CHEMICAL SAFETY REPORT

CHEMICAL SAFETY REPORT

Substance Name: zinc sulphide

EC Number: 215-251-3

CAS Number: 1314-98-3

Registrant's Identity:

EC number:

215-251-3 zinc sulphide CAS number:

1314-98-3

Table of Contents

Part A ...................................................................................................................................................................... 1

1. SUMMARY OF RISK MANAGEMENT MEASURES ................................................................................ 1

2. DECLARATION THAT RISK MANAGEMENT MEASURES ARE IMPLEMENTED ............................ 1

3. DECLARATION THAT RISK MANAGEMENT MEASURES ARE COMMUNICATED ........................ 1

Part B ...................................................................................................................................................................... 2

1. IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES ......................... 2

1.1. Name and other identifiers of the substance ............................................................................................ 2

1.2. Composition of the substance .................................................................................................................. 2

1.3. Physico-chemical properties .................................................................................................................... 3

2. MANUFACTURE AND USES ...................................................................................................................... 6

2.1. Manufacture ............................................................................................................................................. 6

2.2. Identified uses .......................................................................................................................................... 8

2.3. Uses advised against .............................................................................................................................. 52

3. CLASSIFICATION AND LABELLING ..................................................................................................... 53

3.1. Classification and labelling according to CLP / GHS ............................................................................ 53

3.2. Classification and labelling according to DSD / DPD ........................................................................... 55

3.2.1. Classification and labelling in Annex I of Directive 67/548/EEC .................................................. 55

3.2.2. Self classification(s) ........................................................................................................................ 55

4. ENVIRONMENTAL FATE PROPERTIES ................................................................................................ 56

4.1. Degradation ........................................................................................................................................... 57

4.1.1. Abiotic degradation ........................................................................................................................ 57

4.1.1.1. Hydrolysis ................................................................................................................................ 57

4.1.1.2. Phototransformation/photolysis ............................................................................................... 58

4.1.1.2.1. Phototransformation in air ................................................................................................ 58

4.1.1.2.2. Phototransformation in water ............................................................................................ 58

4.1.1.2.3. Phototransformation in soil ............................................................................................... 58

4.1.2. Biodegradation ................................................................................................................................ 58

4.1.2.1. Biodegradation in water ........................................................................................................... 58

4.1.2.1.1. Estimated data ................................................................................................................... 58

4.1.2.1.2. Screening tests .................................................................................................................. 58

4.1.2.1.3. Simulation tests (water and sediments) ............................................................................. 58

4.1.2.1.4. Summary and discussion of biodegradation in water and sediment .................................. 58

4.1.2.2. Biodegradation in soil .............................................................................................................. 58

4.1.3. Summary and discussion of degradation ........................................................................................ 59

4.2. Environmental distribution .................................................................................................................... 59

4.2.1. Adsorption/desorption .................................................................................................................... 61

4.2.2. Volatilisation................................................................................................................................... 61

4.2.3. Distribution modelling .................................................................................................................... 61

4.2.4. Summary and discussion of environmental distribution ................................................................. 61

4.3. Bioaccumulation .................................................................................................................................... 62

4.3.1. Aquatic bioaccumulation ................................................................................................................ 62

4.3.2. Terrestrial bioaccumulation ............................................................................................................ 63

4.3.3. Summary and discussion of bioaccumulation ................................................................................. 64

4.4. Secondary poisoning .............................................................................................................................. 65

4.5. Natural background ............................................................................................................................... 65

4.6. Additional information on environmental fate and distribution ............................................................ 66

5. HUMAN HEALTH HAZARD ASSESSMENT .......................................................................................... 70

5.1. Toxicokinetics ....................................................................................................................................... 71

5.1.1. Non-human information ................................................................................................................. 71

5.1.2. Human information ......................................................................................................................... 75

5.1.3. Summary and discussion of toxicokinetics ..................................................................................... 81

5.2. Acute toxicity ........................................................................................................................................ 82


5.2.1.1. Acute toxicity: oral .................................................................................................................. 82

5.2.1.2. Acute toxicity: inhalation ......................................................................................................... 84

5.2.1.3. Acute toxicity: dermal ............................................................................................................. 85

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5.2.1.4. Acute toxicity: other routes ...................................................................................................... 86


5.2.3. Summary and discussion of acute toxicity ...................................................................................... 88

5.3. Irritation ................................................................................................................................................. 88

5.3.1. Skin ................................................................................................................................................. 89

5.3.1.1. Non-human information........................................................................................................... 89

5.3.1.2. Human information .................................................................................................................. 90

5.3.2. Eye .................................................................................................................................................. 90



5.3.3. Respiratory tract .............................................................................................................................. 91



5.3.4. Summary and discussion of irritation ............................................................................................. 92

5.4. Corrosivity ............................................................................................................................................. 92



5.4.3. Summary and discussion of corrosion ............................................................................................ 92

5.5. Sensitisation ........................................................................................................................................... 92

5.5.1. Skin ................................................................................................................................................. 92



5.5.2. Respiratory system .......................................................................................................................... 94



5.5.3. Summary and discussion of sensitisation........................................................................................ 94

5.6. Repeated dose toxicity ........................................................................................................................... 94


5.6.1.1. Repeated dose toxicity: oral ..................................................................................................... 94

5.6.1.2. Repeated dose toxicity: inhalation ........................................................................................... 97

5.6.1.3. Repeated dose toxicity: dermal ................................................................................................ 99

5.6.1.4. Repeated dose toxicity: other routes ........................................................................................ 99


5.6.3. Summary and discussion of repeated dose toxicity ...................................................................... 103

5.7. Mutagenicity ........................................................................................................................................ 104

5.7.1. Non-human information ............................................................................................................... 104

5.7.1.1. In vitro data ............................................................................................................................ 104

5.7.1.2. In vivo data ............................................................................................................................. 107

5.7.2. Human information ....................................................................................................................... 109

5.7.3. Summary and discussion of mutagenicity .................................................................................... 109

5.8. Carcinogenicity .................................................................................................................................... 110

5.8.1. Non-human information ............................................................................................................... 110

5.8.1.1. Carcinogenicity: oral .............................................................................................................. 110

5.8.1.2. Carcinogenicity: inhalation .................................................................................................... 110

5.8.1.3. Carcinogenicity: dermal ......................................................................................................... 110

5.8.1.4. Carcinogenicity: other routes ................................................................................................. 110

5.8.2. Human information ....................................................................................................................... 110

5.8.3. Summary and discussion of carcinogenicity ................................................................................. 112

5.9. Toxicity for reproduction ..................................................................................................................... 113

5.9.1. Effects on fertility ......................................................................................................................... 113

5.9.1.1. Non-human information......................................................................................................... 113

5.9.1.2. Human information ................................................................................................................ 115

5.9.2. Developmental toxicity ................................................................................................................. 115

5.9.2.1. Non-human information......................................................................................................... 115

5.9.2.2. Human information ................................................................................................................ 117

5.9.3. Summary and discussion of reproductive toxicity ........................................................................ 117

5.10. Other effects................................................................................................................................... 118

5.10.1. Non-human information ......................................................................................................... 118

5.10.1.1. Neurotoxicity ....................................................................................................................... 118

5.10.1.2. Immunotoxicity .................................................................................................................... 119

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5.10.1.3. Specific investigations: other studies ................................................................................... 119

5.10.2. Human information ..................................................................................................................... 120

5.10.3. Summary and discussion of specific investigations .................................................................... 120

5.11. Derivation of DNEL(s) / DMEL(s) ................................................................................................... 120

5.11.1. Overview of typical dose descriptors for all endpoints ............................................................... 121

5.11.2. Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DN(M)EL ................................................... 127

5.11.3. Selection of the critical DNEL(s) for critical health effects ........................................................ 132

6. HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES .................. 132

6.1. Explosivity ........................................................................................................................................... 132

6.2. Flammability ........................................................................................................................................ 133

6.3. Oxidising potential .............................................................................................................................. 133

7. ENVIRONMENTAL HAZARD ASSESSMENT ...................................................................................... 134

7.1. Aquatic compartment (including sediment) ......................................................................................... 134

7.1.1. Toxicity test results ....................................................................................................................... 134

7.1.1.1. Fish ........................................................................................................................................ 134

7.1.1.1.1. Short-term toxicity to fish ............................................................................................... 134

7.1.1.1.2. Long-term toxicity to fish ............................................................................................... 135

7.1.1.2. Aquatic invertebrates ............................................................................................................. 135

7.1.1.2.1. Short-term toxicity to aquatic invertebrates .................................................................... 135

7.1.1.2.2. Long-term toxicity to aquatic invertebrates .................................................................... 136

7.1.1.3. Algae and aquatic plants ........................................................................................................ 136

7.1.1.4. Sediment organisms ............................................................................................................... 137

7.1.1.5. Other aquatic organisms ........................................................................................................ 137

7.1.2. Calculation of Predicted No Effect Concentration (PNEC) .......................................................... 139

7.1.2.1. PNEC water ........................................................................................................................... 139

7.1.2.2. PNEC sediment ...................................................................................................................... 140

7.2. Terrestrial compartment ....................................................................................................................... 141

7.2.1. Toxicity test results ....................................................................................................................... 141

7.2.1.1. Toxicity to soil macro-organisms .......................................................................................... 141

7.2.1.2. Toxicity to terrestrial plants ................................................................................................... 142

7.2.1.3. Toxicity to soil micro-organisms ........................................................................................... 143

7.2.1.4. Toxicity to other terrestrial organisms ................................................................................... 143

7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil) ................................................... 143

7.3. Atmospheric compartment ................................................................................................................... 144

7.4. Microbiological activity in sewage treatment systems ........................................................................ 144

7.4.1. Toxicity to aquatic micro-organisms ............................................................................................ 144

7.4.2. PNEC for sewage treatment plant ................................................................................................. 144

7.5. Non compartment specific effects relevant for the food chain (secondary poisoning) ........................ 145

7.5.1. Toxicity to birds ............................................................................................................................ 145

7.5.2. Toxicity to mammals .................................................................................................................... 146

7.5.3. Calculation of PNECoral (secondary poisoning) .......................................................................... 146

7.6. Conclusion on the environmental hazard assessment and on classification and labelling ................... 146

7.6.1. Classification under Annex I dangerous substances directive 67/548/EEC .................................. 146

7.6.2. Classification under 2nd Adaptation to Technical Progress (ATP) to the CLP Regulation (2 nd ATP

CLP)

....................................................................................................................................................... 146

8. PBT AND VPVB ASSESSMENT ............................................................................................................. 147

8.1. Assessment of PBT/vPvB Properties ................................................................................................... 147

8.1.1. Summary and overall conclusions on PBT or vPvB properties .................................................... 147

9. EXPOSURE ASSESSMENT ..................................................................................................................... 147

10. RISK CHARACTERISATION ................................................................................................................ 147

REFERENCES ................................................................................................................................................... 148

ANNEX 1: Exposure scenario building and environmental release estimation for the waste life stage of the manufacture and the use of zinc and zinc compounds ........................................................................................ 165

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List of Tables

Table 1. Substance identity ..................................................................................................................................... 2

Table 2. Constituents .............................................................................................................................................. 3

Table 3. Impurities .................................................................................................................................................. 3

Table 4. Overview of physico-chemical properties ................................................................................................ 4

Table 5. Overview of quantities (in tonnes/year) .................................................................................................... 6

Table 6. Waste types, amounts and waste treatment processes for zinc and zinc compounds from manufacturing

................................................................................................................................................................................ 7

Table 7. Uses by workers in industrial settings ...................................................................................................... 9

Table 8. Uses by professional workers ................................................................................................................. 37

Table 9. Uses by consumers ................................................................................................................................. 48

Table 10. Waste types, amounts and waste treatment processes for zinc from identified uses ............................ 51

Table 11. Waste types, amounts and treatment of waste from service life sated subsequent to the identified uses for zinc from identified uses ................................................................................................................................. 51

Table 12. (taken from the RA zinc, ECB 2008): Possible chemical forms (speciation) of dissolved zinc in seawater (Cleven et al., 1993). .............................................................................................................................. 60

Table 13. Overview of studies on aquatic bioaccumulation ................................................................................. 62

Table 14. Overview of studies on terrestrial bioaccumulation ............................................................................. 63

Table 15 : transformation/dissolution of zinc sulphide tested at pH 6 and 8 (ECTX 2010).

................................ 67

Table 16: transformation/dissolution of zinc sulphide tested at pH 6 and 8(ECTX 2010bis).

............................. 68

Table 17. Water solubility values of the eleven zinc compounds covered in this CSR ........................................ 70

Table 18. Grouping based on water solubility ...................................................................................................... 71

Table 19. Dermal absorption of Zn (% of dose) through pig skin in vitro within 72 hours .................................. 72

Table 20. Deposition fractions for oral breathers and for oronasal augmenters, using a polydisperse particle distribution (MMAD 15.2

 m, GSD 4.0) ............................................................................................................. 77

Table 21. Assumptions used for estimating the inhalation absorption ................................................................. 78

Table 22. Percentage estimations for inhalation absorption of soluble, slightly soluble and insoluble zinc compounds ............................................................................................................................................................ 78

Table 23. Elimination data obtained following thirty humans dosed with 18 to 900

 moles of 65 Zn .................. 80

Table 24. Overview of experimental studies on acute toxicity after oral administration according to decreasing water solubility of zinc compounds ...................................................................................................................... 82

Table 25. Re-calculation of oral LD

50 rat values ................................................................................................... 84

Table 26. Overview of experimental studies on acute toxicity after inhalation exposure according to decreasing water solubility of zinc compounds ...................................................................................................................... 84

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Table 27. Overview of experimental studies on acute toxicity after dermal exposure ......................................... 86

Table 28. Overview of experimental studies on skin irritation according to decreasing water solubility of zinc compounds ............................................................................................................................................................ 89

Table 29. Overview of experimental studies on eye irritation according to decreasing water solubility of zinc compounds ............................................................................................................................................................ 90

Table 30. Overview of experimental studies on skin sensitisation according to decreasing water solubility of zinc compounds .................................................................................................................................................... 92

Table 31. Overview of experimental studies on repeated dose toxicity after oral administration ........................ 94

Table 32. Overview of experimental studies on repeated dose toxicity after inhalation ...................................... 97

Table 33. Overview of experimental in vitro genotoxicity studies according to decreasing water solubility .... 104

Table 34. Overview of experimental in vivo genotoxicity studies according to decreasing water solubility ..... 107

Table 35. Overview of experimental studies on fertility .................................................................................... 113

Table 36. Overview of experimental studies on developmental toxicity ............................................................ 115

Table 37. Overview of experimental studies on immunotoxicity ....................................................................... 119

Table 38. OELs for zinc chloride ....................................................................................................................... 120

Table 39. OELs for zinc oxide ............................................................................................................................ 121

Table 40. Available dose-descriptor(s) per endpoint for water soluble zinc compounds (i.e., zinc chloride, zinc sulphate, zinc bis(dihydrogen phosphate), diammonium tetrachlorozincate and triammonium pentachlorozincate). ............................................................................................................................................ 122

Table 41. Available dose-descriptor(s) per endpoint for sparingly or insoluble soluble zinc compounds (i.e., zinc oxide, zinc hydroxide, zinc phosphate, zinc carbonate, zinc metal, zinc sulphide) ............................................ 125

Table 42. Summary of absorption rates through different routes of exposure .................................................... 127

Table 43.

Assessment factors (AF) for zinc compounds .................................................................................... 128

Table 44. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for workers ...................... 130

Table 45. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for consumers .................. 130

Table 46. Overview of short-term effects on fish ............................................................................................... 134

Table 47. Overview of short-term effects on aquatic invertebrates .................................................................... 135

Table 48. Overview of effects on algae and aquatic plants................................................................................. 136

Table 49. Overview of effects on other aquatic organisms: communities .......................................................... 137

Table 50. PNEC water ........................................................................................................................................ 139

Table 51. PNEC sediment................................................................................................................................... 140

Table 52. PNEC soil ........................................................................................................................................... 143

Table 53. PNEC sewage treatment plant .....................................................

Ошибка! Закладка не определена.

Table 54. PNEC oral ........................................................................................................................................... 146

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List of Figures

Figure 1. Base case total zinc removal from the water column using EUSES model parameters. The initial total zinc concentration in the water column ( C

0

) is 413 μg/L. The horizontal dashed line represents C / C

0

= 0.3 or

70% removal of zinc (from Mutch Associates 2010b). ........................................................................................ 69

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Part A

1. SUMMARY OF RISK MANAGEMENT MEASURES

The risk management of zinc focuses on the 2 relevant routes of exposure of workers, i.e. by inhalation and dermal exposure. Exposure to zinc containing dust and fumes by inhalation is controlled by the general application of local exhaust ventilation at the workplace, in specific cases combined with personal protection measures. Inhalation exposure can be prevented by enclosures of systems as well. Dermal exposure is prevented by the general use of specialised protective clothing, including the wearing of specialised working gloves.

The risk management for environment includes on-site waste water treatment techniques (if applicable) e.g.: chemical precipitation, sedimentation, filtration, the containment of liquid volumes in sumps to collect/prevent accidental spillage, and the control of air emissions by use of bag-house filters and/or other air emission abatement devices.

Under section 9, risk management measures and operational conditions are described in more detail.

2. DECLARATION THAT RISK MANAGEMENT

MEASURES ARE IMPLEMENTED

“I, … declare hereby that risk management measures as described in this CSR are implemented.”

3. DECLARATION THAT RISK MANAGEMENT

MEASURES ARE COMMUNICATED

“I, … declare hereby that risk management measures as described in this CSR are communicated to downstream users.”

2013-05-27 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 1

EC number:


1314-98-3

Part B

1. IDENTITY OF THE SUBSTANCE AND PHYSICAL

AND CHEMICAL PROPERTIES

1.1. Name and other identifiers of the substance

The substance zinc sulphide is a mono constituent substance (origin: inorganic) having the following characteristics and physical–chemical properties (see the IUCLID dataset for further details).

Table 1. Substance identity

EC number:

EC name:

215-251-3 zinc sulphide

CAS number (EC inventory): 1314-98-3

IUPAC name: thioxozinc

Molecular formula:

Molecular weight range:

SZn

97.474

Structural formula:

1.2. Composition of the substance

Name: zinc sulphide


EC number:


1314-98-3

Description: zinc sulphide

Degree of purity: > 97.0 — < 99.0 % (w/w)

Table 2. Constituents

Constituent zinc sulphide

Typical concentration ca. 98.0 % (w/w)

Concentration range

EC no.: 215-251-3

Table 3. Impurities

Impurity barium sulfate

EC no.: 231-784-4 zinc oxide

EC no.: 215-222-5 cobalt sulfide

EC no.: 215-273-3

Typical concentration ca. 0.2 % (w/w)

Concentration range

> 1.0 — < 2.0 % (w/w)

Remarks

Remarks

> 0.15 — < 0.25 % (w/w)

> 300.0 — < 400.0 ppm As a process aid for the achievement of a smooth and even precipitation and cristallisation process a small amount of Cobalt

Sulfate is added to the starting materials. In the presence of Sodium

Sulfide Cobalt Sulfide is formed and precitpitated simultaneously together with the Zinc Sulfide.

ZnSO4 + Na2S -- ZnS +

Na2SO4 CoSO4 + Na2S --

CoxSy + Na2SO4 The precipitate is filtered and washed thoroughly for purification. Unless as

Cobalt Sulfide is poorly soluble and partly enclosed by the Zinc

Sulfide a concentration of approx 300 – 400 ppm remains as an impurity in the Zinc Sulfide.

According to further testing the Cobalt shows extremely low solubility and in consequence low bioavailability. We therefore do not consider this impurity relevant for the classification and labeling of the substance.

1.3. Physico-chemical properties


EC number:


1314-98-3

Table 4. Overview of physico-chemical properties

Property Results

Physical state at

20°C and 1013 hPa

Melting / freezing point

The physical state of the substance is solid powder, its clour is white, it is odourless. no melting is observed.

Value used for CSA / Discussion

Value used for CSA: solid

During the melting test of the studied zinc sulphide sample in nitrogen atmosphere, no exothermic or endothermic peaks are detected. So

Relative density

Water solubility

Granulometry no melting is observed.

The density of the substance is 4.16 g/cm3. Value used for CSA: 4.16 at 20°C

The calculated solubility of ZnS is very low, 0.00045µg Zn/l (insoluble).

Value used for CSA: 0.00045 µg/L at 20

°C

The D50 of the substance is 0.71 µm, the

D80 is <20 µm..

The solubility of the substance was calculated according to standard state-ofthe-art scientific principles.

Data waiving

Information requirement: Boiling point

Reason: study scientifically unjustified

Justification: Not relevant; the sample decomposes before boiling

Information requirement: Vapour pressure

Reason: other justification

Justification: endpoint is not relevant; the sample is salt and has negligible vapour pressure at 25 °C.

Information requirement: Vapour pressure


Justification: The study does not need to be conducted if the melting point is above 300°C (Column 2 of

Annex VII REACH regulation)

Information requirement: Surface tension


Justification: endpoint is not relevant for solid powder

Information requirement: Partition coefficient n-octanol/water (log value)


Justification: Not applicable to metal compounds; The study does not need to be conducted if the substance is inorganic (column 2 of Annex VII of the REACH regulation)


EC number:


1314-98-3

Information requirement: Flash point


Justification: not applicable. The study does not need to be conducted if the substance is inorganic (Column

2 of Annex VII of REACH regulation)

Information requirement: Flammability


Justification: Based on the thermogravimetric and differential scanning calorimetric measurements and mineral composition the substance has no flammability, explosiveness or auto-inflammability properties.

Information requirement: Explosive properties



Information requirement: Self-ignition temperature



Information requirement: Oxidising properties


Justification: No oxidising properties; The study does not need to be conducted if the substance is inorganic and does not contain oxygen or halogen atoms (Column 2 of Annex VII of Reach regulation)

Information requirement: Stability in organic solvents and identity of relevant degradation products


Justification: Stability in organic solvents and identity of relevant degadation products is not an applicable endpoint for inorganic substances according to column 2 of Annex IX of the REACH Regulation.

Information requirement: Dissociation constant


Justification: The dissociation constant relating to the acidity constant, pKa, as required by the IUCLID database and REACH Guidance document, is not relevant for the substance.

Information requirement: Viscosity

Reason: study technically not feasible

Justification: ZnS does not melt. Testing of viscosity on the melted liquid form is thus not possible.

Discussion of physico-chemical properties


EC number:


1314-98-3

For generating an updated, consistent and well-referenced database on the physico-chemical properties of the substance, a typical sample from the lead registrant was analysed for all parameters relevant for REACH at the

Outotec Oy laboratories, Pori, Finland.

Outotec Research Oy has a certified Quality system ISO 9001:2000, Environmental system ISO14001 and

Occupational Health and Safety system ISO18001. Laboratory accreditation according to ISO/IEC 17025 covers gas and emission measurements and metal analyses.

Inspecta Sertifiointi Oy evaluates the management systems and FINAS (Finnish Accreditation Service) evaluates the accredited methods. These audits are carried out annually. A couple of internal audits are also done every year, for instance laboratory functions are audited annually. Besides audits, Outotec Research Oy takes part in interlaboratory comparisons concerning metal analytics and emission measurements.

In 2008, Outotec Research Oy took part in the Finnish Excellence Quality Awards and received the prestigious award, "Recognised for Excellence". Outotec Research Oy achieved a score of over 500 points, which entitles the winner to use the five-star Recognised for Excellence, R4E emblem.

By this approach, a consistent, high quality and complete dataset on physicochemical properties of the substance has been established, using state-of-the-art anaylitical techniques. This updated information is encoded in the

IUCLID V format.

2. MANUFACTURE AND USES

Quantities

Table 5. Overview of quantities (in tonnes/year)

Year Total tonnage Own use Used for article

2009 Manufactured: 0.0

Imported: 0.0

0.0

Used as intermediate under strictly controlled conditions

Used for research purposes

Transported: 0.0 0.0

Imported: 0.0


Imported: 0.0


Imported: 0.0

0.0

0.0

Imported in article: 0.0

Used in production of article: 0.0





Transported: 0.0

Imported: 0.0

Transported: 0.0

Imported: 0.0

0.0

0.0

2.1. Manufacture

Manufacturing process

Manufacturing of Zinc Sulfide (ZnS)

Process:

The precipitation of the insoluble zinc sulfide is generated by the mixing of the aqueous solutions of sodium sulfide and zinc sulfate in a precipitation tank.

ZnSO4 + Na2S - ZnS + Na2SO4

The precipitation solution is subsequently filtered and washed thoroughly to separate the precipitated zinc sulfide from the mother liquor. In the next step the zinc sulfide is dried and calcined in a rotary kiln at 300 °C.

After the calcination the raw pigment is again dispersed in water, washed and dried.


EC number:


1314-98-3

Literature: Integrated Pollution Prevention and Control - Reference Document on Best Available Techniques for the Production of Speciality Inorganic Chemicals - August 2007 (http: //eippcb. jrc. es/reference/sic. html)

WASTE (cfr Annex 1, Arche, 2012) :

Table 6. Waste types, amounts and waste treatment processes for zinc and zinc compounds from manufacturing

Waste from

Type waste of Suitable waste code

Amount

(t/y)

Composition Waste treatment process/ recycling

Information source

Manufactu re

Sludge from on-site

WWTP

Sludges from zinc hydrometallur gy (Jarosite, goethite, …)

Cadmium cake/sponge

Cement

Copper

Hg residue/ sludge/ calomel

06 05 02 *

19 02 05 *

General dust 10 05 03 *

10 05 05 *

10 10 09 *

10 10 11 *

12 01 03

12 01 04

Slags 10 05 01

10 10 03

11 02 02 *

10 05 06 *

11 01 09 *

Not considered as waste

100% recycled

10 05 06 *

06 04 04 *

Range: 0 –

22,000 t/y.

Median:

2,500 t/y

Range: 0 –

36 t/y.

Median: 11 t/y

Range: 0 –

135,000 t/y.

Median:

49,500 t/y

Range: 0 –

230,000 t/y.

Median:

101,500 t/y

Range: 0 –

1,000 t/y.

Median:

670 t/y

Range: 0 –

4,000 t/y.

Median:

1,450 t/y

Range: 0 –

100 t/y.

Median: 20 t/y

Range: 250 –

300,0000 mg

Zn/kg dw.

Median: 8,700 mg Zn/kg dw

Range: 700 –

800,000 mg

Zn/kg dw.

Median: 400,000 mg Zn/kg dw.

Range: 12,000 –

450,000 mg

Zn/kg dw.


Range: 27,000 –

100,000 mg

Zn/kg dw.


Range: 30,000 – mg 200,000

Zn/kg dw.


Range: 50,000 –

125,000 mg

Zn/kg dw.


Range: 100 –

9000 mg Zn/kg dw.

Median: 550 mg

Zn/kg dw.

Internal or external landfilling

Recycling internally

Incineration

Recycled in other applications

Recycled internally or externally

(e.g. ZnSO4 production)

Internal or external landfilling.

Recycled in another application

(road constructio n, profiling, covering layer, zinc recyclers)


Recycled internally


Recycled in copper production

Landfilled in special concrete bunkers, eventually stabilization prior to landfilling.

In house questionnaire

2011


EC number:


Anodic sludge/ cell mud/ sludge

Mn

Pb leach

Casting/smelti ng residues:

Zn skimming, drosses and ashes sludge/

Other wastes: slimes, sludges, leach residues, solid wastes salts, lead silver anode, precipitates, adsorbents, packaging materials, spoilt products, soaps, refractories

…

11 02 07

10 05 11

11 02 03

*

10 05 03 *

06 03 13 *

06 03 14

06 03 15 *

06 04 05 *

08 01 11 *

10 05 99

10 10 03

10 10 05 *

10 10 07 *

12 01 12 *

15 02 02 *

15 01 10 *

16 11 02

16 11 03 *

16 11 04

16 11 06

Range: 0 –

4857 t/y.

Median:

3,000 t/y

Range: 0 –

40,000 t/y.

Median:

24,767 t/y

Range: 0 –

4,000 t/y.

Median:

2,400 t/y

Range: 0 –

150,000 t/y.

Median:

190 t/y

Range: 550 –

300,000 mg

Zn/kg dw.


Range: 25 –

200,000 mg

Zn/kg dw.


Range: 745 –

950,000

Zn/kg dw. mg


Range: 592 –

600,000

Zn/kg dw.

Median: 50,000 mg Zn/kg dw. mg



Recycled in lead or lead alloy production

Recycled internally or externally

Recycled in another application

Recycled internally


Internal or external landfilling/ mine filling

Incineration

2.2. Identified uses

CAS number:

1314-98-3


EC number:


1314-98-3

Table 7. Uses by workers in industrial settings

Confidential IU number

1

5

Identified Use

(IU) name

Zinc sulphide production-Wet

Substance supplied to that use as such

(substance itself)

Component for production of inorganic zinc compounds as such

(substance itself) in a mixture

Use descriptors

Process category (PROC):

PROC 2: Use in closed, continuous process with occasional controlled exposure

PROC 3: Use in closed batch process (synthesis or formulation)

PROC 8b: Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at dedicated facilities

PROC 9: Transfer of substance or preparation into small containers (dedicated filling line, including weighing)

PROC 22: Potentially closed processing operations with minerals/metals at elevated temperature.

Industrial setting

PROC 26: Handling of solid inorganic substances at ambient temperature

Market sector by type of chemical product:

PC 20: Products such as ph-regulators, flocculants, precipitants, neutralisation agents

Environmental release category (ERC):

ERC 1: Manufacture of substances

Sector of end use (SU):

SU 8: Manufacture of bulk, large scale chemicals (including petroleum products)

SU 9: Manufacture of fine chemicals

Subsequent service life relevant for that use?: yes






PROC 15: Use as laboratory reagent

PROC 21: Low energy manipulation of substances bound in materials and/or articles


EC number:

215-251-3

6

2013-05-27 CSR-PI-5.2.1 zinc sulphide

Laboratory reagent as such

(substance itself)

CAS number:

1314-98-3


Industrial setting


PC 19: Intermediate


PC 21: Laboratory chemicals



ERC 2: Formulation of preparations

ERC 6a: Industrial use resulting in manufacture of another substance (use of intermediates)




SU 10: Formulation [mixing] of preparations and/or re-packaging (excluding alloys)



PROC 1: Use in closed process, no likelihood of exposure



PROC 4: Use in batch and other process (synthesis) where opportunity for exposure arises

PROC 5: Mixing or blending in batch processes for formulation of preparations and articles

(multistage and/or significant contact)





PC 19: Intermediate


PC 28: Perfumes, fragrances

PC 39: Cosmetics, personal care products

CHEMICAL SAFETY REPORT 10

EC number:

215-251-3

7

2013-05-27 CSR-PI-5.2.1 zinc sulphide CAS number:

1314-98-3

Component for production of organic zinc compounds as such





ERC 4: Industrial use of processing aids in processes and products, not becoming part of articles


ERC 6b: Industrial use of reactive processing aids



SU 24: Scientific research and development











PC 19: Intermediate



PC 24: Lubricants, greases, release products

PC 29: Pharmaceuticals







EC number:

215-251-3

8


1314-98-3

Component for production of

Inorganic pigments as such

















Industrial setting


PC 9a: Coatings and paints, thinners, paint removes

PC 9b: Fillers, putties, plasters, modelling clay

PC 9c: Finger paints

PC 0: Other: UCN F05990: Other colouring agents




ERC 5: Industrial use resulting in inclusion into or onto a matrix





SU 13: Manufacture of other non-metallic mineral products, e.g. plasters, cement


EC number:

215-251-3

9


Component for production of

Coatings / paints, inks, enamels, varnishes as such


CAS number:

1314-98-3

SU 0: Other: Nace C20.1.2: Manufacture of dyes and pigments












PC 1: Adhesives, sealants




PC 14: Metal surface treatment products, including galvanic and electroplating products

PC 15: Non-metal-surface treatment products

PC 18: Ink and toners

PC 19: Intermediate

PC 26: Paper and board dye, finishing and impregnation products: including bleaches and other processing aids

PC 32: Polymer preparations and compounds




ERC 3: Formulation in materials



ERC 7: Industrial use of substances in closed systems



EC number:

215-251-3

10

2013-05-27 CSR-PI-5.2.1

Use of ZnScontaining paints & coatings zinc sulphide in a mixture

CAS number:

1314-98-3

SU 4: Manufacture of food products

SU 5: Manufacture of textiles, leather, fur

SU 6a: Manufacture of wood and wood products

SU 6b: Manufacture of pulp, paper and paper products




SU 11: Manufacture of rubber products

SU 12: Manufacture of plastics products, including compounding and conversion


SU 14: Manufacture of basic metals, including alloys






PROC 7: Industrial spraying



PROC 10: Roller application or brushing

PROC 11: Non industrial spraying

PROC 13: Treatment of articles by dipping and pouring

PROC 19: Hand-mixing with intimate contact and only PPE available.











