Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
1
Modified dose descriptor starting point:
NOAEC
DNEL value:
5 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL of 50 mg Zn/day is the basis for the derivation of the inhalatory DNEL. Hence, the derivation of the inhalatory DNEL requires a route to route extrapolation as described in the following: *) Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i. e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day); *) Calculation of a inhalatory exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; the following assumptions are made: bioavailability of soluble zinc compounds following inhalatory exposure – 40%; bioavailability of slightly soluble/insoluble zinc compounds following inhalatory exposure – 20%; NOAELinhal sol. Zn= 10 mg Zn/day / 40% = 25 mg Zn/day NOAEL inhal insol Zn=10 mg Zn/day / 20% = 50 mg Zn/day Corrected dose descriptor for workers considering a breathing volume of 10m3per 8hr shift NOAELinhal sol. Zn= 25 mg Zn/day / 10m3/day = 2.5 mg/m3 NOAEL inhal insol. Zn= 50 mg Zn/day / 10m3/day = 5 mg/m3 *) No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows: DNELinhal sol Zn (worker) = 2.5 mg/m3; DNEL inhal insol Zn (worker) = 5 mg Zn/m3
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
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:
83 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):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The derivation of a dermal DNEL on the basis of an oral NOAEL of 50 mg Zn/day derived from human volunteer studies requires a route to route extrapolation.In this process, the follow steps are required *) Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst = 50 mg Zn/day x 20% = 10 mg Zn/day); *) Calculation of a dermal exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; assumption: bioavailability of soluble zinc compounds following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds following dermal exposure – 0.2%; NOAELdermal sol Zn = 10 mg Zn/day / 2% = 500 mg Zn/day ; NOAELdermal insol Zn = 10 mg Zn/day / 0.2% = 5000 mg Zn/day *) No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows: DNELdermal sol Zn = 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day); DNELdermal insol Zn = 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day)
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
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

To derive the endpoint specific NOAELs for workers and consumers on the basis of the established NOAEL of 50 mg zinc/day (0.83 mg/kg bw/day based on a woman’s body weight of 60 kg), the NOAEL has to be corrected by assessment factors to account for the uncertainties of the database that led to the establishment of the NOAEL. As the toxicity of zinc compounds is well understood and the NOAEL has been based on human experience and data following chronic exposure to zinc through food supplementation, no assessment factors are considered to be required for zinc compounds

Derivation of the oral DNEL

The most relevant dose descriptor has been derived from oral human volunteer studies and human experience from the use of zinc in food supplementation. Neither correction of the dose descriptor nor the use of an assessment factor is considered necessary. Therefore, the oral DNEL for all zinc compounds (i.e., soluble or slightly soluble/insoluble) for workers and consumers equals the most relevant quantitative external dose descriptor for systemic exposure:

DNELoral sol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

DNELoral insol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

This setting of the DNEL is fully in line with the approach and result that was concluded in the EU Risk Assessment- part II Human Health (EU RAR 2004).

Derivation of the dermal DNEL (workers, consumers)

The derivation of a dermal DNEL on the basis of an oral NOAEL of 50 mg Zn/day derived from human volunteer studies requires a route to route extrapolation. In this process, the follow steps are required

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a dermal exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; assumption: bioavailability of soluble zinc compounds following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds following dermal exposure – 0.2%;

NOAELdermal sol Zn= 10 mg Zn/day / 2% = 500 mg Zn/day

NOAELdermal insol Zn= 10 mg Zn/day / 0.2% = 5000 mg Zn/day

No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows:

DNELdermal sol Zn= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day)

DNELdermal insol Zn= 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day)

No further differentiation between worker and consumer DNELs is considered necessary.

Derivation of the inhalatory DNEL (workers, consumers)

The oral NOAEL of 50 mg Zn/day is also the basis for the derivation of the inhalatory DNEL. Hence, the derivation of the inhalatory DNEL requires a route to route extrapolation as described in the following:

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a inhalatory exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; the following assumptions are made: bioavailability of soluble zinc compounds following inhalatory exposure – 40%; bioavailability of slightly soluble/insoluble zinc compounds following inhalatory exposure – 20%;

NOAELinhal sol. Zn= 10 mg Zn/day / 40% = 25 mg Zn/day

NOAELinhal insol Zn=10 mg Zn/day / 20% = 50 mg Zn/day

Corrected dose descriptor for workers considering a breathing volume of 10m3per 8hr shift

NOAELinhal sol. Zn= 25 mg Zn/day / 10m3/day = 2.5 mg/m3

NOAELinhal insol. Zn= 50 mg Zn/day / 10m3/day = 5 mg/m3

Corrected dose descriptor for consumers considering a breathing volume of 20m3per day NOAELinhal sol. Zn= 25 mg Zn/day / 20m3/day = 1.25 mg/m3

