Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
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:
1 mg/m³
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:
137 mg/kg bw/day
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

In order to set acceptable DNEL values it is imperative that the determination takes into account the class of compound under review. It is impossible to investigate the exposure to copper and copper compounds without considering that copper is an essential metal present in human body tissues and fluids at concentrations of parts per million or parts per billion. It is also under tight homeostatic mechanisms that can control excess copper exposure by changing the rate of systemic uptake or excretion via the bile in humans. Therefore, in assessing the human health effects of copper the essentiality and homeostaic mechanisms have to be taken into account. In addition, for copper there are both animal studies and human volunteer studies available to determine an appropriate DNEL. For the purposes of this risk assessment, the values used in the human health risk assessment will be determined using both the animal and human data. It will be seen that the outcome of this evaluation is very similar.

 

Long-term systemic DNEL for workers and general population:

 

This document describes the derivation of a long term DNEL for copper and copper compounds based on homeostatic mechanisms involved in the oral absorption and bioavailability of copper in both rats and humans, available mammalian toxicity data and the understanding that copper is an essential metal.

 

In deriving a long term DNEL for a substance, there are several factors that have to be taken into account in determining the global assessment factor to be used in the risk characterization. The default values are set as:

 

Interspecies variation: This is based on the allometric scale as discussed in the Technical Guidance Document and the RIP-8 for human health under REACH and an additional interspecies factor to take into account other differences/similarities between species. 

 

The default values for interspecies variability are as follows:

 

           Allometric scaling based on rat studies                                 4

           Other interspecies differences                                               2.5

           Overall total                                                                        10

 

Intraspecies variation: In the TGD and RIP-8 for REACH the default value for intraspecies variation is 10. This can be reduced when for instance, the risk characterization only considers a sub-population e.g. workers.

 

Sub-chronic to chronic factor. If no reliable chronic studies are available, then a default value of 2 is used to determine a long term AEL from sub-chronic NOAELs (e.g. 90 day studies).

It is proposed that the assessment factors used in setting the long-term systemic DNEL for copper should be based on the following assessment factors:

 

 

Default Values

Proposed Assessment Factor for copper

Interspecies variation:

Allometric scaling – rat

Other interspecies variability

 

4

2.5

 

4

1.25

Intraspecies variation

10

10

Subchronic-chronic factor

2

2

Proposed assessment factor for long term AEL

200

100

It can be seen from the Table, that the only Assessment Factor to change from the default values is Interspecies variability – other observations. It was considered scientifically invalid to change the other factors, especially workers to general population based on the lack of reliable scientific evidence. Therefore this DNEL is acceptable for workers and general population.

The justification for the reduction from 2.5 to 1.25 was based on the similarities observed between rat and human toxicokinetic mechanism for uptake of copper following oral administration. It was not considered relevant to define factors for dermal and inhalation uptake as the pivotal mammalian toxicity studies (90 day rat dietary study) was based solely on the oral route of administration.

 

The long-term DNEL is therefore calculated using the following studies/criteria:

 

Pivotal study  90-day oral repeat dose toxicity study in the rat             16.7 mg/kg bw/d

Oral absorption factor                                                                        25%

Assessment factor                                                                              100

Long-term systemic DNEL                                                             0.041 mg/kg bw/d

 

Short-term systemic DNEL:

 

A short-term systemic DNEL can also be calculated from above by taking into account that the 90-day study is an appropriate term of exposure and removing the need for an assessment factor of 2 (sub-chronic-chronic factor). This would result in a short-term systemic DNEL of 0.082 mg/kg bw/d.

 

Acute systemic DNEL:

 

The need for assessment factors for acute effects is based on the NOAEL identified in the human volunteer studies of Araya et al (2001 and 2003). The NOAEL for nausea, the earliest and most frequently reported GIT symptom, was 4 mg Cu/L. In deriving a assessment factors for acute oral effects, it is significant that the NOAEL was derived from an internationally-diverse study population, involving a large number of subjects who were fasted prior to copper consumption and thus most susceptible to copper-induced GIT effects. In addition, the second and largest of the two studies involved only female subjects, who have been shown to be the most sensitive gender with respect to copper-induced GIT symptoms (Araya et al 2001; 2004). Consequently, the study population from which the NOAEL was identified may be considered as representing a fairly worst case. With respect to other members of the general population, the available data do not indicate that children are more at risk of acute effects associated with copper (Olivares et al, 1998; Pettersson et al, 2003).  Further, the critical effect involved, a GIT effect, is a local effect which is not affected by toxicokinetic factors and consequently requires no assessment factors to address any uncertainty.