EC number:

215-251-3

12


Component for

Paper coating as such


CAS number:

1314-98-3






Article category related to subsequent service life (AC):

AC 0: Other: coatings for art and creative items






PROC 6: Calendering operations










PC 35: Washing and cleaning products (including solvent based products)







EC number:

215-251-3

13


Downstream use of ZnS containing paper coating products as such


CAS number:

1314-98-3


SU 7: Printing and reproduction of recorded media




























EC number:

215-251-3

14


1314-98-3

Component for

Textile & leather coating / treatment as such



AC 8: Paper articles













PC 19: Intermediate



PC 23: Leather tanning, dye, finishing, impregnation and care products

PC 34: Textile dyes, finishing and impregnating products; including bleaches and other processing aids

PC 35: Washing and cleaning products (including solvent based products)











EC number:

215-251-3

15

16


Use of ZnScontaining textile & leather coatings as such


Additive for the production of

Lubricants / in a mixture

CAS number:

1314-98-3
























AC 6: Leather articles

AC 5: Fabrics, textiles and apparel




EC number:

215-251-3

17

2013-05-27 CSR-PI-5.2.1

Grease pastes zinc sulphide

Additive / component for production of as such

(substance itself)

CAS number:

1314-98-3










PC 25: Metal working fluids








ERC 6d: Industrial use of process regulators for polymerisation processes in production of resins, rubbers, polymers



SU 18: Manufacture of furniture



AC 1: Vehicles

AC 2: Machinery, mechanical appliances, electrical/electronic articles

AC 7: Metal articles





EC number:

215-251-3

18

2013-05-27 CSR-PI-5.2.1 ceramics

Additive zinc sulphide in a mixture as such

CAS number:

1314-98-3








PROC 14: Production of preparations or articles by tabletting, compression, extrusion, pelletisation



Industrial setting



PC 19: Intermediate












SU 0: Other: Nace C23.2: Manufacture of refractory products



AC 4: Stone, plaster, cement, glass and ceramic articles



EC number:

215-251-3


/component for production of frits


CAS number:

1314-98-3











PROC 17: Lubrication at high energy conditions and in partly open process


Industrial setting



PC 19: Intermediate

PC 0: Other: UCN R30100-R30200: Raw materials for synthesis and intermediate products/Raw materials for production of glass and ceramics














EC number:

215-251-3

19

20



Friction agents as such


Downstream use of ZnS containing friction agents

(breakpads) in a mixture

CAS number:

1314-98-3

AC 0: Other: TARIC 8541 21 transistors other than photosensitive transistors

AC 3: Electrical batteries and accumulators










PC 0: Other: UCN F40000: Friction agents - (e.g. brake pads)







SU 0: Other: Nace C23.9.1: Production of abrasive products



AC 0: Other: TARIC 6813 81: brake linings and pads




Industrial setting

PROC 24: High (mechanical) energy work-up of substances bound in materials and/or articles



EC number:

215-251-3

21


Additive / component for production of glass as such


CAS number:

1314-98-3

PC 0: Other: UCNF40000: Friction agents - (e.g. brake pads)


ERC 10b: Wide dispersive outdoor use of long-life articles and materials with high or intended release (including abrasive processing)


SU 17: General manufacturing, e.g. machinery, equipment, vehicles, other transport equipment



AC 0: Other: TARIC 6813 81: brake linings and pads

AC 1: Vehicles











Industrial setting


PC 19: Intermediate


PC 0: Other: UCN R30200: Raw materials for production of glass and ceramics





EC number:

215-251-3

22

23


Use of ZnS containing glass and ceramics in dinnerware in a mixture

Use of ZnS containing glass in displays in a mixture

CAS number:

1314-98-3






SU 0: Other: Nace C23.1: Manufacture of glass and glass products








PC 19: Intermediate





SU 0: Other: C23.4 - Manufacture of other porcelain and ceramic products





AC 0: Other: TARIC 6911: tableware, kitchenware, household products in porcelain or china





EC number:

215-251-3

24


1314-98-3

Use of ZnScontaining optical material in a mixture


PC 19: Intermediate






SU 16: Manufacture of computer, electronic and optical products, electrical equipment

SU 0: Other: Nace C23.1: C23.1 - Manufacture of glass and glass products











PC 33: Semiconductors



ERC 11a: Wide dispersive indoor use of long-life articles and materials with low release



SU 0: Other: Nace C23.1: Manufacture of glass and glass products




EC number:

215-251-3

25

26

2013-05-27 CSR-PI-5.2.1

Use of ZnS containing glassy thin films coating zinc sulphide in a mixture

Additive in the manufacturing of electronic components as such


CAS number:

1314-98-3















SU 0: Other: nace C23.1














Industrial setting


EC number:

215-251-3

27


Additive in the manufacturing of cathode ray tube as such


CAS number:

1314-98-3




PC 0: Other: UCN E0700: Electric and electromechanical components







SU 0: Other: Nace 26.1.1: Manufacture of electronic components













Industrial setting



PC 19: Intermediate




EC number:

215-251-3

28


1314-98-3

Additive in the manufacturing of electroluminesc ent panels as such





















Industrial setting



PC 19: Intermediate







EC number:

215-251-3

29


1314-98-3

Batteries/Fuel cells as such


















PC 19: Intermediate








SU 0: Other: Nace C27.2: Manufacture of batteries and accumulators





EC number:

215-251-3

30


Component for production of rubber, resins and related preparations as such


CAS number:

1314-98-3










PROC 12: Use of blowing agents in manufacture of foam























EC number:

215-251-3

31


Component for polymermatrices, plastics and related preparations as such


CAS number:

1314-98-3




AC 10: Rubber articles















PC 19: Intermediate













EC number:

215-251-3

33

34


1314-98-3

Use of ZnS containing latex coagulant in a mixture

Use of ZnSin a mixture



AC 1: Vehicles




AC 13: Plastic articles









Industrial setting



PC 19: Intermediate












EC number:

215-251-3

35

2013-05-27 CSR-PI-5.2.1 containing catalysts

Use of ZnScontaining adsorbents zinc sulphide in a mixture

CAS number:

1314-98-3











PC 2: Adsorbents


PC 19: Intermediate


PC 40: Extraction agents


















EC number:

215-251-3

36



Sealants /

Adhesives /

Mastics as such


CAS number:

1314-98-3





Industrial setting


PC 2: Adsorbents


PC 19: Intermediate


PC 40: Extraction agents


















PROC 20: Heat and pressure transfer fluids in dispersive, professional use but closed systems


EC number:

215-251-3

38


Additive for the as such

CAS number:

1314-98-3









PC 19: Intermediate


















AC 1: Vehicles



AC 11: Wood articles



EC number:

215-251-3

39

2013-05-27 CSR-PI-5.2.1 zinc sulphide formulation of biocidal (antiacarids) products


Additive for the formulation of fertilizers as such


CAS number:

1314-98-3






PC 8: Biocidal products (e.g. disinfectants, pest control)

PC 37: Water treatment chemicals



















PC 12: Fertilisers




EC number:


1314-98-3






SU 1: Agriculture, forestry and fishing




Table 8. Uses by professional workers

Confidential IU number Identified Use

(IU) name

6 Laboratory reagent

Substance supplied to that use as such

(substance itself)

Use descriptors












PC 19: Intermediate


PC 28: Perfumes, fragrances



EC number:

215-251-3

10


1314-98-3

Use of ZnScontaining paints & coatings in a mixture




ERC 8a: Wide dispersive indoor use of processing aids in open systems

ERC 8b: Wide dispersive indoor use of reactive substances in open systems

ERC 8d: Wide dispersive outdoor use of processing aids in open systems



SU 24: Scientific research and development























EC number:

215-251-3

11


Artists supply:

Use of ZnScontaining paints & coatings in a mixture

CAS number:

1314-98-3



ERC 10a: Wide dispersive outdoor use of long-life articles and materials with low release




























EC number:

215-251-3

13


Use of ZnScontaining paper coatings in a mixture

CAS number:

1314-98-3








AC 0: Other:coatings for art and creative items






















EC number:

215-251-3

15


1314-98-3

Use of ZnScontaining textile & leather coatings in a mixture






AC 0: Other:coatings for art and creative items

AC 8: Paper articles






















EC number:

215-251-3

20

22


1314-98-3

Use of ZnScontaining friction agents:

Brake pads in a mixture

Use of ZnScontaining glass

& ceramics in in a mixture






AC 6: Leather articles






PC 0: Other: UCN F40000: Friction agents - (e.g. brake pads)




ERC 12a: Industrial processing of articles with abrasive techniques (low release)


SU 17: General manufacturing, e.g. machinery, equipment, vehicles, other transport equipment



AC 1: Vehicles

AC 0: Other:TARIC 6813 81 brake linings and pads





EC number:

215-251-3

23


1314-98-3 dinnerware

Use of ZnScontaining glass in displays in a mixture


PC 19: Intermediate







SU 0: Other:Nace C23.4: Manufacture of other porcelain and ceramic products




AC 0: Other:TARIC 6911: tableware, kitchenware, household products in porcelain or china





PC 19: Intermediate








SU 0: Other:Nace C23.1: Manufacture of glass and glass products


EC number:

215-251-3

24

25


1314-98-3

Use of ZnScontaining optical material in a mixture

Use of ZnScontaining glassy thin film coatings in a mixture




















SU 0: Other:NaceC23.1: Manufacture of glass and glass products










EC number:

215-251-3

32


Use of ZnScontaining plastic thin films coatings in a mixture

CAS number:

1314-98-3










SU 0: Other:Nace C23.1: Manufacture of other porcelain and ceramic products















SU 4: Manufacture of food products



EC number:

215-251-3

36


1314-98-3

Use of ZnScontaining

Sealants /

Adhesives /

Mastics in a mixture



AC 1: Vehicles







PROC 8a: Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at non-dedicated facilities















PC 19: Intermediate







EC number:

215-251-3

40


Use of ZnScontaining fertilizer's formulations in a mixture

CAS number:

1314-98-3

ERC 8c: Wide dispersive indoor use resulting in inclusion into or onto a matrix


ERC 8f: Wide dispersive outdoor use resulting in inclusion into or onto a matrix








SU 15: Manufacture of fabricated metal products, except machinery and equipment

SU 19: Building and construction work



AC 1: Vehicles







PROC 8a: Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at non-dedicated facilities









EC number:


1314-98-3


PC 12: Fertilisers






ERC 8e: Wide dispersive outdoor use of reactive substances in open systems

ERC 9b: Wide dispersive outdoor use of substances in closed systems



SU 1: Agriculture, forestry and fishing



Table 9. Uses by consumers

Confidential IU number

11

Identified Use

(IU) name

Artists supply:

Use of ZnScontaining paints & coatings

Use descriptors

Chemical product category (PC):










EC number:

215-251-3

32

37


1314-98-3

Use of ZnScontaining plastic thin films coatings








AC 0: Other: coatings for art and creative items







Use of ZnScontaining

Sealants /

Adhesives /

Mastics



AC 1: Vehicles











PC 19: Intermediate




EC number:

215-251-3

40 Use of ZnScontaining fertilizer's formulations zinc sulphide CAS number:

1314-98-3




ERC 8c: Wide dispersive indoor use resulting in inclusion into or onto a matrix


ERC 8f: Wide dispersive outdoor use resulting in inclusion into or onto a matrix



AC 1: Vehicles






PC 12: Fertilisers






ERC 8e: Wide dispersive outdoor use of reactive substances in open systems

ERC 9b: Wide dispersive outdoor use of substances in closed systems




EC number:


1314-98-3

WASTE (cfr Annex 1, Arche, 2012) :

Table 10. Waste types, amounts and waste treatment processes for zinc from identified uses

Waste from Type of waste Suitable waste code

Downstream use

Scraps, cuttings, dusts, solvents, solutions, sludges, contaminated material, offspecification batches, …

02 01 10 *

10 10 10

12 01 03 *

15 01 04 *

16 01 04 *

16 01 06 *

16 01 18 *

16 06 02 *

16 08 02 *

16 08 03 *

17 04 07 *

17 04 09 *

17 09 04 *

19 10 02 *

19 12 03 *

…

Amount

(t/y)

0.7% from the

Zndownstre am use tonnage ends up in hazardous waste

Compo sition

Waste treatment process/ recycling

Treated as hazardous waste


Reck 2008

Waste stream profiles EC

2010

Waste report

ARCHE 2011

Table 11. Waste types, amounts and treatment of waste from service life sated subsequent to the identified uses for zinc from identified uses

Waste from

Municipal waste and

EoL

Type of waste

Solid municipal waste:

Paper/cardboard,

Metal,

Glass,

Plastics,

Textile,

Organic matter,

Other

Suitable waste code

20 01 34

20 01 40

20 03 01

20 03 07

Amount

(t/y)

179,430 ktonnes dry weight

Composition Waste treatment process/ recycling

Average concentration:

71 mg Ni/kg dw

Municipal waste landfill

Municipal waste incineration

Recycling


EUROSTAT

2009

Waste report

ARCHE 2011

Most common technical function of substance (what it does):

Colouring agents, pigments

Intermediates

Laboratory chemicals

Lubricants and lubricant additives

Photosensitive agents and other photo-chemicals

Processing aid, not otherwise listed

Semiconductors and photovoltaic agents

Agents adsorbing and absorbing gases or liquids

Anti-set off and adhesive agents

Biocide substances


EC number:

215-251-3

2.3. Uses advised against

None zinc sulphide CAS number:

1314-98-3


EC number:


3. CLASSIFICATION AND LABELLING

3.1. Classification and labelling according to CLP / GHS

Name: zinc sulphide

Implementation: EU

Classification

The substance is classified as follows:

 for physical-chemical properties:

Explosives: Reason for no classification: conclusive but not sufficient for classification

Flammable gases: Reason for no classification: conclusive but not sufficient for classification

Flammable aerosols: Reason for no classification: conclusive but not sufficient for classification

Oxidising gases:

Gases under pressure:

Reason for no classification: conclusive but not sufficient for classification


Flammable liquids: Reason for no classification: conclusive but not sufficient for classification

Flammable solids: Reason for no classification: conclusive but not sufficient for classification

Self-reacting substances and mixtures:


Pyrophoric liquids: Reason for no classification: conclusive but not sufficient for classification

Pyrophoric solids: Reason for no classification: conclusive but not sufficient for classification

Self-heating substances and mixtures:

Substances and mixtures which in contact with water emits flammable gases:



Oxidising liquids: Reason for no classification: conclusive but not sufficient for classification

Oxidising solids: Reason for no classification: conclusive but not sufficient for classification

Organic peroxides: Reason for no classification: conclusive but not sufficient for classification

CAS number:

1314-98-3


EC number:


Corrosive to metals: Reason for no classification: conclusive but not sufficient for classification

 for health hazards:

Acute toxicity - oral: Reason for no classification: conclusive but not sufficient for classification

Reason for no classification: conclusive but not sufficient for classification Acute toxicity - dermal:

Acute toxicity - inhalation:


Skin corrosion/irritation:


Serious damage/eye irritation:


Respiration sensitization:


Skin sensitation: Reason for no classification: conclusive but not sufficient for classification

Aspiration hazard: Reason for no classification: conclusive but not sufficient for classification

Reproductive

Toxicity:


Reproductive

Toxicity: Effects on or via lactation:


Reason for no classification: conclusive but not sufficient for classification Germ cell mutagenicity:

Carcinogenicity: Reason for no classification: conclusive but not sufficient for classification

Specific target organ toxicity - single:


Specific target organ toxicity - repeated:


 for environmental hazards:

Hazards to the aquatic environment

(acute/short- term):


Hazards to the aquatic environment

(long-term):


CAS number:

1314-98-3


EC number:


1314-98-3

Hazardous to the atmospheric environment:

Reason for no classification: data lacking

Labelling

Signal word: No signal word

----------------------------------------------------------------------------------------------------------------------------- ---------

3.2. Classification and labelling according to DSD / DPD

3.2.1. Classification and labelling in Annex I of Directive 67/548/EEC

3.2.2. Self classification(s)

Chemical name: zinc sulphide

Classification according to Directive 67/548/EEC criteria

Endpoints Classification

Explosiveness

Oxidising properties

Flammability

Thermal stability

Acute toxicity

Acute toxicity- irreversible damage after single exposure

Repeated dose toxicity

Irritation / Corrosion

Sensitisation

Carcinogenicity

Reason for no classification

Justification for

(non) classification can be found in section

6.1 conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification

6.3

6.2

5.2

5.2 conclusive but not sufficient for classification conclusive but not sufficient for classification

5.6

5.3.4 and 5.4.3 conclusive but not sufficient for classification

5.5.3 conclusive but not 5.8.3


EC number:


1314-98-3

Mutagenicity - Genetic

Toxicity

Toxicity to reproduction- fertility

Toxicity to reproduction- development

Toxicity to reproduction - breastfed babies

Environment sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification conclusive but not sufficient for classification

5.7.3

5.9.3

5.9.3

5.9.3

7.6

--------------------------------------------------------------------------------------------------------------------------------------

Remark on classification:

The results of the bio-elution test (worst case: gastric fluid) demonstrate that CoS present in the ZnS at 0.3% concentration, is insoluble. as a consequence, the Co-content in ZnS is not a reason for classification of ZnS for human toxicity effects (see section 7.12 of IUCLID).

4. ENVIRONMENTAL FATE PROPERTIES

General introduction to chapters 4, 5, 6 and 7.

Under Regulation 793/93/CEE, an extensive risk assessment on Zinc and 5 zinc compounds

(ZnO, ZnCl

2

, ZnSO

4

, Zn orthophosphate and zinc distearate) has been recently prepared by the Dutch authorities for the EU. The risk assessment report (RAR) on these 6 zinc substances has been recently published (ECB 2008).

Since these RARs were the result of intensive discussions between all stakeholders, and were approved by experts from all the member states; since they provide a recent review of the available evidence on zinc and zinc compounds (the file was closed in September 2006), they will be used as the main reference for this chemical safety report: although ZnS is insoluble and does not have any hazard for the environment, the general data related to the zinc ion its fate and distribution are considered relevant for ZnS, too, and are summarised in this chapter.

In this chemical safety report, the information, data and conclusions of the RAR will be summarised, focusing on the principles applied, the assumptions made and the conclusions.

Where available and relevant, new information and data will be included and discussed.

General remarks on the chapter on environmental fate properties.


EC number:


1314-98-3

Zinc is a natural element, which is essential for all living organisms. It occurs in the metallic state, or as zinc compound, with one valency state (Zn++). All environmental concentration data are expressed as “Zn”, while toxicity is caused by the Zn++ ion. For this reason, the sections on human toxicity and ecotoxicity are applicable to all zinc compounds, from which zinc ions are released into the environment. Some zinc compounds have however very low solubility and will therefore not release zinc ions; this strongly decreases their potential (eco-

)toxicity. As a consequence, distinction is being made between zinc compounds, as a function of their solubility

(see chapters 5 and 7).

For checking the potential of metal substances to release ions in the environment, a specific test, the transformation/dissolution (T/D) test is used. For metallic zinc and some of the zinc compounds, this test has been performed. If applicable, the results of such T/D test are discussed in section 4.6. (data in IUCLID section

5.6.).

The issue of degradation (section 4.1.) is not applicable to inorganic compounds. However, the speciation of zinc in the environment compartments is relevant and is discussed under section 4.2.

When zinc ions are formed in the environment, they will further interact with the environmental matrix and biota. As such, the concentration of zinc ions that is available to organisms, the bioavailable fraction, will depend on processes like dissolution, absorption, precipitation, complexation, inclusion into (soil) matrix, etc.

These processes are defining the fate of zinc in the environment and, ultimately, its ecotoxic potential. This has been recognised e.g. in the guidance to the CLP regulation 1272/2008 (metals annex): “Environmental transformation of one species of a metal to another species of the same does not constitute degradation as applied to organic compounds and may increase or decrease the availability and bioavailability of the toxic species. However as a result of naturally occurring geochemical processes metal ions can partition from the water column. Data on water column residence time, the processes involved at the water – sediment interface (i. e. deposition and re-mobilisation) are fairly extensive, but have not been integrated into a meaningful database.

Nevertheless, using the principles and assumptions discussed above in Section IV.1, it maybe possible to incorporate this approach into classification.“

In the water, the bioavailability of zinc through interaction with components of the water and biota has been studied in detail in the zinc RA (ECB 2008). This has resulted in an approach for quantifying zinc bioavailability into risk assessment. The ultimate fate of zinc in water (in the water column) is assessed via the

“unit world model”, that can quantify the “removal from the water column” of the zinc species. As such, it is shown that zinc (ions) brought into water will be rapidly removed from the water column (>70% removal within

28days). This phenomenon is described in section 4.6. (data in IUCLID 5.6), and is considered for classification.

In sediment, zinc binds to the sulphide fraction to form insoluble ZnS. As such, zinc is not bioavailable anymore to organisms. This has been discussed in the EU RA (ECB 2008), and has resulted in an approach for quantifying zinc bioavailability into risk assessment. Based on experimental data, a default conservative bioavailability factor of 0.5 was proposed in the RA. This approach can be refined when the relevant data on sulphide and Zn in sediment are available. Due to the insolubility of the ZnS (K=9.2 x 10 -25 ) zinc will be sequestered in the (anaerobioc) sediments, and the re-mobilisation of zinc ions into the water column will be prevented. This is also quantified in the unit world model, see section 4.6.

In soil, short-term interaction of zinc ions upon spiking, and long term interactions (“ageing”) have been extensively discussed in the zinc RA (ECB 2008). This has resulted in an approach for quantifying zinc bioavailability into risk assessment. Based on experimental data, a general ageing factor of 3 was derived in the

RA; according to soil type, the bio-availability of zinc can be further determined, when the relevant data on e.g. pH, CEC are available.

4.1. Degradation

4.1.1. Abiotic degradation

4.1.1.1. Hydrolysis

Data waiving


EC number:


1314-98-3


Justification: Waived: According to Annex IX of REACH Regulation, information on hydrolysis is not required for inorganics

The following 4.1.-related endpoints are not relevant for inorganics:

4.1.1.2. Phototransformation/photolysis

4.1.1.2.1. Phototransformation in air

4.1.1.2.2. Phototransformation in water

4.1.1.2.3. Phototransformation in soil

4.1.2. Biodegradation

4.1.2.1. Biodegradation in water

4.1.2.1.1. Estimated data

4.1.2.1.2. Screening tests

Data waiving


Justification: Biodegradation is not applicable to metals/inorganic substances, study does not need to be conducted if substance is inorganic (Annex VII of REACH regulation).

4.1.2.1.3. Simulation tests (water and sediments)

Data waiving



4.1.2.1.4. Summary and discussion of biodegradation in water and sediment

Discussion (screening testing)

Discussion (simulation testing)

4.1.2.2. Biodegradation in soil


EC number:


1314-98-3

Data waiving



4.1.3. Summary and discussion of degradation

Abiotic degradation

Waived: Inorganic substance: According to Annex IX of REACH Regulation, information on hydrolysis is not required for inorganics.

Also the other endpoints under 5.1. e. g; phototransformation in air, water and soil, are not applicable to the substance

Biotic degradation

Biodegradation is not applicable to metals/inorganic substances. Tests are not to be conducted if the substance is inorganic (Column 2 of Annex VII of REACH regulation)

For water, information is available on the removal of metals from the water column (given under IUCLID 5.6.).

The removal from the water column was modeled referring to the EUSES model parameters and different conditions of pH. Zinc is removed by > 70% under the reference conditions for the EU regional waters (EUSES)

(see section 4.6.: "removal from the water column").

4.2. Environmental distribution

The environmental fate and release of zinc and zinc compounds has been discussed extensively in the RAR (ECB 2008).

Environmental distribution in water

Z

inc in freshwater or seawater can occur in both suspended and dissolved forms and is partitioned over a number of chemical species. Depending on the concentration of suspended matter, about 25-40% of the zinc entering the surface water is in dissolved form, the remaining part is bound to the suspended matter. For toxicity, only the fraction not bound is important.

Dissolved forms of zinc in freshwater are e.g.: hydrated zinc ions, zinc ions complexed by inorganic or organic ligands (humic and fulvic acids), zinc oxy ions and zinc adsorbed to solid matter (RAR 2008).

Possible chemical forms of zinc in seawater are presented in the table below. In this table the variation in the percentages of total zinc can for instance be explained by analytical differences or by the different ion strengths of the examined seawaters.


EC number:


1314-98-3

Table 12. (taken from the RA zinc, ECB 2008): Possible chemical forms (speciation) of dissolved zinc in seawater (Cleven et al., 1993).

Zn species

Zn 2+

ZnCl n

2-n (n:1-4)

ZnOH + , ZN(OH)

2

ZnCO

3

ZnHCO +

3

ZnOHCl

ZnSO

4

Reference 1

17

11.4

62.2

6

0.7

-

4

Percentage of total zinc

Reference 2

16.1

63.7

2.3

3.3

0.3

12.5

1.9

Reference 3

12.5

79

0.6

1.6

-

-

1.6

Reference 4

5.7

17.8

71.8

2.4

0.2

-

2.2

The speciation of zinc in the aquatic compartment is of high complexity and depends highly on abiotic factors, such as pH, (dissolved) organic matter content, redox potential, etc. It is assumed that speciation is very relevant for the migration of zinc through sediment, for the distribution of zinc among its truly dissolved and nondissolved forms, and for the uptake of zinc by some aquatic and sediment organisms. The relationship between physicochemical factors driving the speciation of zinc in water, and the bioavailability, and consequently, the toxicity of Zinc has been experimentally elucidated and has been quantified in the biotic ligand model (BLM)

(see further).

Environmental distribution in soil; adsorption/desorption of zinc in soil

Speciation of zinc in soil

The speciation of zinc in soils has been extensively reviewed in the EU risk assessment on zinc (ECB 2008).

The following is being summarised from the risk assessment: in soils, zinc interacts with various reactive soil surfaces. The most important in this respect are soil organic matter, amorphous soil oxides (Al, Fe, Mn) and clay minerals. The major process by which metals are bound to these surfaces is adsorption. Other processes including precipitation of carbonate type minerals can occur but are, in non- and moderately polluted soils, unlikely to control the solubility of metals in soils. An exception to this is the formation of sulphide minerals that are formed, in the presence of sulphate under reducing conditions.

Zinc in soil is distributed between the following fractions (ECB 2008):

1.

Dissolved in pore water (which includes many species)

2.

Exchangeable, bound to soil particles

3.

Exchangeable, bound to organic ligands (of which a small part in the dissolved fraction and the major part in the solid fraction)

4.

Present in secondary clay minerals and metal oxides/hydroxides

5.

Present in primary minerals

So, zinc is present in the soil in various forms, that have varying degree of extractability. The soil pH is an important parameter that affects the speciation and the distribution of the zinc species over the soil and the solution. Zinc tends to be more sorbed and complexed at higher pH (pH > 7) than at lower pH. Below pH 7, the amount of zinc in solution was reported to be inversely related to soil pH (Janssen et al., 1997). The pH of the soil not only determines the degree of complexation and adsorption of zinc, but also the solubility of the various zinc minerals. The solubility of zinc in soil decreases with increasing pH (Cleven et al., 1993).

After addition of a metal to a soil, often a slow decrease in the soil solution concentration, or the available fraction as determined in an extraction solution (e.g. by CaCl

2

) decreases as a result of (presumably) slow diffusion processes of metals into the matrix of the reactive surfaces. It is this process, or sum of as of yet poorly defined slow processes, that can be defined as ‘ageing’ (ECB 2008).

The challenge is to develop models that scale from the theoretical and laboratory level to the field scale.

Following an extensive discussion in the risk assessment process, an integrative research program has been conducted aiming to reveal the relevant information required for using bioavailability corrections within the framework of the terrestrial risk assessment. The various relationships between on the one hand abiotic soil parameters and on the other hand the toxicity of zinc to plants, invertebrates and microbial endpoints were used to develop “soil sensitivity” functions i.e. relationships that express the potential toxicity of zinc in various soil types as a function of soil characteristics. Long-term distribution of zinc in soil was also recognised as an important process that affects the distribution of zinc and bioavailability in soil and toxicity towards soil species.

Based on recent studies and a recent evaluation of older studies, the ‘ageing’ phenomenon was also quantitatively taken into account in the EU RAR (ECB 2008).


EC number:


1314-98-3

4.2.1. Adsorption/desorption

Data waiving


Justification: For metals, adsorption/desorption translates in the distribution of the metals between the different fractions of the environmental compartment, e. g. the water (dissolved fraction, fraction bound to suspended matter), soil (fraction bound or complexed to the soil particles, fraction in the soil pore water...).

This distribution between the different compartments is translated in the partition coefficients between these different fractions. information on partition coefficients is given under IUCLID 5.6.

Discussion

For metals, adsorption/desorption translates in the distribution of the metals between the different fractions of the environmental compartment, e. g. the water (dissolved fraction, fraction bound to suspended matter), soil

(fraction bound or complexed to the soil particles, fraction in the soil pore water...). This distribution between the different compartments is translated in the partition coefficients between these different fractions. Study records on partition coefficients are given under IUCLID 5.6.

Partition coefficients for zinc in freshwater has been reviewed in the RAR (ECB 2008). Based on the extensive experimental evidence, a partition coefficient for the distribution between solid particulate matter and water

(Kpsusp) of 5.04 (log value) has been defined for EU waters and used throughout the RAR.

The Kp for the distribution between sediment and water (Kp sed particulate matter, as follows: Kp sed

= Kp susp

) was estimated in the RAR from that for

/ 1.5, based on the average difference in concentrations of zinc and other metals in both media. For zinc this results in a Kp sed of 73,000 l/kg. (ECB 2008)

The marine Kd was derived based on data from several marine waters. the geomean value for zinc in seawater is

6010 l/kg

For soil, a solids-water partitioning coefficient of 158.5 l/kg (log value 2.2) was determined experimentally on

11 American soils. This value was used in the RA Zinc.

The following information is taken into account for any environmental exposure assessment:

Kp for solid particulate matter and water (Kpsusp): 110000 l/kg (log value: 5.04) (ECB 2008)

Kp for water and sediment (Kpsed); 73000l/kg (log value:4.86) (ECB 2008)

Kd for marine waters is 6010 l/kg (log value: 3.78)

Kd for solids-water in soil is 158.5 l/kg (log value: 2.2)

4.2.2. Volatilisation

Not relevant

4.2.3. Distribution modelling

4.2.4. Summary and discussion of environmental distribution

For metals, the transport and distribution over the different environmental compartments e. g. the water


EC number:


1314-98-3

(dissolved fraction, fraction bound to suspended matter), soil (fraction bound or complexed to the soil particles, fraction in the soil pore water...) is described and quantified by the metal partition coefficients between these different fractions. Information on these partition coefficients is given under IUCLID 5.6.

Partition coefficients for zinc in freshwater have been reviewed in the RAR (ECB 2008). Based on this experimental evidence, a partition coefficient for the distribution between solid particulate matter and water

(Kpsusp) of 5.04 (log value) has been defined for EU waters and was used throughout the RAR.

The Kp for the distribution between sediment and water (Kp sed particulate matter, as follows: Kp sed

= Kp susp

) was estimated in the RAR from that for

/ 1.5, based on the average difference in concentrations of zinc and other metals in both media. For zinc this results in a Kp sed

of 73,000 l/kg. (ECB 2008)

These partition coefficients have been used since then in other legislative processes in the EU (e. g. the water framework directive) and will also be used for REACH.

For the marine water, a partition coefficient water/suspended matter of 6010 l/kg has been derived.

