Fatty acids, tallow, zinc salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 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

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

refer to Discussion

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for intraspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for the quality of the whole database:

1

Justification:

Limitations of all available studies have been identified and accounted for

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

830 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

Value:

830 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

refer to Discussion

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for other interspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for intraspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for the quality of the whole database:

1

Justification:

Limitations of all available studies have been identified and accounted for

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

It is assumed that after intake of fatty acids, tallow, zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. A full read-across of data and conclusions based on a molecular weight correction and the solubility of fatty acids, tallow, zinc salts (being slightly soluble) is considered (see also the hazard assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in the technical dossier (IUCLID section 13)).

The DNEL values for fatty acids, tallow, zinc salts were derived based on the DNEL values for slightly soluble/ insoluble zinc compounds (as described below) assuming an average zinc content of fatty acids, tallow, zinc salts of 10%.

DNELs Worker
DNEL-Dermal:               83 mg Zn/kg bw/d       --> 830 mg/kg bw/d fatty acids, tallow, zinc salts

DNEL-Inhalation:          5 mg Zn/m³                    --> 50 mg/m³ fatty acids, tallow, zinc salts

DNEL derivation:

The most relevant dose descriptors for zinc and zinc compounds are the NOAELs derived from repeated dose toxicity studies in humans and rats. For systemic toxicity the data from all zinc compounds can be used for determining specific systemic toxicity of zinc with the ion release rate of zinc becoming the factor that determines the dose. Since slightly soluble and insoluble zinc compounds (i.e., zinc sulphide, zinc oxide, zinc carbonate, zinc phosphate and zinc metal) have low solubility this will result in a worst-case estimate.

The oral NOAEL of 50 mg Zn/day will be used as the starting point for deriving DNELs for worker and general population. NOAELs for zinc exposure via the dermal or inhalatory route can be estimated by taking into account the bioavailability of zinc via the different exposure routes (for details see section 5.1). The following table summarises the absorption rates of soluble and slightly soluble/insoluble zinc compounds as derived in IUCLID section 5.1 ‘Toxicokinetics’.

Summary of absorption rates through different routes of exposure

Exposure route	Zinc compound category	Absorption rate
Oral	Soluble zinc	20%
	Slightly soluble/insoluble zinc	12%
Dermal	Soluble zinc	2%
	Slightly soluble/insoluble zinc	0.2%
Inhalation	Soluble zinc	40%
	Slightly soluble/insoluble zinc	20%

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, the assessment factors to be used for zinc compounds are relatively small. The table provides an overview of the assessment factors under consideration for zinc compounds

Assessment factors (AF) for zinc compounds

Uncertainties	Assessment Factor	Justification
Interspecies	1	No AF required; NOAEL has been derived from human experience through food supplementation
Intraspecies -worker	1	No AF required; NOAEL has been derived from human experience through food supplementation
Intraspecies –general population	1	No AF required; NOAEL has been derived from human experience through food supplementation
Exposure duration	1	No AF required; NOAEL has been derived from human experience through food supplementation
Dose response and endpoint specific/severity issues	1	No spefic AF required; NOAEL is considered to be reliable.
Quality of database	1	No specific AF required; limitations of all available studies have been identified and accounted for.

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:

DNEL_{oral sol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

DNEL_{oral 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., NOAEL_syst= 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%;

NOAEL_{dermal sol Zn}= 10 mg Zn/day / 2% = 500 mg Zn/day

NOAEL_{dermal 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:

DNEL_{dermal sol Zn}= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day)

DNEL_{dermal 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., NOAEL_syst= 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 workers considering a breathing volume of 10m³ per 8hr shift

NOAEL_{inhal 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

Corrected dose descriptor for consumers considering a breathing volume of 20m³ per day NOAEL_{inhal 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:

DNEL_{inhal sol Zn (worker)}= 2.5 mg/m³;

DNEL_{inhal insol Zn (worker)}= 5 mg Zn/m³;

DNEL_{inhal sol Zn (consumer)}= 1.25 mg/m³;

DNEL_{inhal 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.

