Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
10 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
Justification:
of conversion of oral dose to inhalation concentration, using the section R.8.4.2 of the REACh guidance document
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
10
Justification:
, in addition a factor of 10 was used for differences between dermal absorption of 6-8% in humans and assumed to be well absorbed by the oral route.
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

In the case of 4-aminophenol, the following key DNELs have been derived:

Where:        NOAEL  =  No-Observed-Adverse-Effect Level (also referred to as a No-Observed- Effect-Level) for the endpoint of concern = 10 mg/kg/day from subchronic 13-week study in the rat

 

This is considered the key DNEL “departure point” because it is assumed that the negative carcinogenicity study will be a weight of evidence” WOE argument over the positive chromosome effects studies.

 

Worker-DNEL long-term for inhalation route-systemic

First step is to look at Example B.3 (page 68 of Guidance Document) of Appendix R.8-2 of Chapter R.8. The following formula applies in this case:

[corrected] Inhalation NOAEL (mg/m3) = oral NOAEL (mg/kg-day from rat study) x 1/sRV (rat) x ABS (oral-rat)/ABS (inhalation-human)

The following are used:

·        oral NOAEL (from rat study) = 10 mg/kg/day

·        sRV (rat) = 0.38 m3/kg (for 8-hour exposure) [found in Table R.8-2 (page 26)

 

·        ABS (oral-rat) = if you have data for the chemical in question, use it; otherwise the ECHA default = 50% (Section R.8.4.2; page 25);

 

·        ABS (inhalation-human) = if you have data for the chemical in question, use it; otherwise the ECHA default = 100% (Section R.8.4.2; page 25)


Therefore, the [corrected] Inhalation NOAEL (mg/m3) = 52.6 mg/m3

 

To this value, the following assessment factors to arrive at a worker DNELlong-term for inhalation route-systemic.

 

1)     Assessment factors for interspecies differences

Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Where human data are used as the starting point for the risk characterisation, no extrapolation is necessary and hence no assessment factor is normally suggested for interspecies differences in sensitivity. Where data from animal studies are the typical starting point for risk characterisation, the default assumption in general is that humans are more sensitive than experimental animals. The traditional default suggested for interspecies extrapolation is 10, which is incorporates both allometric scaling factor of 4 for rat and 2.5 for pharmacodynamics. As allometric scaling has already been accounted for by the respiratory rate calculation, then a factor of 2.5 is applied for “other differences” and pharmacodynamics.

2)     Assessment factor for intraspecies differences

Humans differ in sensitivity due to a number of biological factors (such as age, gender, genetic composition and nutritional status). The intraspecies variation in humans is greater than in the more homogeneous experimental animal population. Although other values have been proposed, defaults typically suggested for the general population (representing all age groups, including children and elderly) are a factor of 10. A lower default factor is generally suggested for the worker population, because the very young and very old are not part of this population; therefore 5 is applied for workers.

3)     Assessment factor for differences in duration of exposure

Taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration is normally applied in risk assessment.  In this case, the default for sub-chronic to chronic was applied, or 2

4)     Assessment factor for uncertainty in route-to-route extrapolation

No additional assessment factor was used for route-to-route extrapolation as this is accounted for in the determination above.

5)     Assessment factor for dose-response relationship

For the dose-response relationship, consideration should be given to the uncertainties in the NOAEL as the surrogate for the true no-adverse-effect-level (NAEL), as well as to the extrapolation of the LOAEL to the NAEL (in cases where only a LOAEL is available or where a LOAEL is considered a more appropriate starting point). In this case, the assessment factor was applied was 1 (no adjustment).

6)     Other aspects relating to the dataset

Next to extrapolation, other important aspects of risk characterisation are the adequacy of and confidence in the available dataset. The US-EPA uses the term modifying factor to cover uncertainties other than the ‘extrapolation’ assessment factors. In this case, no modifying factor was needed.

Composite safety factor = (2.5) (5)(2) (1)(1) (1) = 25

DNEL = 52.6 mg/m3 / 25= 2.1 mg/m3

Worker-DNEL long-term for dermal route-systemic

The guidance document states that the NOAEL from the oral study can be used for determining this value as follows.

·        NOAEL  =  No-Observed-Adverse-Effect Level (also referred to as a No-Observed- Effect-Level) for the endpoint of concern = 10 mg/kg/day from subchronic 13-week study in the rat

 

This NOAEL can be modified based on the human dermal absorption potential of 6-8% (reported in pharmacokinetics portion of the dossier.  A factor of 1 is typically used in the absence of data, but the difference between oral and dermal absorption is conservatively a difference of a factor of 10 or the NOAEL for dermal systemic effects can be raised by a factor of 10 (actually it could be more than 10 but the precautionary principle is applied)

 

10 mg/kg/day x 10 (difference in human oral absorption versus animal oral absorption)= No Adverse Effect Dose (Human dermal) = 100 mg/kg/day

 

To this value, the following assessment factors to arrive at a worker DNELlong-term for dermal route-systemic were applied:

 

7)     Assessment factos for interspecies differences

Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Where human data are used as the starting point for the risk characterisation, no extrapolation is necessary and hence no assessment factor is normally suggested for interspecies differences in sensitivity. Where data from animal studies are the typical starting point for risk characterisation, the default assumption in general is that humans are more sensitive than experimental animals. The traditional default suggested for interspecies extrapolation is 10, which is applied here; alternatively, the allometric scaling factor of 4 for rat and 2.5 for pharmacodynamics is applied which is also equivalent to a factor of 10.

8)     Assessment factor for intraspecies differences

Humans differ in sensitivity due to a number of biological factors (such as age, gender, genetic composition and nutritional status). The intraspecies variation in humans is greater than in the more homogeneous experimental animal population. Although other values have been proposed, defaults typically suggested for the general population (representing all age groups, including children and elderly) are a factor of 10. A lower default factor is generally suggested for the worker population, because the very young and very old are not part of this population; therefore 5 is applied for workers.

9)     Assessment factor for differences in duration of exposure

Taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration is normally applied in risk assessment.  In this case, the default for sub-chronic to chronic was applied, or 2.

10) Assessment factor for uncertainty in route-to-route extrapolation

This value has already been accounted for in above.

11) Assessment factor for dose-response relationship

For the dose-response relationship, consideration should be given to the uncertainties in the NOAEL as the surrogate for the true no-adverse-effect-level (NAEL), as well as to the extrapolation of the LOAEL to the NAEL (in cases where only a LOAEL is available or where a LOAEL is considered a more appropriate starting point). In this case, the assessment factor was applied was 1 (no adjustment).

12) Other aspects relating to the dataset

Next to extrapolation, other important aspects of risk characterisation are the adequacy of and confidence in the available dataset. The US-EPA uses the term modifying factor to cover uncertainties other than the ‘extrapolation’ assessment factors. In this case, no modifying factor was needed.

Composite safety factor = (10) (5)(2) (1)(1) (1) = 100

DNEL = 100 mg/kg/day / 100 = 1 mg/kg/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

To our knowledge the only direct exposure of the general population to 4-aminophenol is via its use in commercial hair dyes. In accordance with article 14.5(b) of the REACH regulation the Chemical Safety Report need not include consideration of the risks to human health from the end use in cosmetic products within the scope of Directive 76/768/EEC.