For soil, a solids-water partitioning coefficient of 158.5 l/kg (log value 2.2) was determined experimentally on

11 American soils. This value was used in the RA Zinc.

4.3. Bioaccumulation

Due to homeostatic control mechanisms, bioaccumulation is not relevant to essential elements in general and to like zinc in particular.

In experimental work, high BCF factors are observed at the lowest zinc exposure levels, due to the fact that organisms will concentrate zinc to satisfy internal physiological needs for the essential element. For the same reason of homeostasis, the BCF will strongly decrease when exposure concentrations increase. This results in a general negative relationship between BCF and exposure (McGeer et al 2003).

On bioaccumulation, the EU risk assessment report (ECB 2008) concludes that “it is concluded that secondary poisoning is considered to be not relevant in the effect assessment of zinc. Major decision points for this conclusion are the following. The accumulation of zinc, an essential element, is regulated in animals of several taxonomic groups, for example in molluscs, crustaceans, fish and mammals. In mammals, one of the two target species for secondary poisoning, both the absorption of zinc from the diet and the excretion of zinc, are regulated. This allows mammals, within certain limits, to maintain their total body zinc level (whole body homeostasis) and to maintain physiologically required levels of zinc in their various tissues, both at low and high dietary zinc intakes. The results of field studies, in which relatively small differences were found in the zinc levels of small mammals from control and polluted sites, are in accordance with the homeostatic mechanism.

These data indicate that the bioaccumulation potential of zinc in both herbivorous and carnivorous mammals will be low. "

4.3.1. Aquatic bioaccumulation

The studies on aquatic bioaccumulation are summarised in the following table:

Table 13. Overview of studies on aquatic bioaccumulation

Method Results

Palaemon elegans (crustaceae) BCF: 28960 (whole body d.w.)

(steady state) aqueous (saltwater) semi-static

BCF: 2558 (whole body d.w.)

(steady state)

Total uptake duration: 28 d BCF: 843 (whole body d.w.)

(steady state)

Remarks

2 (reliable with restrictions) key study read-across based on grouping of substances (category

Reference

Rainbow PS and

White SL. (1989)


EC number:


1314-98-3

Total depuration duration: 1 min BCF: 277 (whole body d.w.)

(steady state)

The decapod Palaemon elegans was exposed to sublethal concentrations of zinc over 28 days time period; total zinc accumulation was measured.


(steady state)

Echinogammarus pirloti


(steady state)


(steady state) aqueous (saltwater) semi-static


(steady state)

Total uptake duration: 21 d

Total depuration duration: 1 min


(steady state)


(steady state)

The amphipod Echinogammarus pirloti was exposed to sublethal concentrations of zinc over 21 days time period; total zinc accumulation was measured.


(steady state) various wildlife species feed and aqueous (freshwater)


(steady state)

BAF: 4060 (whole body d.w.)

(steady state) (aquatic invertebrates: control water) field study

Type of sediment: natural sediment

BAF: 3483 (whole body w.w.)

(steady state) (aquatic invertebrates, contaminated water) food chain analysis in a contaminated natural environment


(steady state) (snails, control water) approach)

Test material

(IUPAC name): zinc chloride (See endpoint summary for justification of read-across)

2 (reliable with restrictions) key study

Test material

(IUPAC name): zinc chloride (See endpoint summary for justification of read-across)

2 (reliable with restrictions) key study read-across based on grouping of substances (category approach) read-across based on grouping of substances (category approach)


(steady state) (snails, contaminated water)

BAF: 177 (whole body w.w.)

(steady state) (fish, contaminated water)

Test material

(IUPAC name): zinc (See endpoint summary for justification of read-across)

Rainbow PS and

White SL. (1989)

Pascoe GA,

Blanchet RJ and

Linder G (1996)

4.3.2. Terrestrial bioaccumulation

The results of terrestrial bioaccumulation studies are summarised in the following table:

Table 14. Overview of studies on terrestrial bioaccumulation

Method Results various wildlife species food chain analysis in a contaminated natural

BCF: 3.3 (whole body d.w.)

(steady state) (grasshoppers, control soil)

Remarks


Reference

Pascoe GA,

Blanchet RJ and

Linder G (1996)


EC number:


1314-98-3 environment


(steady state) (grasshoppers, contaminated soil)


(steady state) (earthworms, control soil)


(steady state) (earthworms, contaminated soil)


(steady state) (small mammals, contaminated soil)


(steady state) (above ground fodder, control soil)


(steady state) (above ground fodder, contaminated soil)


(steady state) (below ground fodder, control soil)


(steady state) (below ground fodder, contaminated soil)


(steady state) (above ground grasses, control soil)


(steady state) (above ground grasses, contaminated soil)


(steady state) (below ground grasses, control soil)


(steady state) (below ground grasses, contaminated soil) read-across based on grouping of substances (category approach)

Test material


4.3.3. Summary and discussion of bioaccumulation

Aquatic bioaccumulation

Bioaccumulation is not considered relevant for essential elements because of the general presence of homeostatic control mechanisms.

McGeer et al (2003) recently extensively the reviewed evidence on bioconcentration and bioaccumulation of zinc as a function of exposure concentration in a number of taxonomic groups (algae, molluscs, arthropods, annelids, salmonid fish, cyprinid fish, and other fish). The data clearly illustrated that internal zinc content is well regulated. All eight species taxonomic groups investigated exhibited very slight increases in whole body concentration over a dramatic increase in exposure concentration. In fact, most species did not show significant increases in zinc accumulation when exposure levels increased, even when exposure concentrations reached


EC number:


1314-98-3 those that would be predicted to cause chronic effects. This suggests that adverse effects related to Zn exposure are independent of whole body accumulation. Due to the general lack of increased whole body and tissue concentrations at higher exposure levels, the zinc BCF data showed an inverse relationship to exposure concentrations. In all cases, the relationship of BCF to exposure was significant and negative. The slopes of the

BCF/BAF – exposure relations were: algae: -1.0, insects: -0.79, arthropods: -0.73, molluscs: -0.83, salmonids: -

0.92, Centrarchids: -0.80, Killifish: -0.84, other fish: -0.87. Overall, species mean slope was -0.85 +/- 0.03

(McGeer et al 2003).

The physiological basis for the inverse relationship of BCF to zinc exposure concentration arises from Zn uptake and control mechanisms. At low environmental zinc levels, organisms are able to sequester and retain Zn in tissues for essential functions. When Zn exposure is more elevated, aquatic organisms are able to control uptake. There is clear evidence that many species actively regulate their body Zn concentrations, including crustaceae, oligochaetes, mussels, gastropods, fish, amphipods, chironomids by different mechanisms (McGeer et al 2003).

The following information is taken into account for any hazard / risk / bioaccumulation assessment:

Zinc is an essential element which is actively regulated by organisms, so bioconcentration/bioaccumulation is not considered relevant.

Terrestrial bioaccumulation

Bioaccumulation is not considered relevant for essential elements because of the general presence of homeostatic control mechanisms. the data from a field food chain transfer study indicate that bioconcentration of zinc is indeed very low. It is in all cases also lower in contaminated soil, as compared to control soil.

The following information is taken into account for any hazard / risk / bioaccumulation assessment:

Zinc is an essential element which is actively regulated by organisms, so bioconcentration/bioaccumulation is not considered relevant.

4.4. Secondary poisoning

Based on the available information, there is no indication of a bioaccumulation potential and, hence, secondary poisoning is not considered relevant (see CSR chapter 7.5.3 "Calculation of PNECoral (secondary poisoning) ".

Justification for no PNEC oral derivation: Zinc is an essential element that is actively regulted within the body of all organisms. Due to the general lack of increased whole body and tissue concentrations at higher exposure levels, the zinc BCF data show generally an inverse relationship to exposure concentrations (McGeer et al

2003). The physiological basis for the inverse relationship of BCF to zinc exposure concentration arises from Zn uptake and control mechanisms. At low environmental zinc levels, organisms are able to sequester and retain Zn in tissues for essential functions. When Zn exposure is higher, aquatic organisms are able to control uptake.

There is clear evidence that many species actively regulate their body Zn concentrations, including crustaceans, oligochaetes, mussels, gastropods, fish, amphipods, chironomids by different mechanisms (McGeer et al 2003).

The bioaccumulation potential in mammals is also considered low. Based on this, the EU risk assessment concludes that secondary poisoning is considered to be not relevant in the effect assessment for zinc.

4.5. Natural background

4.5.1. Natural background in surface waters

Data on natural background of zinc in surface waters in the EU were discussed in the RAR (ECB 2008). Based on values reported for a number of EU countries, incl. NL, D, F, SF and others, two values were selected for total background concentration, to be used in the risk characterisations:

-3µg Zn/l which is the lower limit of the range reported by the member states in the risk assessment process,

-12µg Zn/l which is the geometric mean value of an extensive EU database on Zn concentrations in lowland


EC number:


1314-98-3 brooks in unpolluted areas in N-Europe, (10P and 90P in this review are 4 and 35 µg total Zn/l resp. - Zuurdeeg

1992).

-Using a Kp susp

of 110,000 l/kg (RA; ECB 2008) and a default particulate matter content of 15 mg/l, these values are equivalent to 4.44 µg dissolved Zn/l, and 1.11 µg dissolved Zn /l, respectively.

Due to geochemical differences, the natural background concentrations in surface waters will differ throughout

Europe. It is thus not appropriate to set one value for the whole of the EU. Recently, an extensive database has become available on a.o. zinc background values in surface waters, covering the whole of the EU (FOREGS

2005). The 10P and 90P values for dissolved zinc following from this analysis performed also on non-polluted head waters (cfr Zuurdeeg 1992) are 0.7 and 18 µg dissolved zinc /l, resp.

( http://www.gtk.fi/publ/foregsatlas/maps/Water/w_icpms_zn_edit.pdf

); the median value of 2.7 µg dissolved

Zn/l corresponds well with the one used in the RAR (ECB 2008).

The FOREGS study thus confirms the data reported in the EU RAR and the Zuurdeeg (1992) analysis. It confirms that the value of 12µg total Zn/l – 4.44 µg dissolved Zn/l can be seen as the median value for zinc background in European freshwaters.

Regarding the sediment, the RAR concluded, based on reported data from a number EU countries, incl NL, D,

F, N, SF, SW, that the range of the background data for sediment was more or less in the same order of magnitude (range 70-175 mg/kg dwt). Based on the data from several EU-regions the value of 140 mg/kg dwt was set for use as a natural background for correcting the EU sediment monitoring data.

It was noted that, if available monitoring data can unequivocally be linked with a particular natural background value in an area, preference should be given to that specific background value (ECB 2008).

For comparison, FOREGS (2005) reports for zinc in sediments 10P and 90P values of 18 and 270 ppm, resp., demonstrating the big variation, due to local geology. The median value is 65 ppm. Because of the great variability, more localised assessments are preferred.

4.5.2. Natural background in the terrestrial compartment

The natural zinc concentrations in soils are highly variable and dependent on soil type and soil properties. The

EU RAR concluded from the available soil data for a number of EU countries that there is a large variation in the natural zinc background concentrations. This variation is related to the native soil material and the present soil characteristics like humus and lutum. The RAR observed a clear relationship between natural background levels and various soil parameters, but noted that a quantification of the exact natural background level for a specific EU soil type is at present still an extremely difficult and complex issue. The RAR mentioned zinc backgrounds usually in the range 50-100 mg Zn/kg DW, which is confirmed by data from the more recent

FOREGS database, reporting 10P, 50P and 90P zinc concentrations of 8, 52, and 140 mg/kg DW, respectively in unpolluted soils throughout Europe. Important to note is that, due to the high variability on the data, the RAR concluded that it was only possible to use monitored soil data for risk characterisation when it was possible to make a correction with the natural zinc background concentration(s) typical for that soil type.

4.6. Additional information on environmental fate and distribution

Transformation dissolution

For ZnS, transformation/dissolution tests have been performed. Based on these test results, it was concluded that

ZnS is insoluble and should not be classified for environmental effect. The results are summarised below.

ZnS powder was tested for its capacity to release zinc ions in aqueous medium, according to standardised protocols. Two tests were performed:

1) Test on pure ZnS, commercial brand “Sachtolith”. This brand is pure ZnS with 0.3% CoS. For this reason, both Zn and Co were tested.

In the transformation/dissolution test for Zn, 1, 10 and 100 mg/L of zinc sulfide (ZnS) was agitated at 100 rpm in a pH buffered aqueous medium at pH 6 and at pH 8 for 7 days. The test with the 1 mg/L loading at pH 6 was prolonged to 28 days. The solutions were sampled at specific time intervals and the concentrations of dissolved zinc in water were determined.


EC number:


1314-98-3

In a similar test, performed at a later time and with a 100 mg/L loading only, the dissolved cobalt concentrations were measured .

The results are summarised in table below (ECTX 2010).

Table 15 : transformation/dissolution of zinc sulphide tested at pH 6 and 8 (ECTX 2010).

Loading @ pH 6 1 mg/L ZnS 10 mg/L ZnS 100 mg/L ZnS

7-day endpoint

28-day endpoint

X µg/L Zn ± σ µg/L Zn X µg/L Zn ± σ µg/L Zn X µg/L Zn ± σ µg/L Zn

<4.00 21.1 ± 2.4 195 ± 9

6.29 ± 2.02 - -

X µg/L Co ± σ µg/L Co

7-day endpoint

X = average of 3 test vessels (3 samples per test vessel)

σ = standard deviation

* results from an additional test started on 08/05/2010

Loading @ pH 8 1 mg/L ZnS 10 mg/L ZnS

<0.50

100 mg/L

*

ZnS

X µg/L Zn ± σ µg/L Zn X µg/L Zn ± σ µg/L Zn X µg/L Zn ± σ µg/L Zn

7-day endpoint <4.00 11.7 ± 0.7

* 80.4 ± 1.1

*

X µg/L Co ± σ µg/L Co

7-day endpoint <0.50

**

X = average of 3 test vessels (3 samples per test vessel)

σ = standard deviation

* results from an additional test started on 03/12/2009

** results from an additional test started on 08/05/2010

The results demonstrate that ZnS is practically insoluble. Zinc is released from the ZnS only in a very limited way. The observed levels of zinc released in the medium after 7days are at all loadings below the reference concentrations for aquatic ecotoxicity at the pH range tested (reference values for acute aquatic zinc toxicity are

413 µg Zn/l and 136 µg Zn/l at pH 6 and pH 8 respectively). The observed zinc concentration after 28 days at pH 6 was also smaller than the lowest reference value for chronic aquatic toxicity (19µg Zn/l at pH 8).

Considering this latter result, testing over 28 days at pH 8 was not considered relevant since a) the T/D rate and extent is lower at pH 8 than at pH 6, and b) the reference value for chronic aquatic zinc toxicity is higher at pH

6.

The release of Co was negligible at both pH values tested (6 and 8), and in any case smaller than the reference values for aquatic toxicity of Co (90.1µg Co/l and 1.45 µg Co/l for acute and chronic toxicity, resp.)

The observations mentioned above are confirmed by a) The results on another quality of ZnS (see item 2 below), and b) the systematic absence of ecotoxic effects observed in standard acute aquatic toxicity testing on fish, invertebrates and algae (IUCLID section 6) at loading rates of 100mg /l of the substance.

2) Test on pure ZnS.

Zinc sulfide powder was introduced at 100 mg/L in a pH 6 CO

2

-buffered aqueous medium and in a pH 8 air buffered aqueous medium. Transformation/dissolution was accomplished by standardised agitation, sampling


EC number:


1314-98-3 and analysing of the solutions at specific time intervals. The short-term (acute) transformation/dissolution endpoint is based on the dissolved zinc concentration obtained after a 7 days transformation/dissolution period.

Results are given in table below.

Table 16: transformation/dissolution of zinc sulphide tested at pH 6 and 8(ECTX 2010bis).

Loading @ pH 6

7-day endpoint

100 mg/L zinc sulfide

X µg/L

Zn

± σ µg/L

Zn

<4.0

Loading @ pH 8 100 mg/L zinc sulfide

X µg/L Zn ± σ µg/L Zn

7-day endpoint <4.0

The results demonstrate that ZnS is practically insoluble. Zinc is released from the ZnS only in a very limited way. The observed levels of zinc released in the medium after 7days are 100mg/l loading below the reference concentrations for aquatic ecotoxicity at the pH range tested (reference values for acute aquatic zinc toxicity are

413 µg Zn/l and 136 µg Zn/l at pH 6 and pH 8 respectively). Given these results, a test with 1mg/l loading for

28 days was not considered relevant.

The observations mentioned above are confirmed by a) The results on another quality of ZnS (see item 1 above), and b) the systematic absence of ecotoxic effects observed in standard acute aquatic toxicity testing on fish, invertebrates and algae (IUCLID section 6) at loading rates of 100mg /l of the substance.

Conclusion

Because of the results mentioned above, it is concluded that according to standard testing, zinc ions are released from ZnS in aqueous medium in only a very limited way. The amount of zinc released is not sufficient to reach the reference values for aquatic ecotoxicity over the whole pH range and at all loading rates. As a consequence,

ZnS is not classified for environmental effects.

Removal from the water column

The removal of zinc ions from the water column was assessed by using the “Unit World Model” (UWM), a screening level model used to explicitly assess the effects of chemical speciation on metal partitioning, transport and bioavailability in the water column and underlying sediments. Specific processes considered in the UWM include 1) dissolved and particulate phase transport between the overlying water and sediment, 2) metal binding to inorganic ligands, dissolved and particulate carbon (using WHAM V), and iron hydroxides in the water column, 3) metal precipitation, 4) dissolution kinetics for metal powders, massives, etc., and 5) average-annual cycling of organic matter and sulfide production in the lake (Mutch Associates 2010b).

The numerical engine for the model calculations is the Tableau Input Coupled Kinetics Equilibrium Transport

(TICKET) model (Farley et al., 2008). As parameters for the calculation, reference was made to the conditions as prescribed by ECHA (2009) for use with the European Union System for the Evaluation of Substances

(EUSES) to carry out rapid and efficient assessments of the general risks posed by chemical substances.Zinc removal was evaluated at different water chemistries relative to the REACH Implementation Project (RIP) 3.6 definition of rapid removal for soluble metals of greater than 70% removal in a 28-day period.

The model was used to calculate the removal of zinc ions for a standard EUSES lake (“base case”). Additional sensitivity analysis was applied to check on the removal with varying conditions, e.g. pH, zinc concentration

(the initial zinc concentrations in the water column were specified based upon reference zinc toxicity levels at different pH), settling velocity. Finaly, some “real world” experimental evidence is discussed.

The removal of zinc in the base case is described in figure below.


EC number:

215-251-3

0.8

0.6

0.4

0.2

1.2

1 zinc sulphide CAS number:

1314-98-3

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (days)

TICKET-UWM 30% Remaining

Figure 1. Base case total zinc removal from the water column using EUSES model parameters. The initial total zinc concentration in the water column ( C

0

) is 413 μg/L. The horizontal dashed line represents C / C

0

= 0.3 or 70% removal of zinc (from Mutch Associates

2010b).

Zinc removal from the water column is rapid: 70% zinc removal is achieved within 3 days of dosing. Based on the suspended solids concentration of 15 mg/L and the log K

D of 5.04, approximately 62% of the zinc in the water column is associated with settling particles. After 28 days, the total zinc concentration in the water column is 1.74 µg/L.

The following sensitivity analysis was done (

Mutch Associates 2010b

):

 When decreasing settling velocity from the EUSES value of 2.5 m/d to 0.24 m/d, the zinc removal rate is decreased, but the rapid removal benchmark is still met.



Varying the hydraulic residence time between 300 years and 40 days ( EUSES value) has a minimal effect on zinc removal. The rapid removal benchmark is met within 3 days.



The output from the TICKET-UWM indicates that the WHAM V-computed log K

D

varies over the course of the 28-day simulation between 4.32 and 4.55. This variation is associated with decreasing water column zinc concentrations (partitioning in WHAM V not necessarily linear). This range of log

K

D

values is lower than the zinc risk assessment document value of 5.04. As a result of the generally lower log K

D

(and associated lower f

Part values), zinc is removed from the water column at a slower rate but the rapid removal benchmark is still achieved (in approximately 5.5 days).

 When the standard EUSES lake parameters are applied, but pH is varied between 6 and 8, the removal rate is basically similar under all 3 conditions, and zinc is removed > 70% within 28 days ( Mutch

Associates 2010a ).

Experimental evidence on the removal of zinc from is available from the work of Hart et al, 1992. The concentration of zinc added to large (40m3) in situ enclosures of natural water, containing natural phytoplankton community, was followed over >40 days. In this system, the total zinc fraction, the particulate zinc fraction and the ion-exchangeable zinc fraction all decreased steadily over the study period. 70% removal of zinc in the 3 fractions was observed after 11-12 days. A mass balance indicated that most of the zinc ended up in the sediments (84%), about 6% remained in the water column and about 10% was associated with wall epiphytes

(Hart et al 1992).

Further experimental evidence for the removal of zinc from the water column is found in a recent freshwater


EC number:


1314-98-3 microcosm study (Rand et al 2012). In this study, a significant decrease of dissolved zinc in the microcosm water column was monitored over a period of 4 days. Extrapolation of the data indicated that zinc would be removed >> 70% within 28 days.

Re-mobilisation of zinc from the sediment is prevented by binding of zinc to the sulphide fraction to form insoluble ZnS. Due to the insolubility of the ZnS (K=9.2 x 10 -25 ) zinc will be effectively sequestered in the

(anaerobioc) sediments.

In the systems described above, zinc was added as soluble salt that dissolves instantaneously. This is in contrast to e.g. metal powders or powders from insoluble zinc compounds which may dissolve at slower rates, may be only sparingly soluble, and, depending on particle size and density, may be subject to rapid settling. Use of a soluble zinc salt in the TICKET-UWM simulations, therefore, represents a worst-case scenario for metal release and persistence in the water column.

In conclusion, model calculations supported by experimental field evidence show that zinc is rapidly removed from the water column, at a rate of > 70% within 28 days. This result has implications for the classification for aquatic toxicity.

5. HUMAN HEALTH HAZARD ASSESSMENT

General considerations

This chemical safety assessment and chemical safety report focuses on zinc metal and ten zinc compounds (i.e., zinc oxide-ZnO; zinc hydroxide-Zn(OH)

2

; zinc phosphate-Zn zinc sulphate-ZnSO

4

; zinc chloride–ZnCl

2

3

(PO

4

)

2

; zinc carbonate-ZnCO

; diammonium tetrachlorozincate–ZnCl pentachlorozincate-ZnCl2/3NH4Cl; zinc bis(dihydrogen phosphate)-Zn(H

3

PO4)

2

).

3;

zinc sulphide-ZnS;

2

/2NH

4

Cl; triamonium

The zinc compounds have been grouped into three categories on the basis of their water solubility as described in Table below:

Table 17. Water solubility values of the eleven zinc compounds covered in this CSR

Zinc compound Water solubility in mg/L 1

ZnCl

2

ZnSO

4

Zn(H

3

PO4)

2

ZnCl

2

/2NH

4

Cl

ZnCl

2

/3NH

4

Cl

Zn(OH)

2

ZnO

4.3 x10

>1x10 4

>1x10

>1x10

1.6

1.6

4

4

6

0.22x10

6

Water solubility in mg/L

0.851x10

6

0.210x10

6

>1 x10 6

0.291 x10 6

0.155 x10 6

648

2.9

2 Ranking of solubility

Soluble

Soluble

Soluble

Soluble

Soluble

Slightly soluble

Slightly soluble

Zn

3

(PO

ZnCO

4

3

)

Zn metal

2

0.1

<0.2

<0.1

2.7

1.3

0.1

Slightly soluble

Slightly soluble

Slightly soluble

ZnS <10 0.00045x10

-3 Insoluble

1 Values are taken from ESIS database http://ecb.jrc.ec.europa.eu/esis/ ; ATSDR 2005; EU RARs (EU RAR, 2004a-f)

2 Values are taken from section 4 of the IUCLID files on the respective substances. Data by Outotec Research Oy, Pori,

Finland.

Collectively this group of zinc compounds is considered “data rich” with a multitude of information available in the public domain regarding the effects of zinc compounds on human health. The wealth of available toxicological data has been carefully reviewed and scrutinised by the Rapporteur in the framework of the discussions on the EU Risk Assessment Reports (RAR) developed according to EU Regulation 793/93/EEC

(EU RAR, 2004a-f).


EC number:


1314-98-3

The Rapporteur’s analysis of the available toxicological data was extensively discussed by the experts from

Member States and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), during which the relevant data sets were approved. Therefore, the data used in the RARs

(EU RAR, 2004a-f) will be the main data source for this chapter. Decisions on data quality and relevancy approved by TCNES will be used as in the EU risk assessment process. Consequently, the current analysis will focus on the data considered useful for deriving the MOS in the RARs as such (EU RAR, 2004a-f). Also, the data considered not useful in the EU risk assessment process will also not be used in the current analysis.

Given the substantial amount of data, only pertinent data in the IUCLID5 files have been included in this CSR.

Data which were considered not sufficient during the EU risk assessment process have been summarised in this

CSR, with reference to the author mentioned in the EU RARs for completeness. In addition, the dataset from the

EU RARs have been complemented with relevant and reliable information that became available between 2005-

2009 (i.e., after the EU RARs were finalised in 2004). The additional data have also been reported and summarised in IUCLID5 as well as in the following subsequent sections.

Assumptions

Zinc exists in different chemical forms and the bioavailability of these forms depends on various physicochemical parameters of which water solubility is the main determining factor. It is accepted that the actual bioavailable concentration of the zinc cation in both animals and in humans is an important determinant of toxicity, and although there is information available on the various zinc compounds, adequate information is lacking on how to quantitatively determine or estimate the bioavailable fraction of all the different zinc compounds in either laboratory animals or humans (Windholz et al.

, 1983). Since water solubility is the main determinant of bioavailability, zinc compounds with similar solubility characteristics have been grouped in

Table below and, where necessary, the local or systemic toxicity have been read-across within the same group of zinc compounds.

Table 18. Grouping based on water solubility

Zinc compound

ZnCl

2

ZnSO

4

Zn(H

ZnCl

2

/2NH

4

Cl

ZnCl

2

3

ZnS

PO4)

/3NH

4

Cl

ZnO

Zn(OH)

2

Zn

3

(PO4)

2

ZnCO

3

Zn metal

2

Ranking of solubility

Soluble

Soluble

Soluble

Soluble

Soluble

Slightly soluble

Slightly soluble

Slightly soluble

Slightly soluble

Slightly soluble

Insoluble

Solubility-based grouping

Zn(OH)

Zn

ZnCl

2

ZnSO

4

Zn(H

3

PO4)

2

ZnCl

2

/2NH

4

Cl

ZnCl

3

2

/3NH

ZnO

(PO4)

ZnCO

ZnS

3

2

Zn metal

4

Cl

2

As such, this section in the CSR makes an integrated case on the zinc compounds mentioned above and is relevant for all of them. For reasons of consistency, it was decided not to develop partial cases on separate zinc substances.

5.1. Toxicokinetics

5.1.1. Non-human information

Absorption

In vitro dermal penetration studies

The dermal absorption of zinc 2-pyrrolidone 5-carboxylate, ZnO and ZnSO

4

(16 mg formulation/cm 2 ; 0.02 –

5.62% zinc) in different formulations (3 emulsions and 2 ointments) using human abdominal skin was investigated. The receptor medium was 0.9% NaCl. After application for 72 hours, the skin was washed and stripped twice. The percutaneous absorption was determined as a percentage of the applied dose found in


EC number:


1314-98-3 receptor medium and cutaneous bioavailability. It never exceeded 2%. The percentages for the absorption of zinc from ointments containing ZnO and ZnSO

4

were 0.36% and 0.34%, respectively. The percutaneous absorption of zinc from the emulsion containing zinc 2-pyrrolidone 5-carboxylate was 1.60% of the applied dose. Furthermore the experiment showed a vehicle effect on absorption (Pirot et al.

, 1996a).

The dermal absorption of ZnSO

4

and ZnCl

2

(in 20 mg formulation/cm 2 ) in petrolatum and hydrophilic gels using human breast or abdominal skin was also investigated. The receptor medium used was isotonic saline. After application for 72 hours, the skin was washed and the epidermis was removed from the dermis. The result showed that the absorption was low (i.e., ≤ 2%) regardless of the choice of vehicle (Pirot et al.

, 1996b).

The utility of the data generated by Pirot et al.

, 1996a, 1996b, is limited due to the absence of membrane integrity measurements. Moreover, it is not clear whether the skin was occluded. The cutaneous bioavailability might be underestimated in the first study due to double stripping and in the second study, absorption is based on zinc in fresh dermis and receptor fluid, the fresh epidermis is not included.

An industry in vitro percutaneous absorption testing programme on two representative zinc compounds (ZnO and ZnSO

4

) was conducted by (Grötsch, 1999). In this programme, a solution of ZnSO

4

monohydrate and a suspension of ZnO, each at concentration of 40 mg/mL in water, were tested for cutaneous penetration and absorption through pig skin in vitro . Skin preparations measuring 1 mm in thickness with stratum corneum, stratum germinativum and blood-vessel-containing parts of the dermis were obtained from pigs using a modified dermatome. In two independent experiments for each compound seven skin preparations were mounted in

Teflon flow-through diffusion chambers which were continuously rinsed with physiological receptor fluid (0.9%

NaCl in aqua bidest with antibiotics). Following an integrity check using the marker substance caffeine, each of the test formulations were applied to six skins at a dose of 1 mg/cm 2 for 8 hours without occlusion, and subsequently washed off with a neutral shampoo. After 0, 2, 4, 6, 8, 16, 24, 40, 48, 64 and 72 hours, the cutaneous permeation was determined by quantifying zinc with atomic absorption spectroscopic analysis

(detection limit: 10 ng/mL) in the receptor fluid. The experiment was stopped at 72 hours. Zinc was analysed in the skin preparations and the rinsing fluids. In addition, blanks were measured in an unloaded control chamber.

Results are summarized in Table below.

Table 19. Dermal absorption of Zn (% of dose) through pig skin in vitro within 72 hours

Soluble ZnSO

4 a Slightly soluble ZnO a

Receptor fluid

Horny layer

Residual skin

Potentially absorbed dose

0.3 %

1.3 %

0 %

1.6% a Corrected for background levels of zinc in receptor fluid and skin.

0.03 %

12.3 %

2.6 %

14.9%

Total recoveries of applied zinc in both experiments ranged from 82.0 to 109.6%. The results of the analysis of the receptor fluid used and of the blank chambers without topical application of zinc compounds indicated that both the receptor fluid and porcine skin contain an intrinsic level of zinc. The amounts of zinc detected in receptor fluid and different layers of the skin were therefore corrected for background levels. The authors concluded that dermal penetration of zinc was below 1% based on the cumulative amount recovered from the receptor fluid at 72 hours. However, the amount retained in the skin should be regarded as being absorbed because it may become available at a later stage. Hence, the rapporteur concluded that the dermal absorption of zinc from a solution of ZnSO

4 monohydrate and a suspension of ZnO in this

1.6% and 14.9%, respectively (Grötsch, 1999). in vitro system may amount to

Animal studies

Oral

Zinc acetate was added to the diet of Sprague-Dawley rats (9/group) to reach zinc concentrations of 58 (no zinc acetate added; normal zinc concentration in “control” feed), 117, 175, 293, 410 or 664 mg/kg via the feed, corresponding to ca.

3, 6, 9, 14.5, 20.5 or 33 mg Zn/kg bw. After 28 days, the unfasted animals were dosed with

1.2  Ci of 65 ZnCl

2

( ca.

0.15 ng). Whole-body radioactivity was determined at various time points up to 11 days post-dosing using a whole-body gamma counter. In the group which received the non-supplemented diet (i.e., 58 mg Zn/kg feed) ca. 20% of the administered radioactivity was retained at 24 h post-dosing which gradually decreased to about 9% at day 11. The amount of radioactivity retained at 24 h post-dosing declined with increasing dietary zinc levels to about 13% for the group with the highest dietary zinc. In this group after 11 days only ca.

2.3% of the administered radioactivity was left. The data indicated that low dietary zinc intake results in increased zinc retention and that at higher dietary zinc levels absorption of zinc is reduced (Furchner


EC number:


1314-98-3 and Richmond, 1962).

