Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.53 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
264.47 mg/m³
Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step, followed by a correction for the difference between respiratory rates of workers under standard conditions and under light activity in the second step. NAECcorr_inh = oral NOAEL (150) x 1/0.38 m3/kg bw x 6.7 m3/10 m3 = 264.47 mg/m3. As a worst case, oral absorption in rats in humans is assumed to be 100% and inhalation absorption in humans is assumed to be 100%. Therefore, NAECcorr_inh = 264.47 x 1 = 264.47 mg/m3.

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling required for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
5
Justification:
Default assessment factor of 5 for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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:
0.5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a worst case, assume that oral absorption in rats is 100% and dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 150 x 100/100 = 150 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat = 4
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
5
Justification:
Default assessment factor of 5 for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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

There are three repeated dose oral toxicity studies available, one for the substance itself (K2) study, one repeated dose / developmental screening test for a read-across substance and one prenatal developmental toxicity study for a read-across substance. All the substances have been supported under Environmental Protection Agency’s (EPA’s) High Production Volume (HPV) Challenge Program. The American Chemical Councils RAPA Panel, has derived a “Substituted Diphenylamines” category . The lowest NOAEL value was the NOAEL of 150 mg/kg bw/day established in the prenatal developmental toxicity study for maternal toxicity. Therefore, 150 mg/kg bw/day was selected as the starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL on the basis of being the lowest dose. Long-term local DNELs (inhalation) were not derived as the substance is not classified for local effects and it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. An acute system DNEL for inhalation was derived on the basis of the guidance, utilising the acute oral value. Acute and systemic DNELs for dermal were not derived because the substance is not classified for acute effects. In practice, occupational protection for workers does not allow a direct exposure of workers to the test item at a concentration causing dermal irritation, due to PPE as standard in the workplace. The RMMs installed to protect workers are sufficient to prevent any hazard from local dermal exposure. It is considered that the derivation from long term systemic effects provides a suitable margin of safety for use.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.43 mg/m³
Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose, the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hrs exposure of general public). NAECcorr_inh = oral NOAEL (150) x 1/1.15 m3/kg bw = 130.43 mg/m3. As a worst case, oral absorption in rats in humans is assumed to be 100% and inhalation absorption in humans is assumed to be 100%. Therefore, NAECcorr_inh = 130.43 x 1 = 130.43 mg/m3.

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling required for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor of 10 for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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:
0.25 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As worst case, assume that oral absorption in rats is 100% and dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 150 x 100/100 = 150 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat = 4
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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:
0.25 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not required
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Factor for allometric scaling for rat
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
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

There are three repeated dose oral toxicity studies available, one for the substance itself (K2) study, one repeated dose / developmental screening test for a read-across substance and one prenatal developmental toxicity study for a read-across substance. All the substances have been supported under Environmental Protection Agency’s (EPA’s) High Production Volume (HPV) Challenge Program. The American Chemical Councils RAPA Panel, has derived a “Substituted Diphenylamines” category . The lowest NOAEL value was the NOAEL of 150 mg/kg bw/day established in the prenatal developmental toxicity study for maternal toxicity. Therefore, 150 mg/kg bw/day was selected as the starting point for deriving the long-term systemic inhalation DNEL, the long-term systemic dermal DNEL and the long-term systemic oral DNEL on the basis of being the lowest dose. Long-term local DNELs (inhalation) were not derived as the substance is not classified for local effects and it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. An acute system DNEL for inhalation was derived on the basis of the guidance, utilising the acute oral value. Acute and systemic DNELs for dermal were not derived because the substance is not classified for acute effects. In practice, given the nature of use of the substance, it is unlikely that long term exposure to the substance by the general population is anticipated.