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 (83.3mg/kg bw/day)	1	5000 mg Zn/day (83.3 mg/kg bw/day)
	Inhalation	Soluble	50 mg Zn/day (0.83 mg/kg bw/day)	2.5 mg Zn/m^3	1	2.5 mg Zn/m^3
		Slightly soluble/ insoluble	50 mg Zn/day (0.83 mg/kg bw/day)	5 mg Zn/ m^3	1	5 mg Zn/m^3

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 (83.3 mg/kg bw/day)	1	5000 mg Zn/day (83.3 mg/kg bw/day)
	Inhalation	Soluble	50 mg Zn/day (0.83 mg/kg bw/day)	1.3 mg Zn/m^3	1	1.3 mg Zn/m^3
		Slightly soluble/ insoluble	50 mg Zn/day (0.83 mg/kg bw/day)	2.5 mg Zn/m^3	1	2.5 mg Zn/m^3

5.11.3. Selection of the critical DNEL(s) for critical health effects

In line with the rationale provided in section 5.11.2, the DNEL’s for workers and consumers following oral or dermal exposure to soluble and slightly soluble/insoluble compounds are as follows:

Oral

DNEL_{oral sol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

DNEL_{oral insol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

Dermal

DNEL_{dermal sol Zn}= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day);

DNEL_{dermal 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 in chapter 5.11.2 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 in chapter 5.11.2, 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.

Table 33 and 34 of the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 (see IUCLID section 13 in the technical dossier) provide an overview of existing OELs for soluble zinc compounds represented by zinc chloride (i.e., Table 33) as well as slightly soluble/insoluble zinc compounds represented by zinc oxide (i.e., Table 34). 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

DNEL_{inhal soluble Zn (worker)}= 1 mg Zn/m³;

DNEL_{inhal insoluble Zn (worker)}= 5 mg Zn/m³;

Inhalation – Consumer

DNEL_{inhal soluble Zn (consumer)}= 1.3 mg Zn/m³;

DNEL_{inhal 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:

25 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

Value:

25 mg/m³

Explanation for the modification of the dose descriptor starting point:

refer to Discussion

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for intraspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for the quality of the whole database:

1

Justification:

Limitations of all available studies have been identified and accounted for

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

830 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

Value:

830 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

refer to Discussion

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for other interspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for intraspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for the quality of the whole database:

1

Justification:

Limitations of all available studies have been identified and accounted for

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 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):

1

Modified dose descriptor starting point:

NOAEL

Value:

8.3 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation required.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for interspecies differences (allometric scaling):

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for other interspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for intraspecies differences:

1

Justification:

NOAEL has been derived from human experience through food supplementation

AF for the quality of the whole database:

1

Justification:

Limitations of all available studies have been identified and accounted for

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute 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

It is assumed that after intake of fatty acids, tallow, zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. A full read-across of data and conclusions based on a molecular weight correction and the solubility of fatty acids, tallow, zinc salts (being slightly soluble) is considered (see also the hazard assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in the technical dossier (IUCLID section 13)).

The DNEL values for fatty acids, tallow, zinc salts were derived based on the DNEL values for slightly soluble/ insoluble zinc compounds (as described below) assuming an average zinc content of fatty acids, tallow, zinc salts of 10%.

DNELs General Population

DNEL-Dermal:               83 mg Zn/kg bw/d       --> 830 mg/kg bw/d fatty acids, tallow, zinc salts

DNEL-Inhalation:         2.5 mg Zn/m³               --> 25 mg/m³ fatty acids, tallow, zinc salts

DNEL-Oral:                     0.83 mg Zn/kg bw/d   --> 8.3 mg/kg bw/d fatty acids, tallow, zinc salts

DNEL derivation:

The most relevant dose descriptors for zinc and zinc compounds are the NOAELs derived from repeated dose toxicity studies in humans and rats. For systemic toxicity the data from all zinc compounds can be used for determining specific systemic toxicity of zinc with the ion release rate of zinc becoming the factor that determines the dose. Since slightly soluble and insoluble zinc compounds (i.e., zinc sulphide, zinc oxide, zinc carbonate, zinc phosphate and zinc metal) have low solubility this will result in a worst-case estimate.

The oral NOAEL of 50 mg Zn/day will be used as the starting point for deriving DNELs for worker and general population. NOAELs for zinc exposure via the dermal or inhalatory route can be estimated by taking into account the bioavailability of zinc via the different exposure routes (for details see section 5.1). The following table summarises the absorption rates of soluble and slightly soluble/insoluble zinc compounds as derived in IUCLID section 5.1 ‘Toxicokinetics’.