After a pre-exposure period of 7 days, male Wistar rats, kept on a semi-synthetic diet, were dosed orally with 86

- 130  g 65 Zn as ZnCl

2

(n=15), ZnCO

3

(n=15) or Zn

5

(OH)

8

Cl

2

 H

2

O (n=20) added to a test meal. It was assumed that during the first 5 days post-dosing non-absorbed zinc was excreted via the faeces. Absorption of labelled zinc was calculated from in vivo whole-body gamma counting results over the period 5-14 days post-dosing.

The uptake was calculated to be 40, 45 or 48 % for Zn

Morros et al.

, 1992).

5

(OH)

8

Cl

2

 H

2

O, ZnCl

2

and ZnCO

3

, respectively (Galvez-

Inhalation

The rate or percentage of absorption of zinc following inhalation exposure is not available, but there are several studies investigating the zinc retention in the lung. Male and female rats were exposed to 15 mg ZnO dust/m 3

(particle size < 1  m) for 4 hours/day, 5 days/week during 1 day or for 2, 4 or 8 weeks. Animals were killed 24 hours after the last exposure and the zinc content of the lungs, liver, kidneys, tibia and femur was measured.

After 1 day of exposure the total zinc content of the lung in males and females were approximately 46 and 49

 g, respectively. In the lung, liver, kidney and bone only minimal differences in tissue zinc content was seen during the experiment. As tissue zinc levels in non-treated animals were not studied, it is not clear whether tissue zinc comes from the experimental or from dietary exposure. However, as the pulmonary zinc level did not rise throughout the study it can be assumed that pulmonary deposition is very low and/or that pulmonary clearance of zinc particles is very high (Pistorius et al.

, 1976).

In another experiment, following exposure to 4.3 mg (rat), 6.0 mg (rabbit), 11.3 mg (guinea pig) mg ZnO

(aerosol)/m 3 (aerosol mass median diameter was 0.17  m) for 2-3 hours, the pulmonary retention in rats, rabbits and guinea pigs was determined to be 11.5%, 4.7% and 19.8%, respectively (Gordon et al.

, 1992).

The lung clearance rate of zinc aerosols was determined in male Wistar rats (8/group) 0, 2, 4, 8 and 24 hours after exposure to ZnO aerosol at a concentration of 12.8 mg/m 3 (mean aerodynamic diameter of 1  m) for 17 hours. The ZnO aerosol was created by pyrolysis of a micronized zinc acetate aerosol at 500 o C. Eight animals were kept in clean air and served as controls. The lungs and trachea of the animals were removed and their zinc content was determined by flame photometry. In comparison with the controls, the lungs of exposed rats were increased in weight (presumably because of oedema), of which the increase was significant at 8 hours and even more pronounced at 24 hours. The zinc content in the trachea was not uniform but was above control values except after 24 hours. The zinc content in the lungs decreased mono-exponentially and was 7% of the initial burden after 24 hours. According to the short half-life of 6.3 hours found in this study for the pulmonary zinc content, a fast dissolution of the particles must occur, as the alveolar clearance of an inert Fe aerosol was affected by the pathological condition of the lungs (Oberdörster et al.

, 1980).

2

O

3 occurred with a half-life of about 34 hours. It was not clear whether the clearance of Zn particles from the lungs

Intratracheal instillation

In a time course experiment male Wistar rats (3/group) received a single intratracheal instillation of 0.4 ml ZnO suspension (i.e., ZnO particles < 2  m; particles appeared to form aggregates of 10-20 particles) at a dose of 100

 g Zn/rat and the rats were killed 1, 2, 3, 5, 7, 14 and 21 days after administration. In a dose-response experiment 0.4 ml ZnO suspension (ZnO particles < 2  m, but they appeared to form aggregates of 10-20 particles) was instilled in the lungs of male Wistar rats (3/group) at doses of 20, 50, 100, 200, 500 and 1000  g

Zn/rat. The rats were killed after 2 days. Control animals were included in the experiments. A significant increase in lung wet weight 1 day after instillation remained throughout the study. Only a limited portion of zinc could be retrieved in the bronchoalveolar lavage fluid (BALF). No measurable amount of exogenous zinc was observed after 5 days. The half-life of ZnO instilled in the lung was calculated to be 14 hours. In the doseresponse experiment, the lung wet weight increased with increasing dose of ZnO, two days after instillation. The results indicated that the rat lung was able to clear ZnO particles up to a dose of 50  g Zn/rat at least within two days. No measurable accumulation of zinc was observed in the liver and kidneys even at a dose of 1000  g

Zn/rat (Hirano et al.

, 1989).

Dermal

The percutaneous uptake of 65 ZnCl

2 of radioactivity emitted by 65 ZnCl

2

ZnCl

2

by the dorsal skin of the guinea pig was estimated by monitoring the decline

in at least 10 trials for each concentration tested ranging from 0.8 to 4.87 M

(pH 1.8-6.1). It appeared that the loss of radioactivity after 5 hours was less than 1% except for the trials with the lowest pH where it might have been between 1 and 2%. The study gives too little details to be used for risk assessment as cited in EU 2004, a, b, c, d, e, f (Skog and Wahlberg 1964).

Zinc oxide, zinc omadine, zinc sulphate and zinc undecylenate (131  Ci/mole of 65 Zn) were topically applied to


EC number:


1314-98-3 shaved skin on the back of rabbits. Each application consisted of 2.5 mg zinc compound containing 5  Ci 65 Zn.

Two animals received one application on four skin areas left of the spine, while the four skin areas on the right side received two applications, the second one 24 hours after the first one. The rabbits were killed 6 and 24 hours after the second application. One rabbit served as the control. No significant differences were found in the amount and location of 65 Zn in skin treated with 4 different zinc compounds. High concentrations of 65 Zn were observed in the cortical and cutical zones of the hair shaft, being the highest in the keratogenous zone.

Accumulation of 65 Zn in epidermis was very low but heavy in the subdermal muscle layer. No difference in the rates of absorption and concentrations of zinc compounds with different oil/water solubility, pH, and molecular weight were seen. It was therefore suggested that the major mode of 65 Zn uptake in skin is by diffusion through the hair follicles due to the heavy localization of the author, this emphasizes that chemical differences in the compounds may not play a very important role in the skin uptake of 65

65 Zn primarily in the hair shaft and hair follicles. According to

Zn. No data were given on systemic absorption (Kapur et al.

, 1974).

The dermal absorption of 65 Zn from ZnCl

2

and ZnO was studied by applying zinc preparations under occlusion on the shaven intact skin on the back of male Sprague-Dawley rats. The zinc absorption, being the ratio between

65 Zn-activity in the carcass, liver and gastrointestinal tract, and the 65 tract, skin and bandage, was reported to range from 1.6 to 6.1%. It should be noted that the higher percentages

(3.6 to 6.1%) were achieved after application of ZnCl

2

Zn-activity in carcass, liver, gastrointestinal

in acidic solution (pH = 1). Less acidic solutions with

ZnCl

2

or with ZnO resulted in a dermal absorption of less than 2%. In this study, only the absorption into the body, excluding the skin, was determined. No data were available as to the effect of ZnCl on dermal integrity (Hallmans and Lidén, 1979).

2

solutions with pH = 1

Topical application of ZnCl

2

in an oil vehicle to pregnant Sprague-Dawley rats which were fed a zinc-deficient diet for 24 hours resulted in an increase in plasma concentration of zinc cations to normal or slightly above normal levels. The absorbed fraction was not determined therefore it can be concluded that dermal absorption is possible but no quantification can be given (Keen and Hurley, 1977).

The application of ZnO dressings (containing 250  g Zn/cm 2 ) to rats for 48 hours with full-thickness skin excision resulted in a 12% delivery of zinc ions from the dressing to each wound, while application of ZnSO

4 dressings (containing 66  g Zn/cm 2 ) resulted in a 65% delivery of ions to each wound. The data suggest that the application of ZnO resulted in sustained delivery of zinc cations causing constant wound-tissue zinc cation levels due to its slow dissociation rate, while the more water soluble ZnSO

4

delivers zinc ions more rapidly to the wound fluid with subsequent rapid transferral into the blood (Agren et al.

, 1991a).

Distribution

The highest levels of radioactivity were found in the small intestine followed by the kidney, liver and large intestine six hours after a single oral administration of 0.1  Ci of 65 Zn 2+ as ZnCl

2

to Wistar rats. Smaller amounts were found in the lungs and spleen. Fourteen days after administration, the highest levels of radioactivity were found in the hair, testicles, liver and large intestines (Kossakowski and Grosicki, 1983).

Organs with high zinc concentrations (ranging from 20 to 60 mg/kg fresh weight) are liver, gut, kidney, skin, lung, brain, heart and pancreas as cited in EU RARs (Bentley and Grubb, 1991; He et al.

, 1991; Llobet et al.

,

1988). High concentrations of zinc were also detected in the retina and in sperm as cited in EU RARs (EU 2004, a, b, c, d, e, f; Bentley and Grubb, 1991).

Metabolism

As described in EU RARs, zinc is primarily bound to organic ligands rather than existing free in solution as a cation (Gordon et al.

, 1981). It is found in diffusible and non-diffusible forms in the blood. About 66% of the diffusible form of zinc in the plasma is freely exchangeable and loosely bound to albumin (Cousins et al.

, 1985).

A small amount of the non-diffusible form of zinc is tightly bound to 

2

-macroglobulin in the plasma and is not freely exchangeable with other zinc ligands. Zinc is incorporated into and dissociated from  only in the liver (Henkin et al.

, 1974).

2

-macroglobulin

Excretion

After a single oral dose of 86 – 130  g of 65 Zn as ZnCl

2

, ZnCO

3

or Zn

5

(OH)

8

Cl

2

 H

2

O, male rats eliminated from the body with a rate of about 1.7% of the absorbed dose during day 5 to 14 post-dosing as determined from stool, urinary and in vivo whole-body gamma counting results. Male rats who received 25 mg ZnCO

3

65 Zn

/kg feed or

100 mg Zn

5

(OH)

8

Cl

2

 H

2

O/kg feed for 14 days, the radioactivity from a subcutaneous dose of 37 kBq of 65 ZnCl disappeared from the body with a rate of approximately 1% during the period 5 to 14 days post dosing (Galvez-

2

Morros et al.

, 1992).


EC number:


1314-98-3

As described in EU RARs (EU RAR, 2004a-f) within certain limits, mammals can maintain the total body zinc and the physiologically required levels of zinc in the various tissues, constant, both at low and high dietary zinc intakes. The sites of regulation of zinc metabolism are: absorption of zinc from the gastrointestinal tract, excretion of zinc in urine, exchange of zinc with erythrocytes, release of zinc from tissue, and secretion of zinc into the gastrointestinal tract. Regulation of gastrointestinal absorption and gastrointestinal secretion most likely contributes the most to zinc homeostasis. In spite of the mechanism for whole-body zinc homeostasis, a regular exogenous supply of zinc is necessary to sustain the physiological requirements because of the limited exchange of zinc between tissues ((EU RAR, 2004a-f). It has been hypothesized by Hempe and Cousins (1992) that zinc entering the luminal cells is associated with cysteine-rich intestinal protein (CRIP), a diffusible intracellular zinc carrier, and that a small amount is bound to metallothionein; however, as the luminal zinc concentration increases, the proportion of cytosolic zinc associated with CRIP is decreased and zinc binding to metallothionein is increased. CRIP binds 40% of radiolabelled zinc entering the intestinal cells of rats when zinc concentration is low; but only 14% when the concentration is high.

Zinc is initially concentrated in the liver after ingestion, and is subsequently distributed throughout the body.

When plasma zinc levels are high, liver metallothionein synthesis is stimulated, which facilitates the retention of zinc by hepatocytes (EU RAR, 2004a-f).

5.1.2. Human information

Absorption

Oral

A wide range of absorption (8-80%) is observed in humans (EU RAR, 2004a-f). This is likely due to differences in eating habits (Hunt et al.

, 1991; Reinhold et al.

, 1991; Sandstrom and Sandberg, 1992). Persons with adequate nutritional levels of zinc absorb approximately 20-30% of all ingested zinc. Those who are zincdeficient absorb greater proportions of administered zinc while persons with excessive zinc intake, gastrointestinal uptake can be less (Babcock et al.

, 1982; EU RAR, 2004a-f).

Zinc absorption in the gastrointestinal tract occurs throughout the entire small intestine with the highest rate in the jejunum and the rate of total absorption appears to be concentration-dependent (Lee e t al ., 1989) as cited EU

RARs (EU RAR, 2004a-f).

The zinc absorption process in the intestines includes both passive diffusion and a carrier-mediated process

(Tacnet et al., 1990). At low zinc concentrations CRIP is involved in this process. This protein binds zinc entering the intestinal cells from the lumen but this process appears to be saturable. Metallothionein, a metalbinding protein (also rich in cystein), may be involved at higher zinc concentrations (Gunshin et al.

, 1999;

Hempe and Cousins et al.

, 1992; Struniolo et al.

, 1991). Zinc cations can induce metallothionein production in intestinal mucosa cells (Richards and Cousins, 1975; EU 2004 a-f).

The intestinal absorption following a single oral administration of 65 ZnCl

2

to 6 groups of 5 healthy adult volunteers has been determined by comparison of whole body radioactivity counting and faecal excretion data.

The individuals fasted overnight prior to dosing. Approximately 55% of the administered 65 ZnCl

2

was absorbed at doses of 18, 45 and 90  mol of zinc (i.e., approximately 1.2, 2.9 or 5.8 mg Zn). The absorption was reduced with increasing dose, indicating that zinc absorption is saturable. At test dose levels of 180, 450 and 900  mol

(i.e., approximately 11.6, 29 or 58 mg Zn), only 51, 40 and 25% of the 65 Zn was absorbed, respectively.

Additional studies in 15 human volunteers with various intestinal diseases indicated that absorption of zinc occurred mainly in the proximal parts of the intestine, This study suggests that uptake levels vary maximally by a factor of 2 in healthy persons with intake levels differing by a factor of 10 (Payton et al.

, 1982).

The absorption of orally administered 65 Zn was studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases: Prior to the start of the study 10 patients were admitted to a metabolic ward and put on a fixed daily diet containing 8-13 mg Zn. In the first phase, all patients were studied for 21 days after receiving a single oral dose of 3-18  Ci of 65 Zn (i.e., approximately 0.4 to 1.2 ng Zn) as ZnCl

2

after an overnight fast. In the second phase, which started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received a placebo. To study the effect of additional zinc intake on the elimination of previously sequestered radioactivity, in the third phase of the study 14 patients continued on the placebo while 36 received

ZnSO

4

(100 mg Zn/day) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of the 65 Zn tracer. The results of phase two and three are described under excretion. Total body retention and activity in plasma and red cells were measured for all patients throughout the study. It was estimated that for the ten in-patients ca.

55% of the administered radioactivity was absorbed


EC number:


1314-98-3 while for the whole group of 50 patients the absorption was approximately 60 %. From the study description it is not clear whether the radioactivity was administered as pure radioactive ZnCl

2

or whether it was diluted with unlabelled ZnCl

2

. The authors stated that “patients were given 3 to 18  Ci carrier free calculation of the dose of 65

65 Zn”, therefore for the

Zn in terms of nanogram zinc, it has been assumed that all zinc administered was in fact radiolabelled zinc (Aamodt et al.

, 1982).

The absorption of zinc from soluble zinc acetate, zinc sulphate, zinc aminoate, zinc methionine and insoluble zinc oxide were compared in ten human volunteers who were dosed orally with 50 mg zinc in various forms separated by two week intervals. The bioavailability of zinc from the various forms was compared on the basis of plasma zinc levels and area under the plasma curve analysis. Plasma peak levels were observed after about

2.5 h for all forms, but maximal plasma zinc concentration amounted to 221 and 225  g/dL for the acetate and the sulphate form while the peak plasma level for zinc from the oxide was only 159  g/dL. When AUC values for the different zinc forms were compared, it appeared that the bioavailability of insoluble ZnO was about 60% of the bioavailability of the soluble forms. Information on absolute bioavailability was not obtained (Prasad et al.

, 1993).

A study to measure the absorption half-life of zinc as ZnSO mg zinc as ZnSO

4

was administered once to 10 healthy young men. Serum concentrations were measured frequently during a total investigation time of 8 hours. A mean maximum concentration of 8.2  mol Zn/L serum was found after 2.3 hours (t max after 1.4 hours during the absorption phase before t

4

was performed. Gelatine capsules containing 45

). There was evidence of an enteral recirculation, the first rebound effect appeared max

was reached, and exhibited mean reabsorption rates of

70% of the dose given. The subsequent ones (max. of 5) appeared at regular intervals of 1.2 hours with a decrease of the quantity reabsorbed. The absorption half-life of zinc administered as ZnSO et al.

, 1991).

4

was 0.4 hours (Nève

Factors that influence the gastrointestinal absorption of zinc cations include ligands (for example a decreased zinc absorption may occur by intake of plant proteins, such as soy and phytate), by intake of alcohol, use of

EDTA or other trace elements in the diet (EU 2004 a-f). Also the zinc status of the body, the endogenous zinc secretion into the intestinal lumen via epithelial cells, bile and pancreatic secretion, and the intracellular transport have an influence on the zinc absorption in the gastrointestinal tract (Cunnane, 1988 ) ; Flanagan et al.

,

1983). However, the mechanism by which zinc is transferred to or across the mucosal surface of the microvilli is unknown (Cousins, 1989).

Inhalation

Elevated zinc concentrations in blood and urine of persons occupationally exposed to ZnO fumes suggest that there is some pulmonary absorption, but no quantitative human data are available (Hamdi et al.

, 1969 and

Trevisan et al.

, 1982 cited in EU RAR, 2004a-f).

Data on the particle size distribution of zinc aerosol in three different industry sectors, i.e. the galvanising sector

(three plants, 4 samples each), the brass casting sector (two plants, 3 and 4 samples respectively) and the zinc oxide production sector (one plant, 10 samples), has been provided using personal cascade impactors with cutoff diameters of 0.52, 0.93, 1.55, 3.5, 6.0 and 21.3  m, and a final filter diameter of 0.3  m (Groat et al.

, 1999;

EU 2004, a-f). These data served as input for the Multiple Path Particle Deposition Model (MPPDep version

V1.11; Freijer et al.

, 1999) in order to estimate the airway deposition (in head, tracheobronchial and pulmonary region) for workers, by using:

 The human – five lobar lung model;

 A polydisperse particle distribution (i.e. this distribution contains a wide range of particle sizes), by taking the mean size distribution of the 10 samples for zinc oxide production (MMAD 15.2  m, GSD 4.0). Using this MMAD and GSD for the total polydisperse distribution is preferred above treating the polydisperse particles on individual impactor stages (with given cut-off diameters) as being monodisperse particles, also because the maximum particle size in the MPPDep model (20  m) is lower than the largest size fraction of the cascade impactor (21.3  m).

 Both the oral breathing and the oronasal (normal augmenter) mode, but not the nasal breathing mode. The latter is considered to present an underestimate because (1) many people are oronasal or oral breathers, independent of their activities, (2) people with a cold will not normally breath nasally and (3) with heavy exercise, short-term deep oral breathing will occur, resulting in increased deep pulmonary deposition.

 The possibility of inhalability adjustment for the oronasal augmenter. Inhalability is defined as that fraction of particles in an aerosol that can enter the nose or mouth upon inhalation. It must be noted that inhalability is different from respirability (which relates to the deposition of particles after making their entrance inside the airways). If “inhalability adjustment” is “off”, the calculations start by assuming that the airflow is in


EC number:


1314-98-3 line with the direction of the nasal entrance. However, in reality this will not be the case because the airflow has to make turns to enter the nose. This results in losses that are larger with increasing particle size.

Ménache et al., (1995) described the relationship between exposure concentration and concentration at the entrance of the airways for laboratory animals and humans as cited in EU RARs (EU RAR, 2004a-f).

 A tidal volume and breathing frequency corresponding to the default breathing rate of 10 m 3 for an 8-hr shift (1100 mL and 20 breaths/min, respectively).This breathing rate is more representative for light exercise activities than for more moderate or heavy exercise activities (EPA, 1997), which can be expected to take place in the zinc industry. Therefore, also a non-default tidal volume and breathing frequency corresponding to a breathing rate of 19 m 3 for an 8-hr shift have been taken (1700 mL and 23 breaths/min, respectively, based on a breathing volume of 40 L/min for moderate exercise activities (EPA, 1997)). It must be noted that at a minute volume <35.3 L/min for normal augmenters breathing is only through the nose, while at a minute volume  35.3 mL/min there is combined nose and mouth breathing. For oral breathers, breathing is always only through the mouth, independent of the minute volume used.

The results of the MPPDep modelling are given in Table below . It must be noted that the MPPDep only models deposition, not clearance and retention.

Table 20. Deposition fractions for oral breathers and for oronasal augmenters, using a polydisperse particle distribution (MMAD 15.2



m, GSD 4.0)

Inhalability

Adjustment

Tidal volume

(mL)

Breaths

(min -1 ) Head

Deposition region

Tracheobronchial

Pulmonary Total

Oral

Oronasal

Oronasal

Off

Off

On

1100

1700

1100

1700

1100

1700

20

23

20

23

20

23

0.638

0.676

0.927

0.804

0.519

0.585

0.071

0.100

0.011

0.064

0.011

0.063

0.139

0.101

0.021

0.064

0.021

0.064

0.848

0.877

0.960

0.932

0.551

0.713

From the above table it can be seen that for oral as well as for oronasal breathers the largest part of the deposition takes place in the head region when inhalability adjustment is “off”, irrespective of the breathing rate.

When inhalability adjustment is “on” the head region deposition is reduced. However, as stated above, the corrections for inhalability of particles is based on relationships derived by Ménache et al., (1995). For humans this is based on experiments with 4 healthy adult volunteers. From the available data it is not possible to conclude that this correction is valid for all human subjects in all situations (children, elderly, exercise activity, etc). Therefore it is reasonable to estimate the deposition with the inhalability adjustment “off” which leads to a worst case scenario and therefore the inhalability adjustment “on” will not be considered further.

The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion (not the case for oral breathers) or by translocation to the gastrointestinal tract (half-life 10 min). A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. This is concluded to be almost the same for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx

(mainly by mucociliary clearance (half-life 100 min)) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Higher uptake rates may be assumed for the pulmonary region than for the head and tracheobronchial region.

Once translocated to the gastrointestinal tract, uptake will be in accordance with oral uptake kinetics. Hence, for the part of the material deposited in head and tracheobronchial region that is cleared to the gastrointestinal tract, the oral absorption figures 20% for soluble zinc compounds and 12% for slightly soluble and insoluble zinc compounds can be estimated. However, there are no data available on zinc to estimate the part that is cleared to the gastrointestinal tract and the part that is absorbed locally in the different airway regions. With respect to the latter, there are some data available for radionuclides. After instillation of small volumes (2-3  L for rats, 10  L for hamsters, 0.3 mL for dogs) of solutions or suspensions of radionuclides into each region of the respiratory tract, retention and absorption into blood was measured. For the more soluble chemical forms (a.o. citrate and nitrate) absorption values of 4.8-17.6% in the nasopharynx, 12.5-48% in the tracheobronchial region and up to

100% in the pulmonary region was found. For the slightly soluble chemical forms (i.e. oxide) retention and absorption in the nasopharynx and tracheobronchial region was negligible (ICRP, 1994). There are no data on how the solubility of the different chemical forms of the radionuclides compares to the solubility of the soluble


EC number:


1314-98-3 zinc compounds. Although the applicability of the radionuclide figures to the zinc compounds is not quite clear, it is probably a reasonable worst case scenario to take the upper values found (i.e. 20, 50 and 100% in head, trachebronchial and pulmonary region, respectively) for local absorption of the soluble zinc compounds (zinc chloride and zinc sulphate). For the slightly soluble and insoluble zinc compounds (zinc oxide, zinc phosphate and zinc metal) it is probably safe to assume negligible absorption for the head and tracheobronchial region and

100% absorption for the pulmonary region. This is supported by the findings in the study by Oberdörster et al.,

(1980), where the dissolution half-life of 1  m diameter zinc oxide particles in the deep lung was approximately

6 hrs. Given that the clearance to the gastrointestinal tract occurs within a time frame of minutes (10-100 min in head and tracheobronchial region), there will be no significant dissolution in these areas. Furthermore, most of the particles in these areas will have a diameter >1  m, thus dissolution half-lives for these larger particles will be longer. Based on the above, Table below describes the assumptions used in estimating the absorption by inhalation.

Table 21. Assumptions used for estimating the inhalation absorption

Soluble zinc compounds

(e.g., ZnCl

2

, ZnSO

4

)

Slightly soluble to insoluble zinc compounds

(e.g., Zn; ZnO; Zn

3

(PO

4

)

2

)

Fraction absorbed in airway region

20% head

50% tracheobronchial

100% pulmonary

0% head

0% tracheobronchial

100% pulmonary

Fraction cleared to GI tract, followed by oral uptake kinetics

80% head x 20%

50% tracheobronchial x 20%

0% pulmonary

100% head x 12%

100% tracheobronchial x 12%

0% pulmonary

By applying the above assumptions to the deposition fractions (Table 21) , the % of inhalatory absorption of the soluble zinc compounds (zinc chloride and zinc sulphate) and slightly soluble to insoluble zinc compounds (zinc oxide, zinc phosphate and zinc metal) can be estimated as described in Table below.

Table 22. Percentage estimations for inhalation absorption of soluble, slightly soluble and insoluble zinc compounds

Inhalability Tidal volume

(mL)

Breaths

(min -1 )


(e.g., ZnCl

2

, ZnSO

4

)

Slightly soluble to insoluble zinc compounds

(e.g., Zn; ZnO; Zn

3

(PO

4

)

2

)

Oral

Oronasal off off

1100

1700

1100

1700

20

23

20

23

41.1

40.4

36.1

39.2

22.4

19.4

13.4

16.8

Inhalation absorption for the soluble zinc compounds (zinc chloride and zinc sulphate) is at maximum 40%, while for the slightly soluble and insoluble zinc compounds (zinc oxide, zinc phosphate and zinc metal) inhalation absorption is at maximum 20%. These values are assumed to be a reasonable worst case and are thought to cover existing differences between the different zinc industry sectors with respect to the type of activities (therefore breathing rate) and the particle size distribution.

Dermal

Zinc has been reported to be absorbed through damaged or burned skin however in the absence of quantitative data it is difficult to assume that zinc can be absorbed through intact skin (EHC, 1996).

An increase in serum zinc levels was observed in 8 patients suffering from second and third degree burns, who were treated with adhesive zinc-tape (ca. 7.5 g ZnO/100 g dry weight). The maximum value (up to 28.3

 mol/litre) was reached within 3-18 days during treatment. It is noted that the absorption through intact skin could not be assessed (Hallmans, 1977).

The systemic absorption from topical application of 40% zinc oxide ointment (with petrolatum) was investigated in 6 healthy subjects in a cross-over study. On two separate days, one week apart the subjects received a topical application of 100 g of the 40% zinc oxide ointment or 60 g of control ointment (100% white petrolatum base) to the chest, upper legs and lower legs (exposed skin area: not specified; occlusion: not specified) for 3 hours. Each subject fasted for 12 hours before treatment started (only water ad libitum ). During the study no food or water was consumed. Blood samples were taken after the 12 hr-fast (baseline value), and at


EC number:


1314-98-3

1, 2 and 3 hours after the start of the topical application. Mean serum zinc concentrations at these time points were 107.3, 116.1, 105.3 and 112.6  g/dL for the zinc ointment and 115.2, 103.5, 105.5 and 110.5 for the control ointment, respectively. Normal serum zinc concentrations were considered to be in the range of 68 to

136  g/dL. An increase in serum zinc over the baseline value was observed in 4/6 subjects. In 3 of them, the rise was most pronounced after 1 hr. In 2/6 no increase was observed throughout the treatment. Overall, 1 hour after application, there was a mean serum zinc increase of 8.8  g/dL over the baseline. This represented an 8.2% rise in serum zinc which was not statistically significant (Derry et al., 1993).

The systemic absorption was also investigated in patients receiving total parenteral nutrition (TPN) for a minimum of 3 days prior to the start of the experiment. TPN is known to result in zinc deficiency (mean decrease 6.6  g/dL/week), and the longer the period of TPN without zinc supplementation, the greater the decrease in serum zinc concentration. In a controlled, cross-over study (on two separate days, one week apart) 6 patients received a topical application of 15 g of the 40% zinc oxide ointment onto the upper legs (10x15 cm) once daily for 8 consecutive days under occlusion. Blood samples were taken before treatment (baseline value), at 4, 6 and 8 days (just prior to application), and at day 10. The mean baseline level of the patients (88.6  g/dL) differed significantly from the mean baseline level of the healthy subjects. The mean zinc concentration in the 3 patients that completed the study remained relatively stable over the 10 day period (78-93  g/dL) (Derry et al.

,

1993).

It can be concluded that topical applications of 40% zinc oxide ointment did not result in a significant increase in serum zinc concentration in healthy human subjects over a 3-hr period nor in TPN-patients over 10 days. The authors suggested that after topical application, zinc is locally absorbed and stored in the hair follicles where it is relatively unavailable for immediate systemic absorption in subjects with normal serum zinc concentrations. In subjects that are hypozincemic, there is absorption from the storage depot at a rate sufficient to prevent a decline in serum zinc concentration. The authors concluded that the 3-hr sampling time in normal subjects may have been insufficient to allow for appreciable systemic absorption from the storage depot (Derry et al.

, 1983).

When ZnO-mediated occlusive dressings (25% w/w; 4x5 cm) were applied to the lower arm of 10 healthy volunteers for 48 hours it appeared that the mean release rate of zinc to normal skin was 5  g/cm 2 /hour. After treatment of 5 other volunteers with the ZnO dressings for 48 hours the zinc content was significantly increased in the epidermis and in the accumulated blister fluid (to model percutaneous absorption, suction blisters were used). It should be noted, however, that the zinc penetration was enhanced during the formation of blisters, indicating that the barrier function was impaired (Agren, 1990).

In another study, five human volunteers were exposed to different occlusive ZnO dressings (with hydrocolloid vehicle or gum rosin). After 48 hours, suction blisters on treated skin were raised and zinc concentration in blister fluid was determined. Furthermore the zinc concentration in the stratum corneum (10 successive tape strippings) was determined. The absorbed amount could not be determined from the data presented but it appeared that the vehicle is an important factor for zinc penetration (Agren, 1991b).

Distribution

After absorption from the gastrointestinal tract, the zinc is bound in plasma primarily to albumin and then transported to the liver and subsequently throughout the body. The normal plasma zinc concentration is ca. 1 mg/L, the total zinc content of the human body (70 kg) is in the range of 1.5-2 g (ATSDR, 2005).

Zinc is found in all tissues and tissue fluids and it is a co-factor in over 200 enzyme systems. In humans, the major part of total body zinc is found in muscle and bone, approximately 60% and 30%, respectively (Wastney et al.

, 1986). Under normal conditions, the highest zinc concentration per tissue weight is found in bone, hair and in the prostate (Cleven et al.

, 1993).

The distribution of zinc in humans appears to be influenced by age. The zinc concentration levels increases in the liver, pancreas and prostate and decreases in the uterus and aorta with age. Levels in kidneys and heart peak at approximately 40-50 years of age and then declines. Levels in the aorta decline after 30 years of age

(Schroeder et al.

, 1967).

The tissue uptake of injection of 15  Ci

65 Zn (as zinc chloride) was determined in adult male Wistar rats after intraperitoneal

65 Zn. The liver displayed the greatest uptake for zinc ions, followed by the kidney, pancreas, spleen, ileum, lung, heart, bone, testis, blood cells, muscle and brain. Additional data on Zn uptake by the brain indicates that the blood-brain barrier is minimally permeable to zinc cations (Pullen et al.

, 1990).

Eight hours following intravenous administration of 65 [Zn]-chloride to rabbits, tissue levels were highest in the liver, intestine and kidney with levels being  10%/g in tissue (Lorber et al.

, 1970).


EC number:


1314-98-3

Metabolism

Zinc is mostly bound to organic ligands rather than existing free in solution (Gordon et al.

, 1981). Zinc is found in diffusible and non-diffusible forms in the blood and about 66% of the diffusible form of zinc in the plasma is freely exchangeable and loosely bound to albumin (Cousins, 1985). A small amount of the non-diffusible form of zinc is tightly bound to 

2

-macroglobulin in the plasma and is not freely exchangeable with other zinc ligands. Zinc is incorporated into and dissociated from 

2

-macroglobulin only in the liver (Henkin, 1974).