NOAELinhal insol. Zn= 50 mg Zn/day / 20m3/day = 2.5 mg/m3

No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows:

DNELinhal sol Zn (worker)= 2.5 mg/m3;

DNELinhal insol Zn (worker)= 5 mg Zn/m3;

DNELinhal sol Zn (consumer)= 1.25 mg/m3;

DNELinhal insol Zn (consumer)= 2.5 mg Zn/m3;

The following Tables summarize DNELs that have been calculated for worker and consumer exposure to soluble and slightly soluble/insoluble zinc compounds according to the ECHA guidance methodology.

Table- Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for workers

Endpoint

 

Zinc compound category

Most relevant quantitative external dose descriptor for systemic exposure(NOEL)

Corrected external dose descriptor for systemic exposure

Overall Assessment factor

Endpoint-specific DNEL (external dose)

Repeated dose toxicity

 

Oral

Soluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

 

Slightly soluble/ insoluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

Dermal

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

 

500 mg Zn/day

(8.3mg/kg bw/day)

1

500 mg Zn/day

(8.3 mg/kg bw/day)

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)

1

5000 mg Zn/day

(83mg/kg bw/day)

Inhalation

 

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

2.5 mg Zn/m3

1

2.5 mg Zn/m3

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5 mg Zn/ m3

1

 

5 mg Zn/ m3

Table43- Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for consumers

Endpoint

 

Zinc compound category

Most relevant quantitative dose descriptor for systemic exposure

Corrected dose descriptor for systemic exposure

Overall Assessment factor

Endpoint-specific DNEL (external dose)

Repeated dose toxicity

 

Oral

Soluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

 

Slightly soluble/ insoluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

Dermal

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

 

500 mg Zn/day

(8.3mg/kg bw/day)

1

500 mg Zn/day

(8.3 mg/kg bw/day)

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)

1

5000 mg Zn/day

(83mg/kg bw/day)

Inhalation

 

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

1.3 mg Zn/m3

1

1.3 mg Zn/m3

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

2.5 mg Zn/ m3

1

 

2.5 mg Zn/ m3

In line with the rationale provided above, the DNEL’s for workers and consumers following oral or dermal exposure to soluble and slightly soluble/insoluble compounds are as follows:

Oral

DNELoral sol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

DNELoral insol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

Dermal

DNELdermal sol Zn= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day);

DNELdermal insol Zn= 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day);

These DNEL’s appropriately protect workers and consumers for the most sensitive health endpoint, i.e. reduced ESOD activity, that has been observed in humans following repeated exposure to zinc compounds.

With regard to establishing the critical DNELs for inhalatory exposure of workers or consumers to zinc compounds, two approaches are considered suitable:

a. the derivation of the DNEL on the basis of existing oral human dietary supplement studies requiring route to route extrapolation as illustrated above and

b. the use of existing OELs as the respective DNELs for worker exposure.

With regard to the latter, the guidance on information requirements and chemical safety assessment states that the OELs and/or the underlying information used for setting the OELs can be used to derive the DNELs for workers (ECHA, 2008).

As presented above, existing data from human supplementary studies results in worker DNELs of 2.5 or 5 mg Zn/m3for soluble and slightly soluble/insoluble zinc compounds respectively and consumer DNELs of 1.3 or 2.5 mg Zn/m3.

An overview of existing OELs for soluble zinc compounds represented by zinc chloride as well as slightly soluble/insoluble zinc compounds represented by zinc oxide is available in the CSR (section 5.11). While a detailed scientific justification for the OELs is not available, these values have ensured workers safety for decades which correlates with the DNELs derived from the human volunteer studies.

Taking a conservative approach it is proposed that for inhalatory exposure to soluble and slightly soluble/ insoluble zinc compounds, the existing OEL values are used as the respective DNEL against which to judge the adequacy of workplace risk management measures (RMM) to control airborne exposure to zinc compounds:

Inhalation – Worker

DNELinhal soluble Zn (worker)= 1 mg Zn/m3;

DNELinhal insoluble Zn (worker)= 5 mg Zn/m3;

Inhalation – Consumer

DNELinhal soluble Zn (consumer)= 1.3 mg Zn/m3;

DNELinhal insoluble Zn (consumer)= 2.5 mg Zn/m3;