Summary of absorption rates through different routes of exposure

Exposure route	Zinc compound category	Absorption rate
Oral	Soluble zinc	20%
	Slightly soluble/insoluble zinc	12%
Dermal	Soluble zinc	2%
	Slightly soluble/insoluble zinc	0.2%
Inhalation	Soluble zinc	40%
	Slightly soluble/insoluble zinc	20%

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, the assessment factors to be used for zinc compounds are relatively small. The table provides an overview of the assessment factors under consideration for zinc compounds

Assessment factors (AF) for zinc compounds

Uncertainties	Assessment Factor	Justification
Interspecies	1	No AF required; NOAEL has been derived from human experience through food supplementation
Intraspecies -worker	1	No AF required; NOAEL has been derived from human experience through food supplementation
Intraspecies –general population	1	No AF required; NOAEL has been derived from human experience through food supplementation
Exposure duration	1	No AF required; NOAEL has been derived from human experience through food supplementation
Dose response and endpoint specific/severity issues	1	No specifc AF required; NOAEL is considered to be reliable.
Quality of database	1	No specific AF required; limitations of all available studies have been identified and accounted for.

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:

DNEL_{oral sol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)

DNEL_{oral 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., NOAEL_syst= 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%;

NOAEL_{dermal sol Zn}=10 mg Zn/day / 2% = 500 mg Zn/day

NOAEL_{dermal 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:

DNEL_{dermal sol Zn}= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day)

DNEL_{dermal 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., NOAEL_syst= 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 workers considering a breathing volume of 10m³per 8hr shift

NOAEL_{inhal 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

Corrected dose descriptor for consumers considering a breathing volume of 20m³per day NOAEL_{inhal 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:

DNEL_{inhal sol Zn (worker)}= 2.5 mg/m³;

DNEL_{inhal insol Zn (worker)}= 5 mg Zn/m³;

DNEL_{inhal sol Zn (consumer)}= 1.25 mg/m³;

DNEL_{inhal 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.

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 (83.3mg/kg bw/day)	1	5000 mg Zn/day (83.3 mg/kg bw/day)
	Inhalation	Soluble	50 mg Zn/day (0.83 mg/kg bw/day)	2.5 mg Zn/m^3	1	2.5 mg Zn/m^3
		Slightly soluble/ insoluble	50 mg Zn/day (0.83 mg/kg bw/day)	5 mg Zn/ m^3	1	5 mg Zn/m^3

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 (83.3mg/kg bw/day)	1	5000 mg Zn/day (83.3 mg/kg bw/day)
	Inhalation	Soluble	50 mg Zn/day (0.83 mg/kg bw/day)	1.3 mg Zn/m^3	1	1.3 mg Zn/m^3
		Slightly soluble/ insoluble	50 mg Zn/day (0.83 mg/kg bw/day)	2.5 mg Zn/m^3	1	2.5 mg Zn/m^3

5.11.3. Selection of the critical DNEL(s) for critical health effects

In line with the rationale provided in section 5.11.2, the DNEL’s for workers and consumers following oral or dermal exposure to soluble and slightly soluble/insoluble compounds are as follows:

Oral

DNEL_{oral sol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

DNEL_{oral insol Zn}= 50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

Dermal

DNEL_{dermal sol Zn}= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day);

DNEL_{dermal 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 in chapter 5.11.2 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 in chapter 5.11.2, 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.

Table 33 and 34 of the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 (see IUCLID section 13 in the technical dossier) provide an overview of existing OELs for soluble zinc compounds represented by zinc chloride (i.e., Table 33) as well as slightly soluble/insoluble zinc compounds represented by zinc oxide (i.e., Table 34). 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

DNEL_{inhal soluble Zn (worker)}= 1 mg Zn/m³;

DNEL_{inhal insoluble Zn (worker)}= 5 mg Zn/m³;

Inhalation – Consumer

DNEL_{inhal soluble Zn (consumer)}= 1.3 mg Zn/m³;

DNEL_{inhal insoluble Zn (consumer)}= 2.5 mg Zn/m³;