Excretion

In humans, the faecal zinc consists of un-absorbed dietary zinc and endogenous zinc from bile, pancreatic juice and other secretions. About 70-80% of the ingested amount of zinc is excreted via faeces (5 to 10 mg/day depending upon the dietary zinc concentration) (Spencer et al.

, 1976; Venugopal and Lucky, 1978; Reinhold et al.

, 1991; Wastney et al.

, 1986). In humans, of the amount of zinc consumed, about 10% is lost through urine

(approximately 200 to 600  g zinc/day). The urinary zinc excretion appears to be sensitive to alterations in the zinc status (Babcock et al.

, 1982; Aamodt et al.

, 1982).

Saliva, hair loss, mother’s milk and sweat appear to be minor routes for zinc excretion. In tropical climates about 2-3 mg Zn/day may be lost in sweat (Venugopal and Lucky, 1978; Rivlin, 1983; Prasad et al.

, 1963;

Rossowka and Nakamoto, 1992; Henkin et al.

, 1975).

In humans with no excessive intake of zinc, the half-life of absorbed radio-labelled zinc ranges from 162 to 500 days. After parenteral administration of 65 Zn, half-lives ranged from 100 to 500 days (Elinder, 1986).

Sixteen healthy adult human volunteers were given oral administration of 92  mol of 65 Zn (as ZnCl

2

) to investigate the body retention of zinc at 7 to 10 days after dosing. The results showed that about 10% of the initially absorbed amount of zinc was excreted during the first 10 days post dosing. Thirty other volunteers were dosed with 18 to 900  moles of dosing.

65 Zn. Table below shows the elimination data following 10 to 60 days post-

Table 23. Elimination data obtained following thirty humans dosed with 18 to 900



moles of

65

Zn

Dose group

(  moles; (mg))

18 (1.2)

45 (2.9)

90 (5.8)

180 (11.6)

450 (29)

900 (58) a significantly different from the 18  moles group

Excretion rate

(% of remaining Zn/day )

0.44

0.62

0.37

0.49

0.37

0.74

a

Biological half-life

(days)

157

111

186

141

186

93

The excretion rates for the 18 to 450  moles dose groups were not significantly different. The 900  mole dose group showed a significant increase in elimination rate (Payton et al.

, 1982).

The effect on excretion following oral administration of radiolabelled zinc as zinc chloride in 50 patients with taste and smell dysfunction was investigated. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving a single oral dose of 3-18  Ci of 65 Zn (i.e., approximately 0.4 to

1.2 ng zinc) as ZnCl

2

after an overnight fast. In the second phase, which started after 21 days and continued for

290 to 440 (mean 336) days, all 50 patients received placebo. To study the effect of additional zinc intake on elimination of previously sequestered radioactivity, in the third phase of the study 14 patients continued on placebo while 36 received ZnSO

4

(100 mg Zn/day) for 112 to 440 (mean 307) days. In the controlled clinical trial of phases two and three, observations were made to see the effects of zinc on retention of the 65 Zn tracer.

The results from the first phase of the study are described under absorption section. Total body retention and activity in plasma and red cells were measured for all patients throughout the study. About one-third of the absorbed radioactivity was eliminated from the body with a half-life of ca.

19 days, while after about 100 days post dosing the remainder of the absorbed dose was eliminated with a biological half-life of 380 days (i.e. phase two of the study). During the third phase patients receiving ZnSO

4

showed an accelerated loss of total body 65 Zn

(half-life ca.

230 days) which was significantly different (P>0.001) from half-life values during placebo


EC number:


1314-98-3 treatment. Accelerated loss of 65 Zn from the thigh was apparent immediately while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean 65 Zn activity from red blood cells (Aamodt et al.

, 1982). From the study description it is not clear whether the radioactivity was administered as pure radioactive zinc chloride or whether it was diluted with unlabelled zinc chloride. As the authors stated that “patients were given 3 to 18  Ci carrier free 65 Zn” for the calculation of the dose of 65 Zn in terms of nanogram zinc, it has been assumed that all zinc administered was 65 Zn (Aamodt et al.

1982).

In ten of the patients from the study described above (Aamodt et al.

1982), the kinetics of more detail by Babcock et al.

(1982). These patients received a fixed diet containing 8 – 13 mg Zn per day for 4 to 7 days before and after the single 65

65 Zn was studied in

Zn dose, followed by 290-440 (mean 336) days of non-restricted diet, followed by an additional intake of 100 mg/day of non-radioactive zinc ion (as ZnSO

4

) over the next 112-440 days (mean 307). The overall kinetic parameters of these 10 patients did not differ from those of the other patients (Aamodt et al.

, 1982). The authors further submitted retention-time curve data for whole body, plasma, red blood cells, liver and thigh to a multi-compartment kinetic model. From this model analysis it could be demonstrated that the increase in elimination of Zn during the third phase of the study by Aamodt et al.

(1982) can be ascribed entirely to the change in parameters: reduction in absorption in the gastrointestinal tract (5-fold: from 43% absorption at the beginning of the study to 9% during the period in which patients were dosed with

ZnSO

4

) and to an increase in the urinary elimination rate (about 2-fold upon administration of ZnSO

4

during phase three of the study). Michaelis-Menten type saturation mechanisms were adequate to explain the observed parameter changes. These changes also accounted for the observed mean plasma zinc mass increase of only 37% above pre-load levels in face of an 11-fold increase in zinc intake (from ca.

10 mg/day to ca.

110 mg/d)

(Babcock et al.

, 1982). From this model analysis it was estimated that the total body Zn contents of these 10 patients at the start of the study was 1.4 g. Babcock et al.

(1982) indicated that normally the body contents of zinc is in the range of 2.1 to 2.5 g. This may indicate that the patients studied by Babcock et al.

(1982) and possibly by Aamodt et al.

(1982) were deficient in total body zinc.

5.1.3. Summary and discussion of toxicokinetics

As described in Section 5 General considerations (assumptions), zinc compounds release, depending on their solubility, zinc cations which determine the biological activity of the respective zinc compounds.

Sufficient data is available on the soluble zinc compounds zinc chloride and zinc sulphate and on the slightly soluble zinc compounds ZnO and ZnCO

3

.

Zinc is an essential trace element which is regulated and maintained in the various tissues mainly by the gastrointestinal absorption and secretion during high and low dietary zinc intake and because of the limited exchange of zinc between tissues, a constant supply of zinc is required to sustain the physiological requirements.

The zinc absorption process in the intestines includes both passive diffusion and a carrier-mediated process. The absorption can be influenced by several factors such as ligands in the diet and the zinc status. Persons with adequate nutritional levels absorb 20-30% and animals absorb 40-50%. Persons that are zinc deficient absorb more, while persons with excessive zinc intake absorb less.

For the soluble zinc compounds, the available information suggests an oral absorption value of 20%. This value can be considered as the lower bound range at adequate nutritional levels. The oral absorption of the slightly soluble zinc oxide has been shown to be 60% of that of the soluble zinc compounds. This corresponds to approximately 12-18%. No oral absorption information is available for the remaining slightly soluble and insoluble zinc compounds (i.e., ZnO, Zn(OH)

2

, Zn

3

(PO

4

)

2

, ZnCO

3

, Zn, ZnS). However, considering that these substances have lower water solubility than ZnO, it can be conservatively assumed that the oral absorption of these compounds is ≤ 12%.

Animal data suggests that there is pulmonary absorption following inhalation exposure. Half-life values of 14 and 6.3 hours were reported for dissolution of zinc oxide. The absorption of inhaled zinc depends on the particle size and the deposition of these particles therefore data was provided on the particle size distribution of zinc aerosol from three different industry sectors. The particle size distribution data was evaluated by using a multiple path particle deposition (MPPDep) model. This model revealed that for zinc aerosols the largest part of the deposition is in the head region and much less in the tracheobronchial and pulmonary region. Although most of the material deposited in the head and tracheobronchial region is rapidly translocated to the gastrointestinal tract, a part will also be absorbed locally.

Based on data for local absorption of radionuclides in the different airway regions, it can be assumed that the local absorption of the soluble zinc compounds will be approximately 20% of the material deposited in the head region, 50% of the material deposited in the tracheobronchial region and 100% of the material deposited in the pulmonary region. For the slightly soluble and insoluble zinc compounds a negligible absorption can be


EC number:


1314-98-3 assumed for materials deposited in the head and the tracheobronchial region. 100% of the deposited slightly or insoluble zinc compounds are assumed to be absorbed in the pulmonary tract. The deposited material will be cleared via the lung clearance mechanisms into the gastrointestinal tract where it will follow oral absorption kinetics. Therefore the inhalation absorption for the soluble zinc compounds is a maximum of 40% and for the slightly soluble and insoluble zinc compounds inhalation absorption is at a maximum of 20%. These values can be assumed as a reasonable worst case, because they are considered to cover existing differences between the different zinc industry sectors with respect to the type of exercise activities (and thus breathing rate) and particle size distribution.

The available information from in vivo as well as the in vitro studies suggests the dermal absorption of zinc compounds through intact skin to be less than 2%. In vitro studies that estimated dermal absorption values only on the basis of the zinc levels in the receptor medium without taking into account the zinc present in the stratum corneum appear to underestimate absorption values derived from in vivo studies. Such zinc trapped in the skin layers may become systemically available at a later stage. Quantitative data to evaluate the relevance of this skin depot are however lacking. Given the efficient homeostatic mechanisms of mammals to maintain the total body zinc and the physiologically required levels of zinc in the various tissues to be constant, the anticipated slow release of zinc from the skin is not expected to disturb the homeostatic zinc balance of the body. Considering the available information on dermal absorption, the default for dermal absorption of all zinc compounds (solutions or suspensions) is 2%. Based on the physical appearance, for dust exposure to zinc and zinc compounds a 10fold lower default value of 0.2% is a reasonable assumption.

Zinc appears to be distributed to all tissues and tissue fluids and it is a cofactor in over 200 enzyme systems. The excretion of zinc is primarily via faeces, but also via urine, saliva, hair loss, sweat and mothers-milk.

5.2. Acute toxicity


5.2.1.1. Acute toxicity: oral

Acute oral toxicity studies are available in rats and mice on zinc compounds across all water solubilities.

Acute oral toxicity studies have been conducted on soluble zinc compounds (zinc chloride, zinc sulphate and zinc bis(dihydrogen phosphate)) and on the slightly soluble (zinc oxide, zinc phosphate, zinc metal) and insoluble zinc compound (zinc sulphide).

Table 24. Overview of experimental studies on acute toxicity after oral administration according to decreasing water solubility of zinc compounds

Test

Substance

Study

Type

Zinc chloride Acute oral

Zinc chloride Acute oral

Zinc sulphate Acute oral



Species Endpoint Exposure Result

LD

50

Rat LD

50

Single dose 1,100 mg/kg bw

Mouse

Rat

Mouse

Rat

LD

50

LD

50

LD

50

LD

50


50, 100,

1,000 or

3,000 mg/kg bw

No information available

200- 2000 mg/kg bw

920 mg/kg bw

926 mg/kg bw

1,000

–

2,000

Remarks



2 (reliable with restrictions) supporting study used in RAR,

(EU 2004 e)


2 (reliable with restrictions) supporting study

Reference

Domingo J L,

Llobet J M,

Paternain J L and Corbella

J (1988a)

Domingo J L,

Llobet J M,


J (1988b)

Litton bionetics

(1974)

Domingo J L,

Llobet J M,


J (1988b)

Sanders A

(2001b)


EC number:

215-251-3

Test

Substance

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc bis(dihydrogen phosphate)

Zinc oxide

Zinc oxide

Zinc oxide

Zinc phosphate

Zinc metal

Study

Type

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral

Acute oral zinc sulphide CAS number:

1314-98-3


LD

50

Rat LD

50 mg/kg bw


Mouse

Rat

Rat

Rat

Rat

Rat

Mouse

Rat

Rat

Rat

LD

LD

LD

LD

LD

LD

LD

LD

LD

LD

50

50

50

50

50

50

50

50

50

50

No further information available


Single dose;


1,891 mg/kg bw

2,280 mg/kg bw

2,949 mg/kg bw

Single dose 300-

2000 mg/kg bw

Single; dose >5,000 mg/kg bw


Single dose >

15,000 mg/kg bw

Single dose;

>

2,000 mg/kg bw ca.

7,950 mg/kg bw

>

5,000 mg/kg bw

Single dose >2,000 mg/kg bw

Remarks Reference used in RAR,

(EU 2004 e)



Domingo J L,

Llobet J M,


J (1988a)

Courtois Ph,

Guillard O,

Pouyollon M,

Piriou A and

Warnet J-M,

(1978)

Lorke D

(1983)


(EU 2004 e)


(EU 2004 e)


1 (reliable without restriction) key study


4 (not assignable) supporting study

Sanders A

(2001a)

Courtois Ph,

Guillard O,

Pouyollon M,

Piriou A and

Warnet J-M,

(1978)

Van

Huygevoort

AHBM

(2007)

Loser E

(1977)

Shumskaya

NI,

Mel’nikova

VV, Zhilenko

VN and

Berezhnova

LI (1986)

Löser E

(1972)


(EU 2004 b)


(EU 2004 d)


Klein and

Glaser (1989)

Prinsen MK

(1996)


EC number:


1314-98-3

Test

Substance

Study

Type


LD

50

Remarks Reference

Zinc sulfide Acute oral

Rat LD

50


>

15,000 mg/kg bw used in RAR,

(EU 2004 d)


Sachtleben

Chemie

GmbH (2000 a)

The acute oral toxicity studies with zinc sulphate do not specifically state which hydrated form of the zinc sulphate was tested. As this impacts the LD understanding the range of LD

50

50

value, all available LD

50

values were re-calculated to provide an

values of currently marketed zinc sulphate products (i.e., mono-, hexa-, and heptahydrate). Table below summarises the results of this re-calculation

Table 25. Re-calculation of oral LD

50

rat values

Reported for

Zinc sulphate form

Dihydrate

LD

50

(mg/kg bw)

1,710

LD

50

(mg/kg bw) recalculated for

Mono Hexa Hepta

1,554 2,334 2,490

Reference

Heptahydrate

Unspecified

Unspecified

2,280

2,949

920

1,423

1,840 1

2,949 2

574 1

920 2

> 1,665

2,137

2,764 1

4,429 2

862 1

1,382 2

> 2,500

2,280

2,949 1

4,725 2

920 1

1,474 2

> 2,667 Hexahydrate

Heptahydrate

> 2,500

1,000 < LD

50

<

2,000

624 < LD

1,248

50

< 937 < LD

1,875

50

< 1000 < LD

1 Assumes testing of the heptahydrate (worst case) ; 2 Assumes testing of the monohydrate

2,000

50

<

Domingo et al.

,

(1988)

Lorke, (1983)

Courtois et al.

,

(1978)

Litton Bionetics,

(1974)

Sanders, (2001a)

Sanders, (2001b)

5.2.1.2. Acute toxicity: inhalation

Acute inhalation data is available on zinc chloride, zinc oxide as well as on zinc metal.

Table 26. Overview of experimental studies on acute toxicity after inhalation exposure according to decreasing water solubility of zinc compounds

Test substance

Zinc chloride

Zinc oxide

Study type

Acute inhalation

Acute inhalation

Specie s

Rat

Endpoint

LC

50

Mouse LC

50

Exposure time

10 min

No informati on available

Result

(mg/L)

< 2

LC

50

(4hrs)

(mg/L)

Not applicable

2.5 Not known-

Remarks


4 (not assignable) supporting study used in RAR,

(EU 2004 b)

Reference

Karlsson

N, Cassel

G,

Fangmark

I and

Bergman

F (1986)

RTECS,

(1991)


EC number:


1314-98-3

Zinc oxide Acute inhalation

Rat LC

50

4 hours >5.7 >5.7 2 (reliable with restrictions) key study used in RAR,

(EU 2004 b)

Zinc metal Acute inhalation

Rat LC

50

4 hours >5.41 >5.41 2 (reliable with restrictions) key study used in RAR,

(EU 2004 a)

Additional inhalation data

Male Syrian hamsters were exposed via inhalation to zinc sulphate aerosols in doses of 1.3 to 34.2 mg /m 3 (1.1-

7.3 mg Zn) for 4 hours. The activity median aerodynamic diameter (AMAD) and geometric standard deviation

(GSD) of the aerosols were 0.59 μm and 1.46, respectively. The rate of phagocytosis of insoluble particles by pulmonary macrophages was determined in situ by introduction of insoluble gold colloid in the respiratory tract under anesthesia. From a dose of 5.2 up to 34.2 mg ZnSO

4

/m³ macrophage endocytosis of colloidal gold was significantly reduced 1 h after exposure compared with that in unexposed control animals. After 24 hours the rate of phagocytosis was still depressed, whereas after 48 hours it had returned to normal values. An increase in macrophage cell number was seen at low concentrations followed by depressions in macrophage numbers at high concentrations. No effects were observed at 1.3 mg/m 3 (0.2 mg Zn) (Skornik and Brain, 1983).

Klimisch

H-J,

Hildebrand B and

Freisberg

KO (1982)

Arts,

MHE

(1996)

In anesthetized dogs the pulmonary mechanics were not significantly changed after inhalation exposure to submicron aerosols of ZnSO

ZnSO

4

(Sackner et al.

, 1981).

4

up to 17.3 mg/m 3 for 7.5 minutes. Also an exposure of 4 hours to 4.1 to 8.8 mg/m 3

to anesthetized dogs showed no effect on breathing mechanics, hemodynamic, or on arterial blood gases

In a lung function test, 23 guinea pigs were exposed by inhalation to 0.9 mg ZnO/m 3 (furnace-generated aerosol;

0.05 microns) for 1 hour. A progressive decrease in lung compliance was observed (from 9% below control value at the end of exposure to 16% after one hour post-exposure), but no change in air flow resistance (Amdur et al.

, 1982). In contrast to these results, no effects on ventilation, lung mechanics, diffusing capacity of carbon monoxide, or most lung volume parameters were observed in another lung function test with 10 guinea pigs exposed for 3 hours to 7.8 mg ZnO/m 3 (furnace-generated aerosol; 0.05 microns). However functional residual capacity was significantly decreased (10% below control value) with only minimal changes in other lung volume subdivisions (Lam et al.

, 1982).

The effect of inhaled ZnO was studied in guinea pigs, rats, and rabbits. Animals were exposed to 0, 2.5 or 5 mg

ZnO/m 3 (furnace-generated aerosol; 0.06 microns) for up to 3 hours and their lungs lavaged at 24 hours thereafter. The lavage lung fluid of both guinea pigs and rats exposed to the highest dose showed significant increases in total cells (guinea pigs 2.5-fold; rats 2-fold), lactate dehydrogenase (guinea pigs 24-fold, rats 9fold),  -glucuronidase (guinea pigs 13-fold; rats 27-fold), and protein content (guinea pigs 3.5-fold and rats 5.6fold). Guinea pigs exposed to 2.5 mg ZnO/m³ for 3 hours resulted in significant increases in LDH (16-fold), βglucuronidase (5-fold), and protein (1.4-fold). Exposure of rats to 2.5 mg ZnO/m³ resulted in significant increases in lactate dehydrogenase (4.5-fold), β-glucuronidase (11-fold), and protein (5-fold). Rabbits, exposed to 2.5 or 5 mg ZnO/m 3 (furnace-generated aerosol; 0.06 microns) for 2 hours, showed no changes in the biochemical or cellular parameters (Gordon et al.

, 1992).

5.2.1.3. Acute toxicity: dermal

Acute dermal toxicity has been investigated with the soluble zinc sulphate. Table below presents the respective study details and results


EC number:


1314-98-3

Table 27. Overview of experimental studies on acute toxicity after dermal exposure

Test substance

Zinc sulphate

Study

Type

Acute dermal

Species Endpoint Exposure

Rat LD

50

Single application;

24 hours; semiocclusive

Result Study Reliability

(Klimisch Score)

>2,000 mg/kg bw


Reference

Van

Huygevoort

AHBM

(1999a)

5.2.1.4. Acute toxicity: other routes

Male Wistar rats (5/group) were given an intratracheal dose of 2.5 mg ZnCl

2

/kg bw and sacrificed 3, 14, 28 or

35 days after dosing. Within 3 hours after dosing all rats were subdued and showed respiratory distress.

Histology showed alveolitis around the major bronchi, most severe on day 3 after treatment. A change from macrophage to lymphocyte infiltration was seen in the damaged areas at day 14, without evidence of fibrosis. At

28 days, early alveolar thickening with increased interstitial reticulum deposition was observed, and at 35 days these changes had amounted to mature, discrete areas of parenchymal scarring (Brown et al.

, 1990).

After intratracheal administration of ZnCl

2

to male Wistar rats at dose levels of 0, 0.25, 0.5, 1, 2, 4 or 5 mg/kg bw, no histological effects on the lung tissue were seen up to dose level of 0.5 mg ZnCl levels, a dose-related intra-alveolar oedema was observed (Richards et al.

, 1989)

2

/kg bw. At higher dose

Exposure of male Wistar rats to a dose of 2.5 mg ZnCl

2

/kg bw by instillation caused oedema of the lung and a ten-fold increase in the level of alveolar surface protein within 6 hours of treatment. The pulmonary oedema was most severe between 6 hours and 3 days after exposure, with more than 50% of the rats showing oedema

(Richards et al.

, 1989).



Oral

Oral intake of ‘one tablespoon’ by a 16-month old boy (McKinney et al.

, 1994, 1995) or ‘about three ounces’ of a zinc chloride solution (soldering flux) by a 24-yr old male (Chobanian, 1981) led to local caustic effects, nausea, vomiting, abdominal pain, hyperamylasemia and lethargy.

A 15-year-old girl with no history of dyspepsia ingested zinc sulphate tablets of 220 mg twice daily (440 mg

ZnSO

4

/day  2.6 mg Zn/kg bw/day) for the treatment of acne. After each capsule the girl experienced epigastric discomfort. After 1 week gastrointestinal haemorrhages accompanied by anemia was observed. No other medicines were used (Moore, 1978).

Inhalation

Inhalation exposure to concentrations between 0.07 and 0.4 mg/m 3 zinc chloride fume for 30 minutes failed to elicit sensory effects. In the same study, an average concentration of 4.8 mg/m 3 over a 30-minute period caused mild, transient irritation of the respiratory tract in bearing manufacture workers (Ferry, 1966; 1974).

Exposure to 40 mg/m chloride for 2 minutes resulted in slight nausea and some cough at 80 mg/m whereas at 120 mg/m mg/m 3

3

3 zinc chloride aerosol a metallic taste was detected. Experimental exposure to zinc

3 in the majority of human subjects,

irritation of the nose, throat and chest were noted (Cullumbine, 1957). Exposure to 4,800

for 30 minutes induced pulmonary effects. No further data available (Lewis, 1992).

Accidental exposure to zinc chloride fume resulted in intoxications (Evans, 1945; Hjortsø et al.

, 1988; Homma et al.

, 1992; Johnson and Stonehill, 1961; Macaulay and Mant, 1964; Matarese and Matthews, 1986; Milliken et al.

, 1963; Pare and Sandler, 1954; Schenker et al.

, 1981), but quantitative data are lacking except for one study

(Johnson and Stonehill, 1961), where the concentration was 4,075 mg/m 3 (duration of exposure not indicated).

After inhalation, shortness of breath, pain in the throat, acute inflammation of the respiratory tract, cyanosis, bronchopneumonia, painful cough with sputum, chest pain and tightness, nausea and vomiting, headache, pulmonary oedema and fibrosis, acute respiratory insufficiency was experienced more or less in increasing order of seriousness. In several cases the symptoms receded one or two hours after exposure, but occasionally aggravated a few hours up to 2 weeks later. In a few cases the high exposure concentration was fatal.

Slightly soluble and insoluble zinc compounds

Oral


EC number:


1314-98-3

A 16-year old boy, who ingested 12 g metallic zinc in 2 days (114 mg/kg bw on the first and 57 mg/kg bw on the second day) in order to hasten healing of a minor laceration, experienced light-headedness, lethargy, staggering gait, and difficulty writing legibly, but no gastrointestinal distress. He showed an increase in serum lipase and amylase, measured eight days after dosing (Murphy, 1970).

Inhalation

Very specific operations using very high temperatures such as cutting or welding of galvanised steel can give rise to the formation of fumes containing ultrafine particulate zinc oxide (<0.1 micron in diameter) (EU 2004 a).

Exposure to these fumes can cause metal fume fever, expressing itself in certain typical symptoms including dry and sore throat, fever, coughing, dyspnoea, pyrexia, muscular pains, headache and metallic taste (Heydon and

Kagan, 1990; Gordon et al.

, 1992; Mueller and Seger, 1985). In addition to these symptoms, gastrointestinal disturbance may be associated with exposure to ultrafine particulate fumes (NIOSH, 1975).

A number of studies have measured exposure levels associated with metal fume fever. In a human study, subjects (n=4) were exposed in a single-blind fashion to control furnace gases or ultrafine ZnO particles (5 mg/m 3 ) for 2 hours. All 4 persons exposed to ZnO showed the typical metal fume fever symptoms beginning 4 to 8 hours after exposure and disappearing within 24 hours. The reported symptoms include fever, chills, dry or sore throat, chest tightness, and headache. No changes were observed in pulmonary function immediately after exposure. The specific airway resistance increased with 16% in all subjects exposed to ZnO (Gordon et al.

,

1992). Therefore, an effect level of 5 mg ZnO/m 3 for metal fume fever can be derived.

Occupational exposure (6-8 hours) to zinc oxide fume generated during welding operations was investigated.

Spirometric lung-function measurements were conducted 5 days before and after the work shift of 11 welders of zinc-coated steel, ten non-welders who were indirectly exposed to welding fumes, and 17 controls. The personnel exposure to zinc was monitored using PAS-6 samplers. The geometric mean concentration for welders was 0.034 mg Zn (as ZnO)/m 3 , for exposed non-welders 0.019 mg ZnO/m³, and for controls 0.004 mg

ZnO/m³. No changes in lung function parameters were observed at a 5% significance level. No symptoms of metal fume fever were reported (Marquart et al.

, 1989).

In another study, the response of humans after exposure to zinc welding fume was investigated. Fourteen welders were acutely exposed to zinc oxide welding fume over a 15- to 30-minute period. The personal exposure to zinc oxide was monitored and the mean cumulative exposure was 2.3 ± 1.7 g.min/m³ resulting in an exposure of 77-153 mg ZnO/m 3 . Pulmonary function, airway reactivity, serum zinc levels and blood cell counts were measured. A bronchoalveolar lavage (BAL) was carried out to assess the cellular inflammatory response in the lung. Changes in pulmonary function and measured airway resistance were minimal. Cumulative zinc exposure and polymorphonuclear leukocyte count were positively correlated. A significant dose-dependent increase of immunological activity (i.e. increased polymorphonuclear leukocytes) was found in the BAL fluid

22 hours after exposure (Blanc et al.

, 1991).

Blanc et al.

(1993), 26 experimental welding fume exposures in 23 volunteers, with a representative range of welding experience, were carried out. Subjects performed electric arc welding on galvanized mild steel over a

15- to 30-min period. Postexposure BAL was performed at 3, 8, or 22 hours after exposure in 6, 11, and 9 subjects, respectively, and compared with BAL obtained from 17 control subjects. The mean zinc exposures were 1.8, 2.0, and 2.6 gmin/m 3 for groups lavaged after 3, 8, and 22 hours, respectively, resulting in an exposure of 20-170 mg zinc/m 3 (equal to 25-212 mg ZnO/m 3 exposure range of 0.6-5.1 g.min/m 3

; calculation based on a 30-min exposure to the reported

). Besides inflammatory cells, BAL fluid supernatant concentrations of several cytokines, i.e. tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) increased in time and exposure-dependent fashion after zinc oxide welding fume exposure.

In another study, 14 volunteers were studied after inhalation exposure to purified zinc oxide fume and after sham exposure to air. The exposure concentrations ranged from 2.76-37 mg zinc/m period of 15 to 120 minutes (cumulative zinc exposure 165-1110 mg.min/m 3

3 (3.4-46 mg ZnO/m 3 ) for a

). Twenty hours after exposure

BAL was performed and analysed for cell contents and cytokines including TNF, IL-8, and interleukin-1 (IL-1).

Polymorphonuclear leukocytes were significantly increased in the BAL fluid obtained post-exposure compared to sham. Cumulative zinc exposure correlated positively with changes in BAL supernatant concentrations of both TNF ( r 2 =0.58) and IL-8 ( r 2 =0.44). Cigarette smoking was not associated with differences in BAL TNF or

IL-8. The data suggests a threshold for zinc exposure-related increased TNF and IL-8 at approximately 500 mg.min/m 3 expressed as zinc (625 mg.min/m 3 as ZnO). However, the correlation coefficients between cumulative exposure levels and rise in TNF or IL-8 were low (Kuschner et al.

, 1995). The data was also analysed for the presence of a concentration-effect relationship, but these correlation coefficients appeared to be even lower. It can be concluded that whether the onset of metal fume fever is governed by the cumulative exposure rather than the exposure concentration cannot be drawn due to the limited amount of data points and the large variability of the data. Hence it is impossible to derive a NOAEL for metal fume fever from this study


EC number:


1314-98-3 with reasonable certainty. Therefore, the data from this study is considered not to supersede the study results found by Gordon et al.

, (1992), from which a 5 mg ZnO/m 3 effect level for metal fume fever can be derived. A number of reports have addressed the etiology of metal fume fever as well, e.g. Barceloux et al.

, (1999), and

Kelleher et al.

, (2000). However, these studies, as well as several case reports (e.g. Vogelmeier et al.

, 1987;

Langham Brown, 1988; Malo et al.

, 1990; Ameille et al.

, 1992) do not allow the establishment of a clear

NOAEL for metal fume fever.

It is clear that metal fume fever is restricted to very specific operations using very high temperatures such as cutting or welding of galvanised steel. It is not related to the production and use of commercial grade zinc oxide.

Metal fume fever is exclusively associated with freshly formed ultrafine particulate zinc oxide (<0.1  m). As these ultrafine particles rapidly agglomerate to bigger particles, which are normally encountered at production and processing sites, at these sites there is no indication for metal fume fever. By means of a questionnaire all zinc companies were asked for the incidence of metal fume fever at their site over the past decades of operation.

Medical surveillance programs have been carried. Eleven companies (mainly zinc oxide producers) reported no observations of zinc metal fume fever over the last decade or in recent occupational practice (EU RAR, 2004af).

5.2.3. Summary and discussion of acute toxicity

The acute toxicity of zinc and its compounds depends on the type of zinc compound as well as on the route of application. While the slightly soluble and insoluble zinc compounds (i.e., zinc oxide, zinc hydroxide, zinc phosphate, zinc carbonate, zinc metal and zinc sulphide) are of low acute, dermal and inhalation toxicity not requiring a classification for acute toxicity according to the EC criteria, the soluble forms of zinc displayed a higher level of acute toxicity requiring classification for oral and possibly inhalation exposure.

Soluble zinc chloride is harmful following acute oral exposure (LD

50

range 1,100 to 1,260 mg/kg bw) and is classified as harmful if swallowed (Xn; R22) according EC criteria (Council Directive 67/548/EEC). Zinc chloride has also demonstrated acute toxicity via the inhalation route (LC

50

≤ 1,975 mg/m 3 ). However, since the exposure of the animals to the size of the particles is not truly representative of exposure to humans under normal conditions, it is difficult to assess whether or not, zinc chloride is acutely toxic since a four hour LC

50 value could not be derived and a clear dose-response relationship could not be established. Airway irritation has been observed both in animals and in humans, zinc chloride has the potential to be a respiratory tract irritant.