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 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):
1
Modified dose descriptor starting point:
NOAEC
DNEL value:
2.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL of 50 mg Zn/day is the basis for the derivation of the inhalatory DNEL. Hence, the derivation of the inhalatory DNEL requires a route to route extrapolation as described in the following: *) Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i. e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day); *) Calculation of a inhalatory exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; the following assumptions are made: bioavailability of soluble zinc compounds following inhalatory exposure – 40%; bioavailability of slightly soluble/insoluble zinc compounds following inhalatory exposure – 20%; NOAEL inhal sol. Zn= 10 mg Zn/day / 40% = 25 mg Zn/day NOAEL inhal insol Zn=10 mg Zn/day / 20% = 50 mg Zn/day Corrected dose descriptor for consumers considering a breathing volume of 20m3per day NOAELinhal sol. Zn= 25 mg Zn/day / 20m3/day = 1.25 mg/m3 NOAEL inhal insol. Zn= 50 mg Zn/day / 20m3/day = 2.5 mg/m3 *) No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows: DNELinhal sol Zn (consumer) = 1.25 mg/m3; DNEL inhal insol Zn (consumer) = 2.5 mg Zn/m3
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
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:
83 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):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The derivation of a dermal DNEL on the basis of an oral NOAEL of 50 mg Zn/day derived from human volunteer studies requires a route to route extrapolation.In this process, the follow steps are required *) Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst = 50 mg Zn/day x 20% = 10 mg Zn/day); *) Calculation of a dermal exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; assumption: bioavailability of soluble zinc compounds following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds following dermal exposure – 0.2%; NOAELdermal sol Zn = 10 mg Zn/day / 2% = 500 mg Zn/day ; NOAELdermal insol Zn = 10 mg Zn/day / 0.2% = 5000 mg Zn/day *) No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows: DNELdermal sol Zn = 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day); DNELdermal insol Zn = 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day)
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
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:
0.83 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):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.83 mg/kg bw/day
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
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

To derive the endpoint specific NOAELs for workers and consumers on the basis of the established NOAEL of 50 mg zinc/day (0.83 mg/kg bw/day based on a woman’s body weight of 60 kg), the NOAEL has to be corrected by assessment factors to account for the uncertainties of the database that led to the establishment of the NOAEL. As the toxicity of zinc compounds is well understood and the NOAEL has been based on human experience and data following chronic exposure to zinc through food supplementation, no assessment factors are considered to be required for zinc compounds

Derivation of the oral DNEL

The most relevant dose descriptor has been derived from oral human volunteer studies and human experience from the use of zinc in food supplementation. Neither correction of the dose descriptor nor the use of an assessment factor is considered necessary. Therefore, the oral DNEL for all zinc compounds (i.e., soluble or slightly soluble/insoluble) for workers and consumers equals the most relevant quantitative external dose descriptor for systemic exposure:

DNELoral sol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

DNELoral insol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

This setting of the DNEL is fully in line with the approach and result that was concluded in the EU Risk Assessment- part II Human Health (EU RAR 2004).

Derivation of the dermal DNEL (workers, consumers)

The derivation of a dermal DNEL on the basis of an oral NOAEL of 50 mg Zn/day derived from human volunteer studies requires a route to route extrapolation. In this process, the follow steps are required

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a dermal exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; assumption: bioavailability of soluble zinc compounds following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds following dermal exposure – 0.2%;

NOAELdermal sol Zn=10 mg Zn/day / 2% = 500 mg Zn/day

NOAELdermal insol Zn=10 mg Zn/day / 0.2% = 5000 mg Zn/day

No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows:

DNELdermal sol Zn= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day)

DNELdermal insol Zn= 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day)

No further differentiation between worker and consumer DNELs is considered necessary.

Derivation of the inhalatory DNEL (workers, consumers)

The oral NOAEL of 50 mg Zn/day is also the basis for the derivation of the inhalatory DNEL. Hence, the derivation of the inhalatory DNEL requires a route to route extrapolation as described in the following:

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAELsyst= 50 mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a inhalatory exposure to a soluble or slightly soluble/insoluble zinc compound that results in a systemic exposure of 10 mg Zn/day; the following assumptions are made: bioavailability of soluble zinc compounds following inhalatory exposure – 40%; bioavailability of slightly soluble/insoluble zinc compounds following inhalatory exposure – 20%;

NOAELinhal sol. Zn= 10 mg Zn/day / 40% = 25 mg Zn/day

NOAELinhal insol Zn=10 mg Zn/day / 20% = 50 mg Zn/day

Corrected dose descriptor for workers considering a breathing volume of 10m3per 8hr shift

NOAELinhal sol. Zn= 25 mg Zn/day / 10m3/day = 2.5 mg/m3

NOAELinhal insol. Zn= 50 mg Zn/day / 10m3/day = 5 mg/m3

Corrected dose descriptor for consumers considering a breathing volume of 20m3per day NOAELinhal sol. Zn= 25 mg Zn/day / 20m3/day = 1.25 mg/m3