 

Taking into consideration these factors, an assessment factor of 1 is considered appropriate for acute oral toxicity for the general population. An assessment factor of 1 is also considered appropriate for workers. Therefore the acute DNEL for copper and copper compounds is 4 mg Cu/L.

 

External Inhalation DNEL:

 

The NOAEL from a repeatd dose inhalation study is >2 mg/m3. Using this value as a point of departure, corresponding conservative HEC values of 1.5 mg/m3 and 3.6 mg/m3 were derived for hot and cold processes, which can be considered as worst-case values that cover the entire range of processes in the copper industry.

These values are also very close to the existing OEL for copper dust of 1 mg/m3 and as this value is currently used by many Member States as a legislative limit, it is proposed that this value is retained for the purposes of the REACH risk assessments and used as an inhalation local DNEL for copper. The corresponding OEL for copper fume is 0.1 mg/m3.

The external inhalation DNEL (short-term and long-term) is therefore:

1 mg/m3 for copper dust.

0.1 mg/m3 for copper fume.

External Dermal DNEL:

For screening purposes in the human health risk assessment, an external dermal DNEL (short-term and long-term) can be calculated using the proposed systemic DNELs (outlined above) and the proposed dermal penetration factors of 0.03% for dry copper and copper compounds and 0.3% for copper and copper compounds in solution/suspension.

The external long-term DNEL for dermal exposure has been set at 136.67 mg Cu/kg bw/d for dry copper and copper compounds.

 

The external short-term DNEL for dermal exposure has been set at 273.34 mg Cu/kg bw/d for dry copper and copper compounds.

 

The external long-term DNEL for dermal exposure has been set at 13.67 mg Cu/kg bw/d for copper and copper compounds in a slurry/solution.

 

The external short-term DNEL for dermal exposure has been set at 27.33 mg Cu/kg bw/d for copper and copper compounds in a slurry/solution.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
0.041 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.082 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

In order to set acceptable DNEL values it is imperative that the determination takes into account the class of compound under review. It is impossible to investigate the exposure to copper and copper compounds without considering that copper is an essential metal present in human body tissues and fluids at concentrations of parts per million or parts per billion. It is also under tight homeostatic mechanisms that can control excess copper exposure by changing the rate of systemic uptake or excretion via the bile in humans. Therefore, in assessing the human health effects of copper the essentiality and homeostaic mechanisms have to be taken into account. In addition, for copper there are both animal studies and human volunteer studies available to determine an appropriate DNEL. For the purposes of this risk assessment, the values used in the human health risk assessment will be determined using both the animal and human data. It will be seen that the outcome of this evaluation is very similar.

 

Long-term systemic DNEL for workers and general population:

 

This document describes the derivation of a long term DNEL for copper and copper compounds based on homeostatic mechanisms involved in the oral absorption and bioavailability of copper in both rats and humans, available mammalian toxicity data and the understanding that copper is an essential metal.

 

In deriving a long term DNEL for a substance, there are several factors that have to be taken into account in determining the global assessment factor to be used in the risk characterization. The default values are set as:

 

Interspecies variation: This is based on the allometric scale as discussed in the Technical Guidance Document and the RIP-8 for human health under REACH and an additional interspecies factor to take into account other differences/similarities between species. 

 

The default values for interspecies variability are as follows:

 

           Allometric scaling based on rat studies                                 4

           Other interspecies differences                                               2.5

           Overall total                                                                        10

 

Intraspecies variation: In the TGD and RIP-8 for REACH the default value for intraspecies variation is 10. This can be reduced when for instance, the risk characterization only considers a sub-population e.g. workers.

 

Sub-chronic to chronic factor. If no reliable chronic studies are available, then a default value of 2 is used to determine a long term AEL from sub-chronic NOAELs (e.g. 90 day studies).