Soluble zinc sulphate (monohydrate, hexahydrate and heptahydrate) has LD

50

oral values ranging from 574 to

2,949 mg/kg bw, 862 to 4,429 mg/kg bw and 920 to 4,725 mg/kg bw, respectively for the three forms of zinc sulphate and is classified as harmful if swallowed (Xn; R22) according EC criteria (Council Directive

67/548/EEC). Zinc sulphate is not acutely toxic via the dermal route (LD50 >2,000 mg/kg bw). Effects of inhalation exposure to zinc sulphate were limited to pulmonary effects only. Soluble zinc bis(dihydrogen phosphate) is also harmful following acute oral exposure (LD50 range 300 to 2000 mg/kg bw) and meets the classification criteria for harmful if swallowed (Xn; R22) according to EC criteria (Council Directive

67/548/EEC). While no specific acute toxicity data were identified for diammonium tetrachlorozincate and triamonium pentachlorozincate, it is (due to its similar solubility characteristics) likely to display a toxicity profile similar to that of zinc chloride, zinc sulphate or zinc bis(dihydrogen phosphate).

With LD

50

values consistently exceeding 2,000 mg/kg bw, slightly soluble or insoluble zinc compounds such as, zinc oxide (LD

50 ranges between 5,000 and 15,000mg/kg bw), zinc phosphate (LD metal (LD50 >2,000mg/kg bw) or zinc sulphide (LD

50

is >5,000mg/kg bw), zinc

50

is >15,000mg/kg bw) show low level of acute oral toxicity. Moreover, zinc oxide and zinc metal were further shown to be of low acute inhalation toxicity (i.e.,

LC50 values of > 5.41 and 5.7 mg/L/4hrs). Given the common characteristics shared via their solubility characteristics, the remaining slightly soluble zinc compounds are also considered to be of low acute inhalation toxicity.

Of significance for humans from an acute toxicity standpoint is the occurrence of metal fume fever following exposure to ultrafine particles of special grades of zinc oxide in context of very specific operations. According to the response from 11 zinc companies to a questionnaire, there have been no observations of zinc metal fume fever over the last decade and in recent occupational practice. However in light of responsible care and since no studies are available that allow the establishment of a NOAEL for metal fume fever with a reasonable degree of certainty, a LOAEL (5 mg ZnO/m 3 ) for 2 hours (showed the typical metal fume fever symptoms beginning 4 to

8 hours after exposure and disappearing within 24 hours) can be used for metal fume fever based on the study by Gordon et al.

(1992).

5.3. Irritation


EC number:


1314-98-3

5.3.1. Skin

5.3.1.1. Non-human information

Table 28. Overview of experimental studies on skin irritation according to decreasing water solubility of zinc compounds

Test substance

Zinc chloride

Zinc chloride

Zinc chloride

Zinc chloride

Zinc sulphate

Zinc sulphate

Zinc sulphate

Study type

Skin irritation

Skin irritation

Skin irritation

Skin irritation

Skin irritation

Skin irritation

Skin irritation

Species

Guinea-pig Erythema, eschar and oedema formation

Rabbit

Rabbit

Mouse

Rabbit

Endpoint Exposure

Erythema, eschar and oedema formation




Daily; 0.5 mL of 1% solution; open-patch; 5 days


Daily; 0.5 mL of 1% solution; occluded; 5 days


0.5g; moistened substance; semiocclusive; 4 hours

Daily; 0.5 mL; openpatch; 5 days


Result

Moderately irritating

Severely irritating

Severely irritating

Severely irritating

Remarks





Not irritating 2 (reliable with restrictions) key study



Reference

Lansdown

ABG,

(1991)

Lansdown

ABG,

(1991)

Lansdown

ABG,

(1991)

Lansdown

ABG,

(1991)

Van

Huygevoort

AHBM

(1999b)

Lansdown

ABG,

(1991)

Lansdown

ABG,

(1991)

Zinc sulphate

Zinc oxide

Zinc oxide

Zinc oxide

Zinc oxide

Skin irritation

Skin irritation

Skin irritation

Skin irritation

Skin

Rabbit

Guinea Pig Erythema, eschar and oedema formation

Mouse


Rabbit


Erythema,

Rabbit eschar and oedema formation


Rabbit Erythema, eschar and oedema formation

Guinea-pig Erythema,


500 mg; occlusive; 24 hours

Daily; 0.5 mL; occlusive; 5 days

Daily; 0.5 mL; open patch; 5 days

Daily; 0.5


Lansdown

ABG,

(1991)



Löser,

(1977)

Lansdown

ABG,

(1991)


Lansdown

ABG,

(1991)

Not irritating 2 (reliable with Lansdown


EC number:


1314-98-3

Test substance

Zinc oxide

Study type irritation

Skin irritation

Species

Mouse

Endpoint Exposure eschar and oedema formation

Erythema, eschar and oedema formation mL; open

Daily; 0.5 mL; open

Result Remarks restrictions) key study


Reference

ABG,

(1991)

Lansdown

ABG,

(1991)

5.3.1.2. Human information


Zinc sulphide was not irritating to human skin (Sachtleben Chemie GmbH, 2000b).

No signs of skin irritation were noted when an occlusive 25% zinc oxide patch (2.9 mg Zn/cm the human skin for 48 hours (Agren, 1990).

2 ) was placed on

A patient who was treated with 40% zinc oxide ointment (15 g on 150 cm 2 ) under occlusive dressing displayed a rash and follicular pustules at 24 hours post-treatment. The dermal reaction disappeared 2 days after removal of the ointment and treatment with cool saline compresses, but reappeared after application of 5% zinc oxide. From the study it could not be derived whether the dermal effects were a result of zinc oxide or from other treatmentrelated stimuli. In 5 other patients who were treated with 40% zinc oxide ointment in a similar way and in 6 volunteers who received 100 g of 40% zinc oxide ointment on chest and legs, no signs of dermal reactions were reported (Derry et al.

, 1983).

5.3.2. Eye


The results of experimental studies on eye irritation are summarised in the following table:

Table 29. Overview of experimental studies on eye irritation according to decreasing water solubility of zinc compounds

Test substance

Zinc sulphate

Study type

Occular irritation


Severely irritating

Remarks

Diammonium tetrachlorozincate

Zinc oxide

Zinc oxide

Occular irritation

Occular irritation

Occular irritation

Rabbit Effects on iris, cornea and conjunctiv ae

Rabbit Effects on iris, cornea and conjunctivae



98.1 mg neat product instilled into one eye; unrinsed

98.1 mg neat product instilled into one eye; rinsed and unrinsed observed

64 mg

(0.1mL) neat product instilled into one eye; rinsed after

24 hours

50 mg neat product instilled into one eye

Moderately irritating

Not irritating

2 (reliable with restrictions) key study used in RAR,

(EU 2004 e)


1 (reliable without restriction) key study used in RAR,

(EU 2004 b)

Not irritating 2 (reliable with restrictions) supporting study used in RAR,

(EU 2004 b)

Reference

Van

Huygevoort

(1999 f)

E.I.Dupont de Nemours and Co

(1992)

Van

Huygevoort

AHBM

(1999 e)

Thijssen J

(1978)


EC number:


1314-98-3

Test substance

Zinc oxide

Zinc phosphate

Study type

Occular irritation



50 mg neat product instilled into one eye slightly irritating

Occular irritation


100 mg neat product instilled into one eye; unrinsed

Not irritating

Remarks

2(reliable with restrictions) supporting study used in RAR,

(EU 2004 a)

1(reliable without restriction) key study used in RAR,

(EU 2004 d)


(EU 2004 a, b)

Reference

Löser E

(1977)

Mirbeau T,

Guillaumat

PPO and

Pelcot C

(1999)

Zinc dust

Zinc powder

Occular irritation

Occular irritation



100 mg instilled into one eye;

Median particle diameter

4µm; rinsed after 24 hours

100 mg neat product instilled into one eye;

Median particle diameter

150µm; unrinsed

Minimally irritating

Minimally irritating


(EU 2004 a, b)



Accidental splash of zinc chloride into three eyes of two patients resulted in corneal oedema and some permanent corneal scarring. Recovery required 6 to 28 weeks. The patient who had also splashes in his nasal passages lost all sense of smell permanently, in spite of medical treatment (Houle and Grant, 1973).


Zinc sulphide is not irritating to human eyes (Sachtleben Chemie GmbH, 2000c).

5.3.3. Respiratory tract



Rats exposed to zinc chloride in single exposure studies exhibited signs of respiratory distress and oedema (see acute inhalation toxicity).


Zinc oxide did not show any signs of upper airway irritation in acute inhalation studies. Single and repeated inhalation exposure to ultra-fine zinc oxide fumes showed changes in pulmonary function and induction of airway inflammatory responses, however a well-performed acute inhalation toxicity study in rats, did not yield any indication of signs of upper airway irritation from commercial zinc oxide aerosol (particle size: MMAD 4

 m ± 2.9 (GSD)) (Klimisch et al.

,1982).


Van

Huygevoort

AHBM

(1999 c)

Van

Huygevoort

AHBM

(1999 d)


EC number:


1314-98-3


5.3.4. Summary and discussion of irritation

Slightly soluble zinc oxide, zinc phosphate, zinc metal and insoluble zinc sulphide are not irritating to skin or eyes. The soluble zinc compounds (i.e., zinc chloride, zinc sulphate and diammonium tertachlorozincate), displayed varying degrees of skin and eye irritation ranging from moderate to severely irritating.

Based on the available data of the soluble zinc compounds, soluble zinc chloride is classified as corrosive

(C;R34) according to EC criteria due to severe skin irritancy seen in animals at concentrations of 1% solution and irreversible damage to eyes caused by zinc chloride after accidental exposure in humans. Zinc chloride has also shown signs of respiratory tract irritation in single exposure studies (see acute inhalation toxicity). On the other hand zinc sulphate was not irritating to skin but is a severe eye irritant and has been classified as a severe eye irritant (Xi R41) according to EC criteria. While no pertinent data exists on zinc bis(dihydrogen phosphate) in vitro data with questionable reliability suggests zinc bis(dihydrogen phosphate) is not irritating to eyes.

Diammonium tetrachlorozincate appears to be a moderate eye irritant however no classification has been assigned. While no specific irritation data were identified for triammonium pentachlorozincate, it is (due to its similar solubility characteristics) likely to display a toxicity profile similar to that of the soluble diammonium tetrachlorozincate.

Based on the available information it appears that the slightly soluble zinc oxide and insoluble zinc sulphide are not skin irritants and therefore slightly soluble zinc hydroxide, zinc phosphate, zinc carbonate and zinc metal are also expected to be not irritating to skin. Zinc oxide, zinc phosphate, zinc metal and zinc sulphide are not eye irritants and therefore zinc carbonate and zinc hydroxide are also expected to be not irritating to eyes. None of the slightly soluble or insoluble zinc compounds appear to cause respiratory tract irritation.

5.4. Corrosivity


Refer to section 5.3


Refer to section 5.3

5.4.3. Summary and discussion of corrosion

As discussed in section 5.3, irritation studies indicate that soluble zinc chloride is corrosive to skin and is classified as such according to Annex I of Directive 67/548/EEC. The remaining soluble zinc compounds are not classified as corrosive. Zinc phosphate and diammonium tetrachlorozincate were moderate to severe eye irritants.

The slightly soluble and insoluble zinc compounds (zinc oxide, zinc hydroxide, zinc phosphate, zinc carbonate, zinc metal and zinc sulphide) are not corrosive based on the available irritation data and therefore no classification is required according to Annex I of Directive 67/548/EEC for corrosivity.

5.5. Sensitisation

5.5.1. Skin


The results of experimental studies on skin sensitisation are summarised in the following table:

Table 30. Overview of experimental studies on skin sensitisation according to decreasing water solubility of zinc compounds

Test substance

Zinc sulphate

Method

Mouse local lymph node assay

Results

Negative

Remarks


Reference

Ikarashi Y,

Tsuchiya T and

Nakamura A

(1992)


EC number:


1314-98-3

Zinc sulphate

Zinc oxide

Guinea pig (Dunkin-

Hartley) female

Guinea pig maximization test



Negative

Negative

2 (reliable with restrictions) supporting study used in RAR, (EU

2004 e)

1 (reliable without restriction) key study used in RAR, (EU

2004 b)

Ambiguous 1 (reliable without restriction) key study

Van Huygevoort

(1999 i)

Van Huygevoort

AHBM (1999 g)

Zinc oxide Van Huygevoort

AHBM (1999h1)

Van Huygevoort

AHBM (1999h2)

Zinc sulphate (ZnSO

4

•7 H

2

O) was tested in a mouse local lymph node assay (Ikarashi et al.

, 1992), according to the testing methods developed by Kimber et al., (1989 and 1990). After gentle dermal abrasion, 25  l of a 5% zinc sulphate solution in 20% ethanol was applied for three consecutive days at the dorsal side of both ears of 3

Balb/c mice. On the fourth day the animals were sacrificed and the ear-draining lymph nodes were collected.

Lymph node lymphocyte proliferation was determined by tritiated thymidin incorporation. The results were compared to those of vehicle-treated controls. Zinc sulphate did not induce proliferative activity, whereas for potassium bichromate, nickel sulphate and cobalt chloride (known dermal sensitizers) positive results were obtained.

The skin sensitising potential of zinc sulphate (ZnSO

4

•7 H

2

O) was also investigated in guinea pigs. A wellperformed maximisation test, conducted according to Directive 96/54/EC B.6 and OECD guideline 406, was carried out in female Dunkin Hartley guinea pigs. Based on the results of a preliminary study, in the main study

10 experimental animals were intradermally injected with a 0.1% concentration and epidermally exposed to a

50% concentration. Five control animals were similarly treated, but with vehicle (water) alone. Approximately

24 hours before the epidermal induction exposure all animals were treated with 10% SDS. Two weeks after the epidermal application all animals were challenged with a 50% test substance concentration and the vehicle. A second challenge followed one week after the first. In response to the 50% test substance concentration, in some experimental animals and controls skin reactions of grade 1 were observed 48 hours after the first (5/10 and 2/5, respectively) and the second challenge (4/10 and 2/5, respectively). As the skin reactions were comparable among the experimental and control animals, and as there was poor consistency of the skin reactions among individual experimental animals after the first and second challenge, the observed skin reactions can be considered to be non-specific signs of irritation. Hence, it can be concluded that zinc sulphate did not induce hypersensitivity in experimental animals (Van Huygevoort, 1999i).

The skin sensitising potential of zinc oxide (purity 99.69%) was investigated in female Dunkin Hartley guinea pigs in two well-performed maximisation tests, conducted according to Directive 96/54/EC B.6 and OECD guideline 406. Based on the results of a preliminary study, in the main studies experimental animals (10 in each test) were intradermally injected with a 20% concentration and epidermally exposed to a 50% concentration (i.e. the highest practically feasible concentration). Control animals (5 in each test) were similarly treated, but with vehicle (water) alone. Approximately 24 hours before the epidermal induction exposure all animals were treated with 10% SDS. Two weeks after the epidermal application all animals were challenged with a 50% test substance concentration and the vehicle. In the first study, in response to the 50% test substance concentration skin reactions of grade 1 were observed in 4/10 experimental animals 24 hours after the challenge (40% sensitisation rate), while no skin reactions were evident in the controls. In contrast, in the second study no skin reactions were evident in the experimental animals (0% sensitisation rate), while a skin reaction grade 1 was seen in one control animal. The skin reaction observed in one control animal is probably a sign of non specific irritation (Van Huygevoort, 1999h1, 1999h2).

In a third well-performed maximisation test, conducted according to the same guidelines and with the same experimental design, another analytical grade zinc oxide was tested (Zincweiß Pharma A; purity 99.9%). The only difference with the studies described above was the intradermal induction concentration, which was 2% as for Zincweiß Pharma A this was considered the highest concentration that could reproducibly be injected. In this test no skin reactions were evident in both experimental and control animals, hence a 0% sensitisation rate for

Zincweiß Pharma A. White staining of the treated skin by the test substance was observed in some animals 24 and 48 hours after challenge (Van Huygevoort, 1999g).



EC number:


1314-98-3

Slightly soluble zinc compound

In a human patch test performed with 100 selected leg-ulcer patients, 11/100 patients gave an allergic reaction with zinc ointment (60% ZnO and 40% sesame oil). However, 14/81 patients gave a positive response when treated with sesame oil alone. This study does not give any indication for a skin sensitizing potential of zinc oxide in humans (Malten and Kuiper, 1974).

The effect of zinc oxide on contact allergy to colophony was investigated. With 14 patients with earlier history of moderate patch test reactions to colophony (a patch test) with 10% ZnO (2.3 mg Zinc/cm²) with and without colophony was performed. No positive response was observed in the 14 patients when only a 10% solution of zinc oxide was used. The addition of zinc oxide to colophony decreased the allergic reaction induced by colophony (Söderberg et al.

, 1990).

5.5.2. Respiratory system


While is no particular study addressing respiratory sensitisation in experimental animals, there is no information suggesting zinc compounds to cause such effects animals. Taking into account the complete absence of skin sensitization potential of zinc compounds, respiratory sensitisation is not expected to be of concern for the zinc and zinc compounds considered in this chemical safety report.


No reports were identified in the literature that associated zinc metal or zinc compounds with respiratory sensitization in humans.

5.5.3. Summary and discussion of sensitisation

Skin sensitisation

The data on slightly soluble zinc oxide indicated no skin sensitising potential (negative in animal and human studies) therefore classification for skin sensitisation is not required according to Annex I of Directive

67/548/EEC. Based on the assumption that zinc compounds with similar water solubility characteristics can be read across, it can be concluded that the other slightly soluble and insoluble zinc compounds are also expected to be non-skin sensitisers.

The data on soluble zinc sulphate indicates no sensitisation potential and therefore no classification is required according to Annex I of Directive 67/548/EEC. Sensitisation is not expected from soluble zinc chloride, zinc bis(dihydrogen phosphate), diammonium tetrachlorozincate and triammonium pentachlorozincate based on the data for zinc sulphate since the soluble zinc compounds share similar solubility characteristics.

Respiratory sensitisation

Considering the absence of evidence of respiratory sensitization responses in, this endpoint is not expected to be of concern for zinc and zinc compounds.

5.6. Repeated dose toxicity

The repeated dose toxicity section provides an overview of the available studies for all zinc compounds which are considered key studies. The subsection “Additional supporting studies” comprises studies conducted in non standard laboratory animals, special investigations into specific parameters and which are limitedly reported.


5.6.1.1. Repeated dose toxicity: oral

The results of experimental studies are summarised in the following table:

Table 31. Overview of experimental studies on repeated dose toxicity after oral administration

Test substance Species Method Results

Zinc sulphate Mouse 90-Day oral feeding in male/female NOAEL:


2 (reliable with Maita K, Hirano


EC number:


1314-98-3

Zinc sulphate

ICR

Rats

Wistar

ICR mice;

Similar to OECD Guideline 408;

Dietary doses: 0, 300, 3,000, 30,000 ppm; equivalent to:

42.7/46.4, 458/479, 4927/4,878 mg

ZnSO

4

/kg bw/day (males/females)

90-Day oral feeding in male/female rats;


Dietary doses: 0, 300, 3,000, 30,000 ppm; equivalent to:

23.2/24.5, 234/243, and 2,514/2,486 mg/kg bw/day (males/females)

458 mg ZnSO

4

/kg bw/day; equalling

104 mg Zn/kg bw/day

At LOEL of 30,000ppm blood and biochemical effects noted.

Pathological and histopathological changes observed in kidneys, thyroid, GI tract and pancreas restrictions) key study

M, Mitsumori K,

Takashi K and

Shirasu Y (1981)

NOAEL:

234 mg ZnSO

4

/kg bw/day; equalling

53.5 mg Zn/kg bw/day

At LOEL of 2,486 mg

ZnSO

4

/kg bw/day blood effects and pancreatic damage noted;


Maita K, Hirano

M, Mitsumori K,

Takashi K and

Shirasu Y (1981)

Zinc Rats monoglycerolate Sprague

Dawley

90-Day oral feeding in male/female

SD rats;


Dietary doses: 0, 0.05%, 0.2%,

30000 ppm; equivalent to:

31.5/35.8, and 127.5/145.9 mg/kg bw/day (males/females)

Exposure: 13 weeks

NOAEL:

31.52 mg Zn mg/kg bw/day; equalling

13.3 mg Zn/kg bw/day

At the LOEL of 53.8 mg Zn/kg bw/day, rats displayed changes in haematological parameters, pancreatic cell necrosis; no effects were seen at LOEL in reproductive organs;


Edwards K and

Buckley P (1995)

ICR mice (12/sex/group) were given daily doses of 300, 3000 or 30000 mg ZnSO

4

•7 H

2

O/kg feed (equivalent to

42.7/46.4, 458/479 and 4927/4878 mg/kg bw for males/females, respectively) during 13 weeks. A control group was included. At the highest dose level 4 males and 1 female were found dead or killed in extremis. Histological findings of these animals revealed impairment of the urinary tract and regressive changes in the exocrine gland of the pancreas. Only the high dose animals showed moderately lower haematocrit (males: from 42% in controls to 29% in high dose animals; females: from 44% in controls to 31% in high dose animals) and haemoglobin concentrations (males and females: 14 to 10 g/dL). The leucocyte counts of high dose males were moderately decreased (lymphocytes 70 to 60%; monocytes 5.3 to 4.9%). Total protein, glucose and cholesterol were reduced and alkaline phosphatase and urea nitrogen were increased in high dose animals. High dose females showed reduced ALAT and increased calcium levels, ASAT was increased in high dose males. Absolute and relative (in parentheses) thyroid weights of males were increased from 3.3 mg (0.007%) in control animals to

4.2 mg (0.0011%) in the highest dose group. Kidney weights of females were also increased from 0.42 g

(0.93%) in controls to 0.53 g (1.62%) at the highest dose. Gross pathology and histopathology showed changes in kidneys, thyroids, pancreas (degeneration/necrosis of acinar cells, clarification of nucleoli), gastrointestinal tract, and spleen. No effects were found on the reproductive organs (i.e. ovaries, testes, accessory sex organs).

The NOAEL in this study is 458 and 479 mg ZnSO

4

•7 H

2

O/kg bw/day for males and females, respectively

(equivalent to approximately 104 mg Zn/kg bw/day) (Maita et al.

, 1981).

Wistar rats (12/sex/group) were given daily doses of 300, 3000 or 30000 mg ZnSO

4

•7 H

2

O/kg feed (equivalent to 23.2/24.5, 234/243, and 2514/2486 mg/kg bw for males/females, respectively) during 13 weeks. A control group was included. At the highest dose level a moderate reduction in leucocyte counts was seen in both sexes

(males: from 7.3 x10³/mm³ in controls to 4.7x10³/mm³ in high dose animals; females: from 4.5x10³/mm³ in controls to 3.3x10³/mm³ in high dose animals). Compared to controls, males also showed slightly decreased


EC number:


1314-98-3 haematocrit (42 to 40%), decreased total protein (5.2 to 4.4 g/dL) and cholesterol values (96 to 62 mg/dL).

Absolute and relative (in parentheses) liver weights were decreased in the high dose males (from 16.1 g (3.55%) in controls to 11.9 g (3.20%) at the highest dose). Absolute kidney weights were decreased in high dose males

(2.29 g vs. 2.93 g in controls). Histopathology showed pancreatic damage (degeneration, necrosis of acinar cells, clarification of centroacinar cells and interstitial fibrosis) in high dose animals. No effects were found on the reproductive organs (i.e. ovaries, testes, accessory sex organs). The NOAEL is 234 and 243 mg ZnSO

H

2 al.

, 1981).

4

•7

O/kg bw/day for males and females, respectively (equivalent to approximately 53.5 mg Zn/kg bw) (Maita et

Groups of 20 male and 20 female Sprague-Dawley rats were fed zinc monoglycerolate at dietary levels of 0,

0.05 or 0.2% (equal to 0, 31.52 or 127.52 mg/kg bw/day for males and 0, 35.78 or 145.91 mg/kg bw for females, respectively) for a period of 13 weeks in a study performed according to OECD 408. A similar group was fed 1% (equal to 719 and 805 mg/kg bw/day for males and females, respectively) of zinc monoglycerolate up to day 58 of the study when a deterioration in their clinical condition (poor physical health and reduced food intake) necessitated reducing the dietary level to 0.5% (equal to 632 and 759 mg/kg bw/day for males and females, respectively). However, as no improvement was noted, these rats were killed on humane grounds on day 64 of the study. These rats developed hypocupremia manifested as a hypochromic microcytic regenerative type anaemia (low haemoglobin and haematocrit, decreased MCV and MCH, and increased MCHC, red blood cell and reticulocyte count). Enlargement of the mesenteric lymph nodes and slight pitting of the surface of the kidneys were noted. Severe pancreatic degeneration and pathological changes in the spleen, kidneys, incisors, eyes and bones were observed. The testes of all males showed hypoplasia of the seminiferous tubules to a varying degree and in addition the prostate and seminal vesicles showed hypoplasia. In all but one female the uterus was hypoplastic. All other rats survived to the end of the 13 weeks treatment. At a dietary level of 0.2% increases in plasma ALAT, alkaline phosphatase and creatine kinase were observed in males and in plasma creatine kinase in females. Total plasma cholesterol was reduced in both males and females. The changes were statistically significant but small in absolute terms. No changes in haematological parameters were seen at 0.05 and 0.2%. A dose related reduction in the quantity of abdominal fat was noted in male rats at 0.05 and 0.2%.

Enlargement of the mesenteric lymph nodes was apparent in 6 out of 20 rats fed 0.2% and in one male fed

0.05%. Microscopic examination showed a reduction in the number of trabeculae in the metaphysis of the tibia of 5 male and 3 female rats fed 0.2%, 4 males and 1 female had a similar reduction in the metaphysis of the femur. Pancreatic cell necrosis was seen in both sexes at 0.2% and a slight, but statistically not significant increase could be noted at 0.05% (3 males and 1 female). This pancreatic cell necrosis was seen also in 1 control male. A reduction in the number of pigmented macrophages in the red pulp of the spleen was observed in both sexes at 0.2% and a marginal reduction was also seen in males at 0.05%. In the animals given 0.05 and 0.2% no effects were found on the reproductive organs. Since the pancreatic cell necrosis, being without statistical significance at 0.05%, was also apparent in 1 control male and because the reduction in pigmented macrophages in the spleen was only marginal at 0.05% without any haematological changes the dose level of

0.05%, is considered as a NOAEL. This dose level is equal to 31.52 or 35.78 mg zinc monoglycerolate/kg bw/day for males and females, respectively, so the NOAEL in this study is 31.52 mg/kg bw/day equalling approximate 13.26 mg Zn/kg bw/day) (Edwards and Buckley, 1995).

Additional supporting studies

Oral

A group of 150 C3H mice was given daily doses of 0.5 g ZnSO exposure equals approximately 100 mg ZnSO

4

4

(unspecified)/l drinking water for 1 year. This

/kg bw/day and 22.6 mg Zn/kg bw in case heptahydrate was used.

A 2 months post observation period and a control group were included. At monthly intervals, 5 control and 5 test animals were investigated for plasma zinc, glucose and insulin, and for zinc in skin, liver and spleen.

Histology, histochemistry and microscopy was performed on adrenals and pancreas, and on adenohypophysis only microscopy. The animals remained healthy throughout the study. Hypertrophy of the adrenal glands

(cellular enlargement) and hypertrophy and vacuolization of pancreatic islets and fasciculata cells in adrenal cortex from month 3 onwards. Changes indicating hyperactivity in the anterior pituitary were noted, such as increased cell size of all cell types in the pituitary. All the other parameters remained the same during the study.

The study was undertaken to further investigate the effects of supplemental zinc on endocrine glands and correlate these effects with any change in body zinc levels produced (Aughey et al.

, 1977).

Minks (3/sex/group) were given diets supplemented with 0, 500, 1000 or 1,500 mg/kg feed zinc sulphate for 144 days. Zinc concentrations in liver, pancreas and kidney increased with increasing zinc content in the diet. No histological lesions were found in these organs (Aulerich et al.

1991).

Wistar rats (2 months, 16 males and 14 females) were given 0.12 mg Zn/mL drinking water (equivalent to 12 mg Zn/kg bw/day; 25 mg ZnCl

2

/kg bw/day) for 4 consecutive weeks. A control group was included. The body


EC number:


1314-98-3 weights of exposed males and food and water intakes of both exposed sexes decreased. A statistically significant decrease in Hb level (85% of control value) and erythrocyte count was reported in the peripheral blood of treated rats. An increased leucocyte count, due to increased lymphocyte numbers was noted in treated males. No inhibition of erythropoiesis in the bone marrow was found. No more details were given in this limited study performed to investigate the effect of simultaneous oral administration of zinc and vanadium (Zaporowska and

Wasilewski, 1992).

Special studies were conducted to examine the morphological and histoenzymatic changes of the brain. Twelve

Wistar rats were given daily doses of 100 mg ZnO (i.e., approximately 600 mg ZnO/kg bw/day or 480 mg Zn/kg bw/day) intragastrically for 10 consecutive days. A control group was included. After 10 days the rats were sacrificed and the brains were examined for morphological and histoenzymatic changes. Morphological changes included degenerative changes of neurocytes, accompanied with moderate proliferation of the oligodendroglia and glial proliferation in the white matter. Furthermore, endothelial oedema was observed in the small arterial and capillary walls. Histoenzymatic changes included decreased activities of AcP (acid phosphatase), ATPase

(adenosinetriphosphatase), AChE (acetylcholinesterase), and BuTJ (Butyrylthiocholin-esterase). The activities of TPPase (thiamine pyrophophatase) and NsE (non specific esterase) were increased. No details on quantitative aspects of enzymatic changes were given. No change was seen in the alkaline phosphatase. The authors indicated that observed morphological and histoenzymatic changes were unspecific, indistinctive and most likely reversible (Kozik et al.

, 1980). Examination of the neurosecretory function of the hypothalamus and the hypophysis in these animals showed an increased neurosecretion in cells of the supraoptic and paraventricular nucleus of the hypothalamus along with a declined neurosecretion in the hypophysis and an enhanced release of antidiuretic hormone in the neurohypophysis (Kozik et al.

, 1981). It is not clear whether these observations represent an adverse effect of zinc on the brain or whether they are secondary to changes somewhere else in the body.

Four groups of ferrets (3-5/group) were given 0, 500, 1,500 or 3,000 mg zinc oxide/kg feed (i.e., equivalent to 0,

81.3, 243.8 or 487.5 mg ZnO/kg bw/day). At the highest dose level (i.e., 487.5 mg ZnO/kg bw/day) all animals

(3) were killed in extremis within 13 days. Macroscopic examination showed pale mucous membranes, dark coloured fluid in the stomach, blood in the intestines, orange coloured liver and enlarged kidneys showing diffuse necrosis, haemorrhages in the intestine and a severe macrocytic hypochromic anaemia. Histology showed nephrosis and extramedullary haematopoesis in the spleen. At the mid dose level of 243.8 mg ZnO/kg bw/day, the animals (4) were killed on day 7, 14 and 21 (1/2 in extremis) showing poor condition. Macroscopy showed pale livers with fatty infiltration and enlarged kidneys. Histology was comparable with the highest dose group. The heamogram showed macrocytic hypochromic anaemia, increased reticulocytes and leucocytosis.At the lowest dose level (81.3 mg ZnO/kg bw) the animals (3) were killed on day 48, 138 and 191, respectively. No clinical signs of toxicity or pathological changes were seen, apart from an extramedullary heamatopoesis in the spleen (Straube et al.

, 1980).

Ellis et al.

(1984) conducted a 14-day and a 49-day feeding study in 3 different breeds of sheep that were receiving feed containing 31 mg Zn/kg feed. The sheep received additional amounts of Zn (from ZnO) at dose levels of 261 and 731 (14 day study) or 731 and 1431 mg Zn/kg feed (49-day study). No effects were seen after

261 mg Zn/kg feed. In all other groups pancreatic lesions were seen.

Administration of 240 mg Zinc (as ZnO)/kg bw for 3 times/week during 4 weeks to 42 castrated sheep resulted in an increased incidence of pancreatic lesions (Smith and Embling, 1993).

5.6.1.2. Repeated dose toxicity: inhalation


Table 32. Overview of experimental studies on repeated dose toxicity after inhalation

Test substance

Zinc sulphate

Species

Rat

Wistar

Kyoto

Method

Subchronic inhalation in

Wistar Kyoto rats

Aerosol concentrations

‘nose only’ of 10, 30 and

100 μg zinc/m 3

Exposure: 16 weeks (5 hrs/day for 3 days/week)

Results

Study focused on the evaluation of effects of zinc sulphate on cardiac changes.