NOAELinhal insol. Zn= 50 mg Zn/day / 20m3/day = 2.5 mg/m3

No assessment factor is considered to be required as the original dose descriptor has been derived from appropriate human volunteer studies; hence the DNELs are as follows:

DNELinhal sol Zn (worker)= 2.5 mg/m3;

DNELinhal insol Zn (worker)= 5 mg Zn/m3;

DNELinhal sol Zn (consumer)= 1.25 mg/m3;

DNELinhal insol Zn (consumer)= 2.5 mg Zn/m3;

The followingTables summarize DNELs that have been calculated for worker and consumer exposure to soluble and slightly soluble/insoluble zinc compounds according to the ECHA guidance methodology.

Table- Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for workers

Endpoint

 

Zinc compound category

Most relevant quantitative external dose descriptor for systemic exposure(NOEL)

Corrected external dose descriptor for systemic exposure

Overall Assessment factor

Endpoint-specific DNEL (external dose)

Repeated dose toxicity

 

Oral

Soluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

 

Slightly soluble/ insoluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

Dermal

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

 

500 mg Zn/day

(8.3mg/kg bw/day)

1

500 mg Zn/day

(8.3 mg/kg bw/day)

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)

1

5000 mg Zn/day

(83mg/kg bw/day)

Inhalation

 

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

2.5 mg Zn/m3

1

2.5 mg Zn/m3

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5 mg Zn/ m3

1

 

5 mg Zn/ m3

Table- Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for consumers

Endpoint

 

Zinc compound category

Most relevant quantitative dose descriptor for systemic exposure

Corrected dose descriptor for systemic exposure

Overall Assessment factor

Endpoint-specific DNEL (external dose)

Repeated dose toxicity

 

Oral

Soluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

 

Slightly soluble/ insoluble

50 mg Zn/day

(0.83 mg/kg bw/day)

Not required

1

50 mg Zn/day

(0.83 mg/kg bw/day)

Dermal

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

 

500 mg Zn/day

(8.3mg/kg bw/day)

1

500 mg Zn/day

(8.3 mg/kg bw/day)

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)

1

5000 mg Zn/day

(83mg/kg bw/day)

Inhalation

 

Soluble

50 mg Zn/day (0.83 mg/kg bw/day)

1.3 mg Zn/m3

1

1.3 mg Zn/m3

Slightly soluble/ insoluble

50 mg Zn/day (0.83 mg/kg bw/day)

2.5 mg Zn/ m3

1

 

2.5 mg Zn/ m3

In line with the rationale provided above, the DNEL’s for workers and consumers following oral or dermal exposure to soluble and slightly soluble/insoluble compounds are as follows:

Oral

DNELoral sol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

DNELoral insol Zn= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

Dermal

DNELdermal sol Zn= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day);

DNELdermal insol Zn= 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day);

These DNEL’s appropriately protect workers and consumers for the most sensitive health endpoint, i.e. reduced ESOD activity, that has been observed in humans following repeated exposure to zinc compounds.

With regard to establishing the critical DNELs for inhalatory exposure of workers or consumers to zinc compounds, two approaches are considered suitable:

a. the derivation of the DNEL on the basis of existing oral human dietary supplement studies requiring route to route extrapolation as illustrated above and

b. the use of existing OELs as the respective DNELs for worker exposure.

With regard to the latter, the guidance on information requirements and chemical safety assessment states that the OELs and/or the underlying information used for setting the OELs can be used to derive the DNELs for workers (ECHA, 2008).

As presented above, existing data from human supplementary studies results in worker DNELs of 2.5 or 5 mg Zn/m3for soluble and slightly soluble/insoluble zinc compounds respectively and consumer DNELs of 1.3 or 2.5 mg Zn/m3.

An overview of existing OELs for soluble zinc compounds represented by zinc chloride as well as slightly soluble/insoluble zinc compounds represented by zinc oxide is available in the CSR (section 5.11). While a detailed scientific justification for the OELs is not available, these values have ensureds workers safety for decades which correlates with the DNELs derived from the human volunteer studies.

Taking a conservative approach it is proposed that for inhalatory exposure to soluble and slightly soluble/ insoluble zinc compounds, the existing OEL values are used as the respective DNEL against which to judge the adequacy of workplace risk management measures (RMM) to control airborne exposure to zinc compounds:

Inhalation – Worker

DNELinhal soluble Zn (worker)= 1 mg Zn/m3;

DNELinhal insoluble Zn (worker)= 5 mg Zn/m3;

Inhalation – Consumer

DNELinhal soluble Zn (consumer)= 1.3 mg Zn/m3;

DNELinhal insoluble Zn (consumer)= 2.5 mg Zn/m3;