Naphthenic acids, zinc salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.18 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):

75

Dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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:

high 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:

3.3 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):

30

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

AF for dose response relationship:

0.1

Justification:

Dermal absorption 10%; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Zinc naphthenate would be expected to dissociate in the human body into naphthenic acid anions and zinc cations. Data have been read across from naphthenic acids and zinc salts to address each component separately. DNELs for zinc naphthenate are presented based on data for naphthenic acids as these present a worst-case scenario. However, for comparison, the DNELs derived based on the zinc cation, using data read across from zinc substances, are provided here to show that they would derive less conservative results.

 

Zinc

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. 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).

 

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)

 

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 following 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, with the assumptions: 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 text. 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 10m3 per 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 20m3 per 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

 

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/m3 for 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:

0.29 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):

150

Dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 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):

60

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

AF for dose response relationship:

0.1

Justification:

Dermal absorption 10%; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.17 ng/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):

600

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

Zinc naphthenate consists of zinc salts of naphthenic acids and is expected to dissociate in the human body to zinc cations and naphthenic acid anions. Data from appropriate read across substances are presented, with data on zinc compounds and naphthenic acids. DNELs for zinc naphthenate are presented based on data for naphthenic acids as these present a worst-case scenario. However, for comparison, the DNELs derived based on the zinc cation, using data read across from zinc substances, are provided to show that they would derive less conservative results.

 

Zinc

 

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. 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).

 

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)

 

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