No cardiac pathology, but cardiac gene array analysis indicated small changes in gene expression;

No NOAEL identified;



Wallenborn JG,

Evansky P,

Shannahan JH,

Vallanat B,

Ledbetter AD,

(2008)


EC number:


1314-98-3

Zinc oxide Guinea pigs

Hartley


Hartley

5day inhalation in guinea pigs;

Ultrafine particle (0.05 µm)

‘nose only’ exposure concentrations of 0, 2.7, and

7 mg ZnO/m 3 ;

Exposure: 5 days (3hrs/day)

6 day inhalation in guinea pigs;


‘nose only’ exposure concentrations of 0 and 5 mg ZnO/m 3 ;

NOAEL : 2.7 mg ZnO/m³

Decreased lung volume: 7 mg/m³ air (analytical) (male)

(Other: Pulmonary function measurement) decrease of Lung volumes and diffusing capacity at peaks occurs rapidly and to a greater extent: 25 — 34 mg/m³ air

(analytical) (male)

(Pulmonary function measurement)

Pulmonary damage: 7 mg/m³ air (analytical) (male) (Wetlung weight/Body weight ratio and Wet-lung weight/Dry-lung weight ratio)

Increased pulmonary damage at peak concentrations: 25 —

34 mg/m³ air (analytical)

(male) (Wet-lung weight/Body weight ratio and

Wet-lung weight/Dry-lung weight ratio)


Decreased Vital capacity, functional residual capacity, alveolar volume and single breath diffusing capacity for carbon monoxide and elevated lung weights due to inflammation

2(reliable with restrictions) supporting study

Exposure: 6 days (3hrs/day)

Lam HF, Chen

LC, Ainsworth

D, Peoples S and Amdur MO

(1988)

Lam HF,

Conner MW,

Rogers AE,

Fitzgerald S and Amdur MO

(1985)


Hartley

Animal examination at 24,

48, and 72 hours post exposure;

1, 2, or 3 day inhalation in guinea pigs;


‘nose only’ exposure concentrations of 0, 2.3, 5.9 and 12.1 mg ZnO/m

Microscopical examination of lung tissue as well as examination of pulmonary lavage fluid;

3 ;

Exposure: 1, 2, or 3 consecutive days (3hrs/day);

Marginal

ZnO/m 3 ;

LOAEL : 2.3 mg

Morphological damage and increase of inflammation markers and enzymes in pulmonary lavage fluid at dose levels of 5.9 and 12.1 mg

ZnO/m 3 ; minimal changes in enzyme levels in lavage fluid but no morphological changes in lung tissue 2.3 mg ZnO/m 3 ;

;


Conner MW,

Flood WH and

Rogers AE

(1988)

A subchronic inhalation study was conducted to evaluate the toxic effects of zinc sulphate on cardiac changes in male Wistar Kyoto rats. Rats were exposed 3days/week for 5hours/day to zinc sulphate heptahydrate concentrations of 10, 30 and 100 μg zinc/m 3 nose only. A control group was exposed to filtered air only.

Animals were sacrificed 48 hours after the last exposure. No significant changes were observed in neutrophil or macrophage count, total lavageable cells, or enzyme activity levels (lactate dehydrogenase, n-acetyl β-

Dglucosaminidase, γ-glutamyl transferase) in bronchoalveolar lavage fluid, indicating minimal pulmonary effect. In the heart, cytosolic glutathione peroxidase activity decreased, while mitochondrial ferritin levels


EC number:


1314-98-3 increased and succinate dehydrogenase activity decreased, suggesting a mitochondria-specific effect. Although no cardiac pathology was seen, cardiac gene array analysis indicated small changes in genes involved in cell signalling, a pattern concordant with known zinc effects. While changes are small in healthy rats, these may be especially relevant in individuals with pre-existing cardiovascular disease (Wallenborn et al.

, 2008).

Male Hartley guinea pigs were exposed to 0, 2.7 or 7 mg ultrafine (0.05  m in diameter) ZnO/m 3 3 hours a day for 5 days. Lung function measurements were performed every day after exposure in 5-8 animals. After the last exposure the animals were sacrificed. At the highest exposure level a gradual decrease in total lung capacity

(18%) and vital capacity (22%) was seen during the exposure period. At day 4 the carbon monoxide diffusing capacity dropped to below 30% of the control level. Wet-lung weights were increased with 29%, indicating the presence of edema. Exposures up to 2.7 mg ZnO/m 3 did not alter any parameters measured (Lam et al.

, 1988).

Male Hartley guinea pigs (73) were exposed (nose-only) 3 hours a day for 6 days to 5 mg ZnO/m 3 (0.05  m in diameter). A group of 53 animals served as control group. Lung function tests (in 38 animals) were performed and the respiratory tract of the animals was morphologically examined 1, 24, 48 and 72 hours after the last exposure. Furthermore epithelial permeability (5 animals at 1 and 24 hours) and DNA synthesis in epithelial cells (5 animals at 24, 48 and 72 hours) were determined. Vital and functional residual capacity, alveolar volume and carbon monoxide diffusing capacity were all decreased and did not return to normal values 72 hours after the last exposure. Lung weights were elevated due to inflammation, still present at 72 hours after last exposure (Lam et al.

, 1985).

Male Hartley guinea pigs were exposed to 0, 2.3, 5.9 or 12.1 mg/m 3 of ZnO (as ultrafine particles with an average diameter of 0.05  m) 3 hours a day for 1, 2 or 3 consecutive nose-only exposures. Three animals from each group were examined after each exposure period, were sacrificed and lung tissues were microscopically examined, and the pulmonary lavage fluid was also examined. Exposure to 12.1 mg/m 3 increased the number of nucleated cells in lavage fluid. Exposures to 5.9 and 12.1 mg ZnO/m 3 were associated with increased protein, neutrophils, and activities beta-glucuronidase, acid phosphatase, alkaline phosphatase, lactate dehydrogenase, and angiotensin-converting enzyme. The increases were dose dependent and were detectable after the second exposure, and generally increased after the third exposure. Significant morphologic damage characterized by centriacinar inflammation in the lung was seen at 5.9 and 12.1 mg/m activities of lactate dehydrogenase and alkaline phosphatase were seen in the pulmonary fluid at the lowest dose level of 2.3 mg/m 3

3 . Minimal changes in neutrophils and

after 3 exposures but no morphologic changes were observed at this dose level. Based on these results 2.3 mg ZnO/m 3 is considered as a marginal LOAEL in this study (Conner et al.

, 1988).

5.6.1.3. Repeated dose toxicity: dermal

Considering that the dermal absorption of zinc compounds is low (see toxicokinetics section 5.1) and the lack of acute dermal effects (see acute toxicity), this endpoint is considered not to be of concern.

5.6.1.4. Repeated dose toxicity: other routes

Considering the available information on repeated dose toxicity via oral and inhalation routes of exposure, other routes are considered not pertinent for this chemical safety assessment.


Dietary levels were not measured in all of the studies reported here. According to a Total Diet Study performed by the US Food and Drug Administration (FDA) over the period 1982 to 1986, adult males (25-35 years of age) consumed an average of 16.4 mg Zn/day. Adult females (25-30 years of age) consumed an average of 9.72 mg

Zn/day (Pennington, 1989).

Oral

In a double-blind cross-over trial 47 healthy volunteers (26 females and 21 men) ingested zinc sulphate capsules containing 220 mg zinc sulphate, three times a day with each meal (resulting in a total daily dose of 150 mg Zn which equals approximately 2.1 and 2.5 mg Zn/kg bw /day for males and females, respectively) for six weeks.

Plasma zinc and copper levels, plasma cholesterol, plasma low-density-lipoprotein (LDL) and high-densitylipoprotein (HDL) cholesterol, serum ceruloplasmin and erythrocyte superoxide dismutase (ESOD) were determined. In 84% of the women and 18% of the men symptoms were reported which included headaches, nausea, vomiting, loss of appetite and abdominal cramps. The study authors reported that the gastric discomfort went together with lower body weights and taking the capsules with small meals (breakfast or morning tea) or no food. Plasma zinc levels rose significantly in both men and women (36% and 57%, respectively). Plasma copper levels did not change significantly. Total plasma cholesterol and HDL were unchanged in both sexes. In females the LDL cholesterol decreased significantly from 2.38 to 2.17 mmol/L. In females a decrease was also


EC number:


1314-98-3 found in serum ceruloplasmin (13% reduction) and in ESOD (20% reduction) (Samman and Roberts, 1987,

1988).

Hooper et al.

(1980) examined the effect of oral zinc administration on human lipoprotein values. Twelve healthy adult men were given oral doses of 440 mg zinc sulphate/day (equals approximate 2.3 mg Zn/kg bw/day in the form of two zinc sulphate capsules containing 220 mg zinc sulphate (80 mg elemental zinc per capsule resulting in a total daily dose of 160 mg Zn), each capsule to be eaten with a main meal for 35 days. Fasting lipid levels were determined on a weekly basis and continued two weeks after zinc supplementation stopped, with a final determination at 16 weeks after start of the experiment. HDL cholesterol levels were decreased by

25% at the 7 th week, but had returned to baseline levels at 16 weeks. Total serum cholesterol, triglyceride and

LDL cholesterol levels were not changed. There is a discrepancy between the dosimetric data in the Samman and Roberts study (1987/1988) as compared to the Hooper et al.

study (1980). In the first study, a daily dose of

660 mg zinc sulphate was declared to be equivalent to a dose of 150 mg Zn per day, while in the second study a daily dose of 440 mg zinc sulphate was stated to have resulted in a daily dose of 160 mg Zn. This discrepancy can only be explained by assuming that in the Samman and Roberts study zinc sulphate was administered in the form of the heptahydrate, while in the Hooper et al.

study the monohydrate has been used. As this is not clearly stated in either of the two studies, the dosimetric data which are presented here are the same as those given in the respective publications.

Chandra (1984) examined the effect of zinc on immune response and serum lipoproteins. Zinc sulphate was administered twice daily to 11 adult men for a total (extra) intake of 300 mg elemental zinc/day (i.e., approximately 4.3 mg Zn/kg bw/day). Dietary zinc intake amounted to ca 11 mg/person/day. None of the subjects showed evidence of any untoward side-effects. There was a significant increase in serum zinc levels and reduction in lymphocyte stimulating response to PHA after 4 and 6 weeks of treatment. A slight increase in

LDL was observed together with a significant reduced level of HDL cholesterol.

In two studies, the side-effects of zinc administration as a medication in the treatment chronic leg ulcers were investigated. In a double-blind trial, 13 humans received 200 mg zinc sulphate (i.e., approximately 135 mg Zn) three times a day for 18 weeks, while 14 humans received a placebo. No signs of nephrotoxicity associated with the zinc treatment were reported, but the study was not sufficiently documented to fully appreciate the relevance of its result (Hallbook and Lanner, 1972).

In a study of Greaves and Skillen (1970) no indications for heamatotoxicity, hepatotoxicity or nephrotoxicity, was determined by several clinical biochemical and haematological parameters, were seen in 18 humans after administration of 220 mg zinc sulphate (i.e., approximately 150 mg Zn) 3 times a day for 16-26 weeks.

In a 12-week double blind study Black et al.

(1988) administered zinc gluconate tablets to 2 groups of healthy male volunteers for 12 weeks at doses equivalent to 50 or 75 mg zinc/kg bw/day (i.e., approximately 0.71 and

1.1 mg Zn/kg bw/day). A control group received a placebo tablet. No changes in serum cholesterol, triglyceride, and LDL and very-low-density-lipoprotein (VLDL) cholesterol levels were observed.

In a 10-week single-blind oral study conducted by Yadrick et al., (1989), 9 healthy female volunteers were given 50 mg Zn/day in form of zinc gluconate (i.e., approximately 0.83 mg Zn/kg bw/day) and 9 other healthy female volunteers were given 50 mg Zn /day plus (as zinc gluconate) 50 mg iron (as iron sulphate monohydrate) in two daily doses via their diet to investigate the effect of zinc supplementation on iron, copper and zinc status.

The subjects served as their own controls. In both groups the erythrocyte superoxide dismutase (ESOD) activity was significantly reduced with 47% after 10 weeks. In the zinc supplemented group, significant decreases in haematocrit (by 4%) and serum ferritin levels (with 23%) were seen after 10 weeks, whereas the haemoglobin levels were unchanged. In the zinc iron supplemented group, serum ferritin levels were significantly increased by approximately 25%, whereas the haematocrit and haemoglobin levels were unchanged. The ceruloplasmin concentration, another indicator for copper status besides ESOD, was not altered in both groups, but the serum zinc concentration was significantly increased. The NOAEL in this study was less than 0.83 mg Zn/kg bw/day.

A significant decrease of 15% in ESOD activity was reported by Fischer et al., (1984) who administered 50 mg

Zn /day in form of zinc gluconate (i.e., approximate 0.71 mg Zn/kg bw/day) divided in two daily doses to 13 healthy young men with assumed mean body weight of 70 kg for 6 weeks in a double-blind study design. The other two indices of copper status, i.e. the ceruloplasmin activity and plasma copper levels were not changed compared to the controls at 2, 4 or 6 weeks, but the serum zinc levels were significantly increased from 2 weeks of supplementation onwards. Serum zinc showed a significant inverse correlation with ESOD activity at 6 weeks.

In a controlled metabolic-unit study by Davis et al., (2000), various indicators of zinc status were measured in

25 healthy postmenopausal women (mean age 64.9 years) to evaluate the usefulness of these indicators as a marker for the functional assessment of zinc status in humans. The subjects were kept under close supervision


EC number:


1314-98-3 for 200 days, divided into two 90-day dietary periods, each preceded by a 10-day equilibration period. The subjects received a daily diet with a total energy content of 8.4 MJ (or 2000 kcal). In the equilibration periods the subjects received a diet containing 2 mg copper/day and 9 mg zinc/day. For the 90-day dietary periods the subjects were randomly divided into two groups, one group (n=12) was fed a low copper diet (1 mg Cu/day) and the other group (n=13) a high copper diet (3 mg Cu/day). In the first 90-day dietary period both groups received no zinc supplement (low zinc; 3 mg Zn/day), while in the second 90-day dietary period both groups received a zinc supplement of 50 mg per day (high zinc; 53 mg Zn/day). Zinc was supplemented as zinc gluconate and copper as cupric sulphate. Blood samples were taken (after overnight fasting for 12 hours) during each of the equilibration periods and one to twice monthly during the dietary periods, and analysed for various zinc-status indicators. Zinc concentrations in erythrocytes and erythrocyte membranes, plasma and erythrocyte membrane alkaline phosphatase activities, and erythrocyte membrane 5’nucleotidase activity did not change statistically significantly with the different dietary treatments. Zinc supplementation significantly increased plasma zinc concentrations and activities of mononuclear 5’nucleotidase and extracellular superoxide dismutase (P<0.0001).

For all three indicators the effect of zinc supplementation was dependent on the copper intake although this was not statistically significant for plasma zinc. In case of mononuclear 5’nucleotidase activity, the difference caused by zinc supplementation was apparent when subjects were fed high dietary copper (92% change) but not when they were fed low dietary copper (5% change). The effects for plasma zinc and for extracellular superoxide dismutase activity were more apparent when subjects were fed low dietary copper (35 vs. 22% and

21 vs. 8% change, respectively). Independent of copper intake, zinc supplementation caused relatively small increases in free thyroxine (7-8%) and triiodothyronine (7-9%) concentrations, platelet zinc concentrations (10-

13%) and bone specific alkaline phosphatase activity (18%) (0.002<P<0.08). The levels of the affected indicators were elevated from the equilibration values at all dietary treatments, with the exception of extracellular superoxide dismutase activity at low copper/low zinc, mononuclear 5’nucleotidase activity at low copper/low zinc, low copper/high zinc and high copper/low zinc, and thyroxine and triiodothyronine concentrations at all dietary treatments. Plasma zinc concentrations were within the normal range for healthy adults (10.7-18.4  mol/L) throughout the low zinc period, but during zinc supplementation 8 out of 23 subjects had plasma zinc concentrations >18.4  mol/L.

Decreased activities upon zinc supplementation were found for plasma 5’nucleotidase activity (P<0.0001), thyroid stimulating hormone concentrations (P<0.07) and erythrocyte superoxide dismutase activity (ESOD; not statistically significant). For these three indicators the decrease was somewhat more apparent when fed high dietary copper (28 vs. 29%, 5 vs. 9%, and 3 vs. 5%, respectively). However, for plasma 5’nucleotidase and

ESOD the levels at high dietary copper were higher than at low dietary copper (only at high copper/low zinc the levels were elevated from equilibration values). For thyroid stimulating hormone the levels were depressed from equilibration values at all dietary treatments. Limited data suggested that zinc supplementation in combination with low dietary copper depresses amyloid precursor protein expression in platelets (Davis et al.

, 2000).

In the same dietary experiment as described by Davis et al., (2000) other parameters (i.e. copper-status and ironstatus indicators) were investigated to study the effect of moderately excessive and deficient intakes of zinc on copper metabolism and utilization in humans fed low and luxuriant amounts of copper (Milne et al.

, 2001). For that purpose, urine and faeces were collected during the last 78 days of each 90-day dietary period and copper and zinc were determined (in faeces in 6-day composite samples). Once weekly blood was sampled (after overnight fasting for 12 hours), and blood samples were analysed for various copper-status and iron-status indicators. Women fed low copper were in negative copper balance. Zinc intake (low or high) did not alter this.

Women fed high copper were put into negative copper balance by low zinc. Upon transition to high zinc, women fed high copper came into positive copper balance, which apparently was the result of a lower amount of dietary copper lost in the faeces; urinary copper was not affected. The zinc balance reflected dietary zinc intake

(more positive with increased zinc intake) and was not significantly affected by copper intake.

Copper-status indicators were variably affected by dietary treatment. The concentrations of serum ceruloplasmin

(enzymatically determined), HDL and VLDL cholesterol, triglycerides and red blood cell zinc did not change statistically significantly with the different dietary treatments.

Independent of zinc intake, plasma copper concentrations were significantly lower on low dietary copper than on high dietary copper (P<0.07). Although plasma copper concentrations were depressed from equilibration values at all dietary treatments, the depression was less for high than for low dietary copper (P<0.03).

Independent of copper intake, zinc supplementation caused increases in the concentrations of serum ceruloplasmin (immunochemically determined; 4-8%, P<0.05) and plasma zinc (19-32%, P<0.0001) and in platelet cytochrome c oxidase activity (on a platelet number basis; 19-27%, P<0.0007), and decreases in the concentrations of red blood cell copper (8-16%, P<0.0008) and whole blood glutathione (8-12%, P<0.009) and in the activities of specific ceruloplasmin (defined as the ratio between enzymatic and immunoreactive


EC number:


1314-98-3 ceruloplasmin; 8-11%, P<0.0003) and erythrocyte glutathione peroxidase (11-15%, P<0.002). The levels of these indicators were elevated from equilibration values at all dietary treatments, with the exception of serum immunoreactive ceruloplasmin concentration (reduced at all dietary treatments), platelet cytochrome c oxidase activity (reduced at high copper/low zinc), specific ceruloplasmin activity and whole blood glutathione concentration (essentially at equilibration values at low copper/high zinc and high copper/high zinc), and red blood cell copper concentration (essentially at equilibration value at low copper/low zinc and reduced at low copper/high zinc).

Zinc supplementation significantly decreased ESOD activity (5-7%, P<0.03) as well as the concentrations of total cholesterol (3-4%, P<0.005) and LDL cholesterol (2-6%, P<0.003), but not by much. The effect on ESOD was dependent on copper intake (P<0.0001): compared to equilibration values, ESOD activity decreased on low copper but increased on high copper. Total cholesterol and LDL cholesterol concentrations were significantly higher on low dietary copper than on high dietary copper (P<0.02 and P<0.03, respectively). This suggests a dependency on copper intake, but it should be noted that women fed low copper had higher equilibration values for both indicators than women fed high copper. The authors stated that measured indicators of iron status

(serum iron, haemoglobin, haematocrit and percent transferrin saturation) were unaffected by dietary treatment

(no data presented), with the exception of haemoglobin, which was lower on high zinc than on low zinc in both the low and high copper groups. The drop in haemoglobin occurred especially during the last month of zinc supplementation, possibly due to the frequent blood sampling. Data from another two volunteers (one on a low copper diet and one on a high copper diet) were not included, because they were using an adhesive containing extremely high amounts of zinc for their false teeth.

In the human studies described above, the effects of high or moderately high dietary zinc on several indicators known to be associated with copper status have been investigated. These indicators included plasma zinc and copper concentrations, cholesterol and lipoprotein cholesterol concentrations, and several enzyme activities (e.g.

ESOD and ceruloplasmin). Effects of zinc on the latter are thought to precede changes in plasma and tissue levels of the elements, given the primary role of zinc as a component of different enzymes. In humans supplemented with zinc, plasma zinc concentration was elevated, while plasma copper concentration was not affected. In the earlier studies by Samman and Roberts (1987/1988), Yadrick et al., (1989) and Fischer et al.

(1984) reductions in ESOD activity were found upon zinc supplementation. This was thought to be associated with copper deficiency, as was the reduction in ceruloplasmin activity found by Samman and Roberts

(1987/1988). In the more recent and more sophisticated studies by Davis et al., (2000) and Milne et al., (2001), however, only very small reductions in ESOD activity were observed that did not correlate with changes in copper balance. The clinical significance of this ESOD reduction is questionable, because the findings in these studies on more specific copper deprivation signs (i.e., decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicate that sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. It might also be that the small decrease in ESOD activity with high zinc intake was not caused by an interference with copper metabolism, but was more reflective of reduced oxidative stress given the serum glutathione and erythrocyte glutathione peroxidase findings. However, one can only conclude from the Grand Forks studies (Davis et al.,

2000; Milne et al.

, 2001) that very subtle changes were induced by the different dietary treatments.

From various studies (e.g. Fischer et al.

, 1990; Barnett and King, 1995; Verhagen et al.

, 1996 and Puscas et al.

,

1999), it can be concluded that ESOD activities in healthy human volunteers may show a coefficient of variation of at least 10 to 20%. Although it is impossible to compare the absolute ESOD activities as reported by these authors to those from the Grand Forks studies, due to methodological differences, the relative changes in activities as reported by Davis et al., (2000) and Milne et al., (2001) can be compared to the coefficient of variation of ESOD activity, showing that the changes found in the Grand Forks studies are within the range of natural variation. In addition, Fischer et al., (1990) have demonstrated that in a large group of male and female human volunteers of different ages, ceruloplasmin and serum copper levels were highly correlated, but that no correlation between serum copper concentration and ESOD could be established. ESOD activity was independent of sex, age, pre-post menopausal status, estrogen use (including that in post-menopausal women), smoking or drinking habits, or level of physical exercise.

The general function of ESOD, also within red blood cells, is to catalyze the dismutation of superoxide anion radicals to hydrogen peroxide and oxygen, thus preventing damage of cell constituents and structures by this radical intermediate generated during the oxygen transport function. Concentrations of superoxide anion radicals are in the order of 0.01 – 0.001 nmol/l under non-pathological conditions. Hydrogen peroxide, on the other hand, is destroyed by catalase being present in high amounts within erythrocytes resulting in concentrations between 1 and 100 nmol/L. According to our knowledge there are only few measured data available showing a direct relationship between changes of intracellular concentrations of free radicals and tissue damage.

Assuming that there is a considerable reduction of the ESOD activity then higher concentration of superoxide


EC number:


1314-98-3 radical anions should occur in red blood cells which may lead to destructive effects. Such effects should be detectable, e.g. by changes in haematological parameters (e.g., increased hemolysis, decreased number of erythrocytes, increase in reticulocytes). However, such findings have not been observed in any study. In the

Grand Forks studies (Milne et al.

, 2001) hematocrit, serum iron, and transferrin saturation were unaffected by a dose of 50 mg Zn/day leading to a 3-7% reduction of ESOD activity. Yadrick et al., (1989) reported a 47% decrease of ESOD activity after giving 50 mg Zn/day over 10 weeks However, this decrease of ESOD is accompanied by a small decrease in hematocit value. The subtle changes in clinical-biochemical parameters, as reported in the Grand Forks studies, are hardly indicative for zinc-induced perturbations of the copper homeostasis. These biochemical changes do not lead to detectable deterioration of red blood cell functioning.

Therefore, these changes are also of marginal biological significance, if any. Hence, it is concluded that in women supplemented with zinc, a dose of 50 mg Zn/day is the NOAEL.

5.6.3. Summary and discussion of repeated dose toxicity

The biological activities of zinc compounds are determined by their ability to release zinc under the respective exposure conditions. Hence, information on the effects of systemically available zinc allows the repeated dose toxicity assessment across all those zinc compounds covered in this safety report.

Non-human information

The repeated dose toxicity of water soluble zinc sulphate and zinc monoglycerolate has been examined in a total of 3 subchronic oral feeding studies. Due to the different dosing regimens, the lowest NOAEL was determined to be 31.5 mg/kg bw/day of zinc monoglycerolate which equals a total zinc exposure of approximate 13 mg/kg bw/day. The zinc NOAEL derived from the feeding studies with zinc sulphate was determined to be 104 mg

Zn/kg bw/day in mice and approximately 53.5 mg/kg bw/day in rats. At higher doses the most important effects in the rats were the development of hypocupremia, and significant changes in the pancreas (i.e., focal acinar degeneration and necrosis) and a decreased number of pigmented macrophages in spleen.

No longer term inhalation studies allowing to derive a robust NOEL for the inhalatory exposure of the respective zinc compounds has been identified. In a short term 3-day inhalation study with guinea pigs, a concentration of 2.3 mg ultrafine ZnO/m 3 (3 hours/day) resulted in changes in neutrophils and activities of lactate dehydrogenase and alkaline phosphatase in the pulmonary fluid. At higher concentrations increased protein concentration, neutrophils, and enzyme activities in lung lavage fluids were seen, together with significant centriacinar inflammation of the pulmonary tissue. Inhalatory doses of 2.7 mg ultrafine ZnO/m 3 for 5 days 3hours/day did not alter the lung function parameters in guinea pigs, but at 5 and 7 mg ultrafine ZnO/m 3 exposure according to a similar pattern, a gradual decrease in total lung capacity, vital capacity and reduction of the carbon monoxide diffusing capacity was seen in combination with inflammatory changes and edema. The relevance of the findings in studies with ultra-fine zinc oxide fumes is unclear with respect to commercial grade zinc oxide, as the latter is of much larger particle size and can have different toxicological characteristics.

Human information

Upon supplementing men and women with 150 mg Zn/day (as zinc sulphate capsules), women appeared to be more sensitive than men to the effects of high zinc intake: clinical signs such as headache, nausea and gastric discomfort were more frequent among women and women but not men had decreased activities of serum ceruloplasmin and ESOD. In some earlier oral studies in which humans were supplemented with moderately high amounts of zinc (50 mg Zn/day), a reduction in ESOD activity was also observed and again women appeared to be more sensitive to this effect. Hence, a reduction in ESOD was thought to be a sensitive indicator of copper status. However, in more recent and more sophisticated studies using the same dose level, ESOD was only marginally reduced (without a correlation with changes in copper balance), while findings on more specific copper deprivation signs (decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicated that a sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. Given this, and the degree of the observed

ESOD reduction in comparison to the natural variability in its activity, the zinc-induced decrease in ESOD activity is considered to have marginal biological significance, if any and also because it may not have been caused by an interference with copper metabolism as deep tissue SOD increases as a function of zinc exposure was observed.

Overall, it can be concluded that from studies in which humans were supplemented with zinc (as zinc gluconate), that women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn/day is the human NOAEL. This equals a daily exposure of 0.83 mg/kg bw. At the LOAEL of 150 mg Zn/day, clinical signs and indications for disturbance of copper homeostasis have been observed.


EC number:


1314-98-3

5.7. Mutagenicity


5.7.1.1. In vitro data


Table 33. Overview of experimental in vitro genotoxicity studies according to decreasing water solubility

Test substance Endpoint

Zinc chloride Bacillus subtilis recombination assay (DNA repair)

Zinc chloride Bacterial assay (gene mutation)

Zinc chloride

Zinc chloride

Eukaryotic assay (gene mutation)

Cytogenetic assay

(chromosomal aberrations)

Species

Bacillus subtilis

E. coli

(strain WP2s

(  ))

Mouse lymphoma cells

Human dental pulp cells (D824 cells)

Method

Bacillus subtilis recombination assay

Other: induction of λ prophage

(adaptation of

McCarroll et al.

1981); conc. 3200

μmol/l; m.a. unknown

Unknown: without m.a.

Results

Negative

Ambiguous

(two-fold increase of

λ prophage induction)



Kada et al.,

(1980)


Rossman et al.,

(1984)

Negative

Negative



Amacher and

Paillet (1980)

Someya et al.,

(2008)

Zinc chloride

Zinc chloride

Zinc chloride

Cytogenetic assay


Cytogenetic assay


Cell transformation assay

Human lymphocytes

Human lymphocytes

Syrian hamster embryo cells

Doses:

Concentration in (uM)

30 100, 300

(met. act.: with and without)

Other: m.a. unknown;

0, 30 and 300

μM (3mM toxic)

Other: without m.a.;

0, 20, and 200

μg/culture

(2000 μg toxic)

Unknown; up to 20 μg /ml

Ambiguous 2 (reliable with restrictions) supporting study

Negative 2 (reliable with restrictions) supporting study used in

RAR (EU

2004 c)

Negative 2 (reliable with restrictions) supporting study

Deknudt and

Deminatti

(1978)

Deknudt (1982)

Di Paolo and

Casto (1979)


EC number:

215-251-3

Test substance

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc bis(dihydrogen phosphate)

Zinc oxide

Zinc oxide

Zinc oxide

Zinc oxide

Endpoint

Bacterial test

(gene mutation)

Bacterial test

(gene mutation)



Cytogenetic assay

Bacterial test

(gene mutation)

Bacterial test

(gene mutation)

Bacterial test

(gene mutation)


Cytogenetic assay (sister chromatide exchange) zinc sulphide CAS number:

1314-98-3

Species

S. typhimurium

(5 strains)

S. typhimurium

(1 strain)

S. cerevisiae

(1 strain)

S. cerevisiae

(1 strain)

Human embryonic lung cells:WI-38

S. typhimurium

(4 strains) and E. coli

(strain WP2 uvrA)

S. typhimurium

(4 strains)

S. typhimurium

(3 strains)


Method

Ames test: with and without m.a. ;

5 doses, up to

3600 µg/plate

Other: without m.a.; up to 3000 nM/plate

Other: without m.a.; single concentration

(0.1 mol/L screening assay

Unknown: m.a.

Unknown;

1000 and

5000 ppm

Unknown: without m.a.;

0.1, 1.0 and

10 µg/plate

Ames test: with and without m.a;

50-

5000µg/plate

Ames test;

1000 – 5000

μg/plate

Ames test

Unknown: with and without m.a.


Unknown; m.a. unknown

Results

Negative

Negative

Weakly positive

(no details given)

Negative

Negative

Negative

Remarks






1 (reliable without restriction) key study

Reference

Gocke et al.,

(1981)

Marzin and Phi

(1985)

Singh, (1983)

Siebert et al.,

(1970)

Litton Bionetics

(1974)

Research

Institute of

Organic

Synthesis inc.,

CETA (2010)

Negative 2 (reliable with restrictions) key study

Negative 2 (reliable with

Positive restrictions) supporting study

2 (reliable with restrictions) supporting study used in

RAR (EU

2004 b)

Ambiguous 2 (reliable with restrictions) supporting study

Crebelli et al.,

(1985)

Litton Bionetics

(1976)

Cameron (1991)

Suzuki (1987)


EC number:


1314-98-3

Test substance Endpoint Species Method Results Remarks Reference

Zinc oxide

Zinc oxide

Cytogenetic assay


Cytogenetic assay


Human dental pulp cells (D824 cells)

Syrian hamster embryo cells)

Doses:


30 100, 300

(met. act.: without)

Doses:


0, 60, 120,

180(met. act.: without


0.3, 1, 3, 10 and 30 µg/mL

Positive

Positive



Someya

(2008)

Hikiba

(2005) et al.

et al.,

,

Zinc oxide

Zinc oxide

Unscheduled

DNA synthesis

Cell transformation assay




0, 1, 3 μg

ZnO/ mL

Positive

1 μg/mL

Positive 1 and 3

μg/mL

 2 (reliable with restrictions) supporting study


Suzuki (1987)

Suzuki (1987)

Zinc monoglycerolate


Bacterial test

(gene mutation)


S. typhimurium

(4 strains)


According to

OECD guideline No.