It is proposed that the assessment factors used in setting the long-term systemic DNEL for copper should be based on the following assessment factors:

 

 

Default Values

Proposed Assessment Factor for copper

Interspecies variation:

Allometric scaling – rat

Other interspecies variability

 

4

2.5

 

4

1.25

Intraspecies variation

10

10

Subchronic-chronic factor

2

2

Proposed assessment factor for long term AEL

200

100

 

 

It can be seen from the Table, that the only Assessment Factor to change from the default values is Interspecies variability – other observations. It was considered scientifically invalid to change the other factors, especially workers to general population based on the lack of reliable scientific evidence. Therefore this DNEL is acceptable for workers and general population.

The justification for the reduction from 2.5 to 1.25 was based on the similarities observed between rat and human toxicokinetic mechanism for uptake of copper following oral administration. It was not considered relevant to define factors for dermal and inhalation uptake as the pivotal mammalian toxicity studies (90 day rat dietary study) was based solely on the oral route of administration.

 

The long-term DNEL is therefore calculated using the following studies/criteria:

 

Pivotal study  90-day oral repeat dose toxicity study in the rat             16.7 mg/kg bw/d

Oral absorption factor                                                                        25%

Assessment factor                                                                              100

Long-term systemic DNEL                                                             0.041 mg/kg bw/d

 

Short-term systemic DNEL:

 

A short-term systemic DNEL can also be calculated from above by taking into account that the 90-day study is an appropriate term of exposure and removing the need for an assessment factor of 2 (sub-chronic-chronic factor). This would result in a short-term systemic DNEL of 0.082 mg/kg bw/d.

 

Acute systemic DNEL:

 

The need for assessment factors for acute effects is based on the NOAEL identified in the human volunteer studies of Araya et al (2001 and 2003). The NOAEL for nausea, the earliest and most frequently reported GIT symptom, was 4 mg Cu/L. In deriving a assessment factors for acute oral effects, it is significant that the NOAEL was derived from an internationally-diverse study population, involving a large number of subjects who were fasted prior to copper consumption and thus most susceptible to copper-induced GIT effects. In addition, the second and largest of the two studies involved only female subjects, who have been shown to be the most sensitive gender with respect to copper-induced GIT symptoms (Araya et al 2001; 2004). Consequently, the study population from which the NOAEL was identified may be considered as representing a fairly worst case. With respect to other members of the general population, the available data do not indicate that children are more at risk of acute effects associated with copper (Olivares et al, 1998; Pettersson et al, 2003).  Further, the critical effect involved, a GIT effect, is a local effect which is not affected by toxicokinetic factors and consequently requires no assessment factors to address any uncertainty.

 

Taking into consideration these factors, an assessment factor of 1 is considered appropriate for acute oral toxicity for the general population. An assessment factor of 1 is also considered appropriate for workers. Therefore the acute DNEL for copper and copper compounds is 4 mg Cu/L.

 

External Inhalation DNEL:

 

The NOAEL from a repeatd dose inhalation study is >2 mg/m3. Using this value as a point of departure, corresponding conservative HEC values of 1.5 mg/m3 and 3.6 mg/m3 were derived for hot and cold processes, which can be considered as worst-case values that cover the entire range of processes in the copper industry.

These values are also very close to the existing OEL for copper dust of 1 mg/m3 and as this value is currently used by many Member States as a legislative limit, it is proposed that this value is retained for the purposes of the REACH risk assessments and used as an inhalation local DNEL for copper. The corresponding OEL for copper fume is 0.1 mg/m3.

The external inhalation DNEL (short-term and long-term) is therefore:

1 mg/m3 for copper dust.

0.1 mg/m3 for copper fume.

 

External Dermal DNEL:

 

For screening purposes in the human health risk assessment, an external dermal DNEL (short-term and long-term) can be calculated using the proposed systemic DNELs (outlined above) and the proposed dermal penetration factors of 0.03% for dry copper and copper compounds and 0.3% for copper and copper compounds in solution/suspension.

The external long-term DNEL for dermal exposure has been set at 136.67 mg Cu/kg bw/d for dry copper and copper compounds.

 

The external short-term DNEL for dermal exposure has been set at 273.34 mg Cu/kg bw/d for dry copper and copper compounds.

The external long-term DNEL for dermal exposure has been set at 13.67 mg Cu/kg bw/d for copper and copper compounds in a slurry/solution.

 

The external short-term DNEL for dermal exposure has been set at 27.33 mg Cu/kg bw/d for copper and copper compounds in a slurry/solution.