NOAEL can be corrected at least by a factor of 10 based on the Dermwin estimation which resulted in a corrected starting point for DNEL derivation for worker of 10000 mg/kg bw/day.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

  - Intraspecies factor: 5

Standard factor as outlined in REACh Guidance document R.8

- Exposure duration: 2

Standard factor as outlined in REACh Guidance document R.8

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8

 

Total AF = 4 x 5 x 2 x 1 x 2.5 = 100

Based on this calculation the resulting DNEL is 100 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.39 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
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:
50 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
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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
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

Consumer

Based on the available data no classification and labeling for toxicology endpoints is required for N,N''-(isobutylidene)diurea.

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 408 study (BASF, 2017) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for systemic toxicity was at 1000 mg/kg bw/day.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 869,5 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8  

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 2

Standard factor as outlined in REACh Guidance document R

- Dose-response: 1

Total AF = 1 x 2.5 x 10 x 2 x 1 = 50

Based on this calculation the resulting DNEL is 17.39 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 408 study (BASF, 2017) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal uptake. The NOAEL for systemic toxicity was at 1000 mg/kg bw/day.

This point of departure was modified to get the corrected starting point for DNEL derivation. Estimations using Dermwin v2.02 show that the estimated Kp value is very low (0.0000414 cm/hour) and consequently also dermal uptake through the skin will be very low. Thus the NOAEL can be corrected at least by a factor of 10 based on the Dermwin estimation which resulted in a corrected starting point for DNEL derivation for the general population of 10000 mg/kg bw/day.

The NOAEL of 10000 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (10), exposure duration (2) (AF = 4 x 10 x 2 x 1 x 2.5 = 200).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 50 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 2

Standard factor as outlined in REACh Guidance document R.8 

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8

Oral long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 408 study (BASF, 2017) was identified as the appropriate starting point for DNEL derivation for long-term exposure following oral uptake. The NOAEL for systemic toxicity was at 1000 mg/kg bw/day.

The NOAEL of 1000 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (10), exposure duration (2) (AF = 4 x 10 x 2 x 1 x 2.5 = 200

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 5 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 2

Standard factor as outlined in REACh Guidance document R.8  

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8