471;

50 - 5000

μg/plate; no toxicity up to

5000 μg/plate

According to

OECD guideline No.

476; without m.a.

1-15 μg/mL

Negative

Positive: without m.a. from

10 μg/mL with m.a. from 15

μg/mL



Jones and Gant,

(1994)

Adams and

Kirkpatrick

(1994)

(toxic at 15

μg/mL) with m.a. 1-

30 μg/mL

(toxic at 30

μg/mL)

According to

OECD


Cytogenetic assay


Human lymphocytes guideline No.

473; cytotoxicity at

40 μg/mL (MI

51%), con. tested: without m.a. 5

– 20μg/mL, with m.a. 10 –

40 μg/mL

Positive in the presence of m.a. at 30 and 40

μg/mL


Akhurst and

Kitching (1994)

In vitro genotoxicity assays are only available for soluble and slightly soluble zinc compounds. No data were identified for zinc sulphide. However, like for the other toxicity endpoints, there is common agreement that the ionic form of zinc is responsible for the biological activities of zinc compounds in general. Hence, information on the in vitro genotoxicity of soluble or slightly soluble zinc compounds is considered to be suitable for the


EC number:


1314-98-3 assessment of any potential genotoxic activity of zinc metal.

The genotoxicity of soluble zinc compounds zinc chloride and zinc sulphate as well as slightly soluble zinc compounds zinc oxide and zinc monoglycerolate in vitro has been extensively studied in various bacterial and mammalian test systems. This included mutagenicity and clastogenicity assays as well as in vitro UDS and cell transformation assays.

All investigated zinc compounds were predominantly negative in bacterial and mammalian mutagenicity assays.

Conflicting information was, however, found in clastogenicity (i.e., chromosomal aberrations, sister chromatide exchange) and the cell transformation assays where negative as well as positive results were obtained. In case clastogenic effects were observed, these were generally considered to be weak and occurred only at high, often cytotoxic concentrations. While zinc acetate and zinc 2,4-pentanedione were negative, Zinc oxide was positive in the in vitro UDS assay.

5.7.1.2. In vivo data


Table 34. Overview of experimental in vivo genotoxicity studies according to decreasing water solubility

Test substance Endpoint

Zinc chloride Cytogenetic assay


Zinc chloride Cytogenetic assay


Species

Mouse

Mouse

Method

Other: 0.5% zinc in calciumdeficient

(0.03% Ca) or standard diet

(1.1% Ca) for

30 days

Other; single i.p. injections of 0, 7.5, 10 or

15 mg

ZnCl

2

/kg bw and repeated i.p. injections every other day of 2 and 3 mg ZnCl

24 days.

2

/kg bw for 8, 16 or

Results

Slightly positive in case of calcium deficient diet in the survivors

(0.5% Zn with poor Cadiet resulted in 50% mortality after 30 days)

Single dose study: positive; repeated dose study:

Positive



Deknudt

(1982)


Gupta et al., (1991)


EC number:


1314-98-3

Test substance

Zinc chloride

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc oxide

Endpoint

Drosophila

SLRL test

Cytogenetic assay


Micronucleus

Host-

Mediated

Assay

Dominant lethal assay

Drosophila

SLRL test

Cytogenetic assay


Species

Drosophila melanogaster

Rat

Mouse

Mouse

Rat

Drosophila melanogaster

Rat

Method

Unknown;

0.247 mg/mL adult feeding

Other: 2.75,

27.5 or 275 mg/kg bw by gavage once or daily for 5 consecutive days

Other: i.p.

28.8, 57.5 or

86.3 mg/kg bw at 0 and 24 hours

Other: 2.75,

27.5 or 275 mg/kg bw by gavage once or daily for 5 consecutive days other: 2.75,

27.5 or 275 mg/kg bw by gavage once or daily for 5 consecutive days other; 5 mM

(in 5% saccharose) adult feeding method

Other: 5 months inhalation of

0.1 to 0.5 mg/m 3

Results

Negative

Negative

Negative

Weakly positive

Negative

Negative

Slight increases of chromosomal aberrations were seen; primarily hyperdiploid cells were seen.

Negative









Carpenter and Ray

(1969)

Litton

Bionetics

(1974)

Gocke al.

Litton

Bionetics

(1974)

Litton

Bionetics

(1974) et

(1981)

Gocke al., et

(1981)

Voroshilin et al.,

(1978)


Micronucleus Rat Other: resembling

OECD guideline No.

474; 0.05%,

0.2%, and 1% in purified diet over a 13 week period


Windebank et al.,

(1995)

The in vivo genotoxicity of zinc compounds has been studied in various test systems including the micronucleus test, sister chromatide exchange and chromosomal aberration test, dominant lethal mutation assay as well as for


EC number:


1314-98-3 sex-linked recessive lethal mutations in drosophila melanogaster.

Neither zinc sulphate nor zinc monoglycerolate induced micronuclei in two reliable mouse and rat micronucleus tests. Further, both zinc sulphate and zinc chloride did not increase the incidence of sex-linked recessive lethal mutations in Drosophila melanogaster (Gocke et al., 1981; Carpenter and Ray, 1969). Zinc sulphate was further negative in a dominant lethal assay in rats.

Equivocal and sometimes contradicting results were found for the induction of chromosomal aberrations which have been studied in bone marrow cells harvest from animals exposed to zinc compounds zinc chloride, and zinc oxide. Negative findings for chromosome aberrations have been produced after intraperitoneal injection of zinc chloride into mice (Vilkina et al ., 1978) or when rats were given zinc sulphate by gavage once or daily for

5 consecutive days (Litton Bionetics, 1974). In contrast, increased aberrations have been reported in rats after inhalation exposure to zinc oxide (Voroshilin et al ., 1978), in rats after oral exposure to zinc chloride and in mice after multiple intraperitoneal injections of zinc chloride (Gupta et al ., 1991). Moreover, increased chromosomal aberrations were found in calcium-deficient mice when fed zinc (in form of zinc chloride) via the diet (Deknudt, 1982).


The only identified publicly available genotoxicity study in humans related to the identification of chromosomal aberrations in lymphocytes of 24 workers in a zinc smelting plant (Bauchinger et al., 1976). This study was, however, not suitable to draw any conclusions to the association of these effects with zinc exposure, as the workers displayed also increased blood levels of lead and cadmium, and the clastogenic effects were predominantly attributed to cadmium exposure.

There were no further reports in the accessible literature on genotoxic effects of zinc compounds in human populations.

5.7.3. Summary and discussion of mutagenicity

The genotoxicity of soluble and slightly soluble zinc compounds have been extensively investigated in a wide range of in vitro and in vivo studies. The in vitro investigations included non-mammalian and mammalian test systems covering the endpoints of gene mutation, chromosomal aberrations, sister chromatide exchange, unscheduled DNA synthesis (UDS), as well as cell transformation. Available in vivo genotoxicity assays included the micronucleus test, sister chromatide exchange (SCE) and chromosomal aberration test and the dominant lethal mutation assay in mouse or rat as well as investigations for sex-linked recessive lethal mutation in drosophila melanogaster.

The investigated zinc compounds did not increase the mutation frequencies in the majority of bacterial or mammalian cell culture systems. For example, zinc chloride, zinc sulphate, zinc bis(dihydrogen phosphate), zinc oxide or zinc monoglycerolate were consistently negative in the Ames test. While zinc chloride was also negative for gene mutations in the mouse lymphoma assays, there was some evidence that zinc oxide, zinc acetate or zinc monoglycerolate induced in the absence of metabolic activation the formation of mutation colonies. Several reviewers noted, however, that these mutations were observed at cytotoxic concentrations and that the analysis did not distinguish between big and small colonies which could be caused by gene mutation or chromosomal aberrations (Thompson et al., 1989, WHO, 2001; EU RAR, 2004; MAK, 2009).

Conflicting information was further found when zinc compounds were examined for their potential to induce chromosomal aberrations or sister chromatide exchange in mammalian cell systems or when evaluated in the cell transformation assay. Positive as well as negative results were obtained in these cell systems with either soluble or slightly soluble zinc compounds. In those studies where chromosomal aberrations or sister chromatide exchange were observed, these were generally considered to be weak and occurred only at high, often cytotoxic concentrations. Moreover, these positive in vitro findings have also to be seen in context of the impact that changes in zinc levels can have on cell system processes that are controlled by a strict metal homeostasis. A change of this metal homeostasis due to increased zinc levels, may lead to a binding of zinc to amino acids like cystein and therefore to an inhibition of certain enzymes. This can lead to interactions with the energy metabolism, signal transmission and apoptotic processes which can lead to the observed clastogenic or aneugenic effects in in vitro systems (EU RAR, 2004; MAK, 2009).

In addition to above mentioned in vitro investigations, various soluble and slightly soluble zinc compounds have also been studied in a range of in vivo studies including the micronucleus test, SCE and chromosomal aberration test or dominant lethal mutation assay in mice or rats as well as in the Drosophila Melanogaster SLRL test. The


EC number:


1314-98-3 zinc compounds were consistently negative in the micronucleus and in the assay with Drosophila Melanogaster.

Zinc sulphate was further negative in a dominant lethal assay in rats.

As discussed in section 5.7.1.2, equivocal and sometimes contradictory results were obtained in the in vivo chromosomal aberration assays. These equivocal finding likely a reflection of inter-study differences in routes, levels, and duration of zinc exposure, the nature of lesions scored (gaps compared to more accepted structural alterations) and great variability in the technical rigour of individual studies (WHO, 2001). The German MAK committee reviewed the existing in vivo evidence and concluded that particularly those studies indicating clastogenic effects involved a lot of methodological uncertainties which do not allow overruling those in vivo studies which did not provide any evidence for chromosomal aberrations in vivo . Moreover, the Dutch rapporteur of EU risk assessment of zinc compounds under the EU existing substance legislation considered the positive in vitro findings for chromosomal aberration and SCE assays to be overruled by the overall weight of evidence of negative in vivo tests for this endpoint (EU RAR, 2004).

The overall weight of the evidence from the existing in vitro and in vivo genotoxicity assays suggests that zinc compounds do not have biologically relevant genotoxic activity. This conclusion is in line with those achieved by other regulatory reviews of the genotoxicity of zinc compounds (WHO, 2001; EU RAR, 2004, MAK, 2009).

Hence, no classification and labelling for mutagenicity is required for any of those zinc compounds covered in this chemical safety report.

5.8. Carcinogenicity


5.8.1.1. Carcinogenicity: oral

A one-year drinking water study was conducted to evaluate the carcinogenic potential of zinc sulphate in

Chester Beatty stock mice. The doses of zinc sulphate were 4.4 g/L (1,000 ppm zinc) and 22 g/L (5,000 ppm zinc) in drinking water along with a control group fed a basal diet and normal drinking water.

The animals were examined thoroughly once a week throughout the experiment and a more cursorily examination daily when fed. Weighing was done once every 2 weeks. Deaths of animals occurred during the first 8 week of experiment due to an epizootic of ectromelia. The survivors were vaccinated with sheep lymph and animals showing a negative or accelerated response were sacrificed. New group of weanling mice (4 -5 wk old) were added to supplement the control group. All the surviving animals were sacrificed after 1 year of treatment and examined for gross pathology. Histopathological examination was done for suspected neoplastic lesions. Stomachs were examined for tumours and other changes in the forestomach and glandular epithelium.

No differences in carcinogenic effects were observed between treatment and control groups under the test conditions. Under the test conditions, the test material was found to be non-carcinogenic in mice (Walters and

Roe, 1965).

5.8.1.2. Carcinogenicity: inhalation

Presently information is unavailable.

5.8.1.3. Carcinogenicity: dermal


5.8.1.4. Carcinogenicity: other routes



Human experience is predominantly available from the use of zinc compounds as dietary supplements. Isolated epidemiological studies examined also the association between occupational exposures to zinc and carcinogenicity. The following presents some of the key studies in this context:

A population based case-control study was conducted to determine the association of dietary zinc level and brain tumour development. The study was conducted between 2001 and 2004 in the UK and comprised adults aged 18–69 years. Dietary information was collected from 637 cases diagnosed with a glioma or meningioma, and 876 controls. Data were obtained from a self-completed food frequency questionnaire (FFQ). Multivariate


EC number:


1314-98-3 logistic regression analysis was conducted, adjusting for socio-demographic factors, season of questionnaire return, multivitamin supplementation and energy intake. Although a weak protective effect was observed for the third quartile of intake (normal compared with low intake) in the meningioma group, this was limited to the specific brain tumour subtype and quartile, and was not significant after also adjusting for intake of other elements. Overall there was no significant effect of zinc intake. In conclusion, no association or dose–response relationship was observed between increased vs. low zinc intake and risk of glioma or meningioma

(Dimitropoulou et al.

, 2008).

A case-control study was conducted for analysing the association of prostatic cancer with the intake of particular nutrients, namely fat, vitamins A and C and zinc. A total of 452 cases of prostatic cancer, identified through the population based Hawaii Tumor Registry during the period 1977-1983, and 899 age-matched population controls were interviewed on the island of Oahu from 1981 to 1983. The subjects and population controls were comprised of five different ethnic groups (i.e., Caucasian, Japanese, Chinese, Philipino, and Hawaiian). All subject interviews were conducted in the home by use of a quantitative dietary history method. The weekly intake of fat, zinc, and vitamins A and C, including supplements was determined for each subject. Among 70 years or older men, but not among younger men, the mean weekly consumption of saturated fat, carotenes, and zinc, adjusted for age and ethnicity, was greater for cases than for controls. In a multiple logistic regression analysis, the odds ratio for the highest quartile of fat intake among the older men was 1.7 (95% confidence interval (CL) 1.0-2.8). The corresponding odds ratios were 1.6 (95% CL1.0-2.5) for carotenes, 1.4 (95% CL 0.9-

2.3) for total vitamin C, and 1.7 (95% CL 1.1-2.7) for total zinc. There were significant linear trends in the odds ratios for saturated fat and zinc, but no synergistic interactions among the nutrients. The results suggest that several different components of the diet may contribute independently to the risk of prostatic cancer in elderly men (Kolonel et al.

, 1988).

In a multicentre hospital based case-control study on prostate cancer, the association between high zinc intake and prostate cancer risk, particularly for advanced cancers was evaluated. The study was conducted between

1991and 2002 and considered 1294 cases and 1451 controls. Zinc intake was computed from a valid and reproducible food frequency questionnaire, with the use of an Italian food composition database. Odds ratios

(OR) of dietary intake of zinc and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models, after allowance for several covariates, including total energy.

Compared with the lowest quintile, the OR for the highest quintile was 1.56 (95% CI, 1.07–2.26), with a significant trend in risk (p = 0.04). The trend in risk was significant for advanced cancers only, the OR being

2.02 (95% CI, 1.14–3.59) for prostate cancers with a high Gleason score. In this case-control study, a direct association between high zinc intake and prostate cancer risk, particularly for advanced cancers was observed and thus excluded the favourable effect of zinc on prostate carcinogenesis (Gallus et al.

, 2007).

A population based case-control study was conducted to examine association of dietary supplement use

(including zinc) with prostate cancer risk in King County, Washington. 697 incident prostate cancer cases (ages

40–64 yr) identified from the Puget Sound Surveillance, Epidemiology and End Results program registry and

666 controls recruited from the same overall population using random-digit dialling sampling. Participants reported their frequency of use of three types of multivitamins and single supplements of vitamins A, C, and E, calcium, iron, and zinc over the 2 yr before diagnosis. Logistic regression analyses controlled for age, race, education, family history of prostate cancer, body mass index, number of prostate-specific antigen tests in the previous 5 yr, and dietary fat intake. Although zinc use was rare, there was a borderline statistically significant

45 % reduction in risk of prostate cancer among those using zinc daily, with a significant test for trend. Adjusted odds ratios (95% confidence limits) for the contrast of ≥7/wk versus no use were 0.55. When cases were stratified by stage of disease at diagnosis, there was no suggestion of different effects among participants with early (stages A and B) and advanced (stages C and D) disease. When stratified by histopathological grade, somewhat stronger protective effect was observed in higher-grade disease, although trends were similar in both groups. The results of this study indicate that use of individual supplement of zinc may be protective against prostate cancer (Kristal et al.

, 1999).

A study was conducted to determine the relationship between supplemental zinc intake and prostate cancer risk among the participants in the Health Professionals Follow-Up Study. The study was approved by the institutional review board on the use of human subjects in research of the Harvard School of Public Health.

Follow-Up study was initiated in 51,529 male health professionals aged 40 to 75 years and follow-up questionnaires mailed biennially to cohort members to update information on newly diagnosed illnesses. Dietary intake was assessed with the use of a 131-item semi quantitative food-frequency questionnaire. Supplemental zinc provided 32% of total zinc intake representing the major source of zinc. Compared with nonusers, men who consumed supplemental zinc also consumed more multivitamins, supplemental calcium, supplemental vitamin

E, lycopene, copper, iron, folate, and fish, but had lower intakes of red meat, and were slightly less likely to have had a history of prostate specific antigen screening. Non significant associations between supplemental


EC number:


1314-98-3 zinc intakes at doses less than or equal to 100 mg/d and the risk of prostate cancer. However, compared with nonusers, men who consumed more than 100 mg/d of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; Trend = .003), and men who took supplemental zinc for

10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; Trend <.001).Residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use cannot be ruled out, so the finding that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation. Supplemental zinc intake at doses of up to 100 mg/d was not associated with prostate cancer risk.

However, excessively high supplemental zinc intake may be associated with an increased risk of advanced prostate cancer (Leitzmann et al.

, 2003).

In an old zinc mining and smelting area in the US, a study was conducted to determine the excess in lung cancer mortality associated with residence. The age- and sex-adjusted mortality rates were compared to state and national rates. Age and sex specific lung cancer mortality rates were calculated for white individuals by county in Missouri (1968-1977) and Kansas (1973-1977) and then age adjusted. Additional lung cancer data were obtained from the Environmental Protection Agency (EPA) for Oklahoma, Kansas, and Missouri. Data were combined for the three counties to form one 'super-county.' The analysis determined that lung cancer mortality was elevated in the region. Quantification of inhabitant’s exposure to zinc was not part of the study. The authors mentioned several possible causes for the increased lung cancer rates such as smoking habits, occupational exposure (e.g. in mining and associated activities) and residence. Ore contaminants were arsenic, cadmium, iron, sulphur, germanium and radioactivity. Tuberculosis and silicosis were commonly seen among the region’s inhabitants. From this study no conclusions on a possible association between exposure to environmental levels of zinc and the increased lung cancer rate could be drawn (Neuberger et al.

, 1982).

A cohort study was conducted on male workers exposed for at least one year in zinc refineries, to determine if the refinery operation is associated with any excess mortality patterns. Employees were incorporated in the study when they had worked in the electrolytic department for at least one year. Age-adjusted standardized mortality ratio’s (SMR) were calculated on the basis of comparison with the mortality rates for the entire population for the year 1970. Of the 1247 workers who were exposed to “zinc” (either alone or in combination with “copper”), 88 died before the end of the follow-up. For 12 of these, the cause of death could not be retrieved. 143 workers were lost to follow-up entirely. Cancer rates were only analysed for the entire cohort of refinery workers (i.e. all 4802 participants). Overall SMRs were calculated to be 92 for the cohort and 83 for the subgroup of zinc refinery workers. Significantly high cause-specific SMRs were as follows: (1) cerebrovascular disease (CBVD) for the cohort; (2) all cancers, cancer of the digestive tract, and CBVD for the copper subgroup;

(3) all cancers, cancer of the respiratory tract, and CBVD for one plant that demonstrated a significantly high overall SMR. The significant excess of cancer deaths among the study cohort was largely due to the plant that exhibited the significantly high overall mortality rate, but lack of smoking data qualifies this finding. An association between cancer mortality and employment in zinc and/or copper refinery was not found, under the study conditions. A conclusion about any association between cancer mortality and zinc exposure cannot be drawn, because cancer mortality for “zinc”-workers was not analysed separately from cancer mortality for

“copper”-workers (Logue et al.

, 1982).

5.8.3. Summary and discussion of carcinogenicity

No adequate experimental animal studies are available to evaluate the carcinogenicity of zinc compounds in humans.

There are a range of epidemiological studies that investigated the association between zinc exposure either through occupational activities or food supplementation and increased cancer risks. While no associations were found between occupational zinc exposure and excess cancer risk, the main association that has been made in this context is related to dietary/supplemental zinc and prostate cancer risk.

In contrast to established clinical and experimental evidence that prostate cancer is associated with a decrease in the zinc uptake, numerous epidemiology studies and reports of the effect of dietary and supplemental zinc on the incidence of prostated cancer have provided divergent, inconsistent and inconclusive results which range from adverse effects of zinc, protective effects of zinc and no effect of zinc on the risk of prostate cancer. Clinical and experimental studies have established that zinc levels are decreased in prostate cancer and support a role of zinc as a tumor suppressor agent. Malignant prostate cells in situ are incapable of accumulating high zinc levels from circulation (Franklin et al., 2005; Costello and Franklin, 2006; Franklin and Costello, 2007).

In a recent critical assessment of epidemiology studies regarding dietary/supplemental zinc and prostate cancer risk, Costello et al., concluded that epidemiological studies have not provided an established relationship for any effect or lack thereof of dietary/supplemental zinc on the risk of prostate cancer. Proclamations of an association of dietary/supplemental zinc and increased prostate cancer are based on inconclusive and uncorroborated reports


EC number:


1314-98-3

(Costello et al., 2007).

On the basis of the existing information it can be concluded that there is no conclusive evidence for carcinogenic activity of any of the zinc compounds considered in this chemical safety report.

5.9. Toxicity for reproduction

5.9.1. Effects on fertility


A range of studies have been conducted to assess the effects of zinc on fertility and reproductive performance, most of them with soluble zinc chloride and zinc sulphate. A complete overview and review of available fertility studies is available in the EU risk assessment of zinc compounds (EU RAR, 2004), the review of the of health effects of zinc compounds by the US Agency for Toxic Substances and Disease Registry (ATSDR, 2005), the toxicological review of zinc and compounds by the US Environmental Protection Agency (US EPA, 2005) or the review by the WHO (WHO, 2001). The results of the key experimental studies addressing potential effects of zinc compounds on fertility are summarised in the following table:

Table 35. Overview of experimental studies on fertility

Test substance Method

Zinc chloride One-generation study in rats administered zinc chloride at doses of 0, 3.6, 7.2, 14.4 mg

Zn/kg bw/d in water over one generation by gavage. Exposure started 77 days prior to mating

Results

As of 3.5 mg Zn/kg bw/day :

P - Mortality  ; body weight gain  ; fertility indext  ; thymus atrophy

F1 - litter size (non significant)  ; number of surviving pubs (non significant)  ;


P – hemosidosis of spleen; lymphocyte deficiency

F1 - number of surviving pubs

 ; BW gain (PND 21) 

Remarks


Zinc chloride One-generation study in mice administered zinc chloride at doses of 0, 0.75, 1.5 and 3, mg Zn/kg bw/d respectively, 0. 1.5, 3 and 6, mg Zn/kg bw/d in water with 1.5mL

HNO

3

/l over one generation by gavage.

Exposure started 49 days prior to mating

0.75 resp. 1.5 mg Zn/kg bw/day :

P - Mortality  ; body weight gain  ; abs./rel. Liver/thymus/ spleen weight  ; fertility indext  ; number pregnancies 

F1 - litter size (non significant)  ; number of surviving pubs (non significant)  ;

1.5 resp. 3 mg Zn/kg bw/day :

P - body weight gain  ;

F1 – 14day survival index  ;

3 resp. 6 mg Zn/kg bw/day :

F1 – only 1 birth; 9 still births.


Zinc chloride Two-generation study in rats administered zinc chloride at doses of 7.5, 15and 30 mg/kg bw/d in water over two successive generations


P - Mortality  ; body weight gain  ; abs/rel liver/kidney weight  ; lesions in GI tract, inflammation in prostate

F1 - Mortality  ; body weight


Reference

Khan et al .,

2001

Khan et al .,

2001

Khan et al .,

2007


EC number:


1314-98-3 via the oral route.

Application procedure not specified but likely oral gavage. Exposure started 77 days prior to mating. gain  ; abs/rel brain/prostate/spleen weight  ;

F2 – no effects

7.2 mg Zn/kg bw/day :

P – abs./rel. brain/seminal vesicle weight  ;

F1 - abs/rel liver/adrenal/seminal vesicle weight 

F2 – no effects

14.1 mg Zn/kg bw/day :

P – abs./rel. Spleen/uterus weight  ;

F1 - body weight gain

(PND21)  ; abs/rel kidney weight  ; litter size and

#surviving pubs until PND4  ;

F2 – body weight gain

(PND21)  ; abs/rel kidney weight  ; litter size and number surviving pubs until PND4  ;

Maternal toxicity at any dose level. The NOAEL for fertility and development toxicity is about 15 mg ZnCl2/kg bw/d, this corresponds to 7.2 mg Zinc/kg bw/day. No NOAEL for systemic toxicity could be derived.

Zinc sulphate Charles foster rats fed with a diet containing

4000ppm Zn (in form of zinc sulphate); exposure equals 200 mg Zn/kg bw exposure started 30-32 days prior to mating.

200 mg Zn/kg bw/day

P – Zn-concentration in testis and sperm  ; sperm mobility  ; number of pregnancies 

F1 – number of live births 


Samanta et al.

,

1986

The reproductive toxicity of zinc compounds, represented by soluble zinc chloride and zinc sulphate has been investigated in one and two-generation reproductive studies with zinc chloride and zinc sulphate conducted by

Khan et al . (2001, 2003, 2007) and Samanta et al.

(1986). Moreover, information on potential effects of zinc compounds on reproductive organs can be derived from subchronic toxicity studies conducted Maita et al .

(1981) and Edwards and Buckley (1995).

The most recent one and two generation reproductive toxicity studies conducted by Khan et al., (2001, 2003,

2007) in rats and mice with zinc chloride provide the most coherent picture on the effects of zinc. All these studies have in common that while effects on fertility such as reduced litter size in F1 and F2 generation have been determined, these were only noticeable at doses which resulted in toxic effects in the dam.

Maita et al ., (1981) reported that mice and rats fed with zinc sulphate in dietary concentrations up to 30,000 mg/kg feed did not produce adverse effects on either male or female sex organs after 13 weeks of exposure. This dietary level was equal to ca. 1100 mg or 565 mg Zn/kg bw/day for mice and rats, respectively. Edwards K. and

Buckley P (1995) showed that rats exposed to 13 or 60 mg Zn/kg bw/day in the diet over a period of 90 days did not show any detrimental effects on sex organs. In the exposure group of 335 mg Zn/kg bw/day, all males showed hypoplasia in testes and seminiferous tubules in males hypoplastic uterus in females, but these findings are not considered reliable as the animals of this high dose group were generally of poor health conditions and killed for humane reasons prior to study termination.

In addition to those key reproductive toxicity studies summarised in Table 35 , some additional studies indicating high oral doses of zinc (i.e., exposures greater that 25 mg day/kg bw/day) to impair fertility as


EC number:


1314-98-3 indicated by a decreased number of implantations sites and increased number of resorptions are of note:

A study was carried out to determine the effect of zinc supplementation on the number of implantation sites and resorptions in pregnant rats. The control group consisting of 12 pregnant females was maintained on 10 % vegetable protein diet (containing 30 ppm zinc) from Day 1 through Day 18 of pregnancy. The experimental group consisting of 13 animals was also maintained on the same diet, but received additionally 150 ppm zinc as a 2% zinc sulphate solution administered daily orally. All the animals were sacrificed on Day 18 of pregnancy, and their uteri examined for implantation sites and resorptions. Of a total number of 101 implantation sites in the

12 control animals there were two resorptions, one in each of two animals. In marked contrast, in the 13 zinc supplemented animals, there were 11 resorptions out of 116 implantations. Eight of the animals had at least one resorption each. This difference was statistically significant. The result indicates that oral administration of moderately high levels of zinc (150 ppm) may be associated with harmful effects in the course of pregnancy of rat (Kumar et al.

, 1976). The low protein diet may have affected the physiology of the animals resulting in an increased sensitivity for zinc. As this hypothesis cannot be further and also considering the limited available study information, this study is only of limited validity for the assessment of effects of zinc exposure on fertility

(EU RAR, 2004).

Another study aimed at determining the effect of post-coitum, and pre- and post-coitum dietary zinc supplementation on the conception in the Charles-Foster rat. In the post-coitum study (test 1), two groups of 15 pregnant rats were fed 0 and 4,000 ppm zinc as zinc sulphate in diet (i.e., approximately 200 mg Zn/kg bw/day) from day 1 through day 18 of pregnancy. In the pre- and post-coitum study (test 2), two groups of 15 female rats were treated with same doses for 21 days pre-mating period, maximum 5 days of mating period and 18 days of post-coitum period. All the females were sacrificed on Day 18 of gestation and uterus content and fetuses were examined. In test 1, significant decrease in the incidences of conception and number of implantation sites per mated female was observed in the treatment group with respect to the control group. However, the difference in implantation sites when considered per pregnant female was not significant. In test 2, no significant difference in incidences of conception and implantation sites was observed in the control and treatment groups. In both the tests, there was no treatment-related change in the fetal and placental weights, stillbirths and malformed fetuses were absent and the number of resorption sites was negligible. Based on these results, dietary zinc supplementation at 4,000 ppm did not affect the fetal growth in pregnant rats. This dose, however, altered the normal conception when started after coitus but showed no effect when initiated sufficient time before coitus

(Pal et al.

, 1987).


In reviews by the World Health Organisation in the Environmental Health Criteria for Zinc (WHO, 2001) and by the US Agency for Toxic Substances and Disease Registry in the Toxicity Profile for Zinc (ATSDR, 2005), existing human studies which examined the responses of women to zinc supplementation during pregnancy have been summarised. Studies on large controlled trials that were conducted to investigate the effects of dietary zinc supplementation in healthy pregnant women were peer reviewed. The reviewers concluded that zinc at a rate of

20mg/day and 30 mg/day did not result in any adverse reproductive effects during pregnancy (Hunt et al., 1984;

Kynast and Saling et al., 1986).Two exemplar studies are summarised in the following:

A double blind trial was conducted in 56 pregnant women at risk of delivering a small for gestational-age baby to determine the effects of dietary zinc supplementation during the last 15-25 weeks of pregnancy following administration of 22.5 mg zinc/day. No adverse reproductive effects were observed (Simmer et al., 1991).

Pregnant women who received 0.3 mg zinc/kg/day as zinc sulphate capsules during the last two trimesters did not exhibit any changes in maternal body weight gain, blood pressure, postpartum haemorrhage or infection, indicating no adverse reproductive effects (Mahomed et al., 1989).

5.9.2. Developmental toxicity


The following table summarizes the key studies addressing the developmental toxicity of zinc compounds in experimental animals:

Table 36. Overview of experimental studies on developmental toxicity

Test substance*

Zinc sulphate

Species Route Method

Mouse

CD-1

Oral Females received daily

Result

No discernible effects were seen on or

Remark

2 (reliable with

Reference

Food and

Drugs


EC number:


Test substance*

Species Route Method

Zinc sulphate

Zinc sulphate

Zinc sulphate

Zinc sulphate

Result Remark

Rat

Wistar

Rat

Charles

Foster doses of 0, 0.3,

1.4, 6.5 and 30 mg ZnSO

ZnSO

4

4

(unspecified)/k g bw by oral gavage during days 6-15 of gestation.

Oral Females received daily doses of 0, 0.4,

2.0, 9.1 and

42.5 mg ZnSO

(unspecified)/k

4 g bw by oral gavage during days 6-15 of gestation.

Oral Females received daily doses of 0, and

200 mg Zn/kg bw (in form of

) in diet during days 1-

18 of gestation

Hamster Oral Females

Rabbit

Dutch received daily doses of 0, 0.9,

4.1, 19, and 88 mg ZnSO

4

(unspecified)/k g bw by oral gavage during days 6-10 of gestation.

Oral Females received daily doses of 0, 0.6,

2.8, 13 and 60 mg ZnSO

4

(unspecified)/k g bw during days 6-18 of gestation. maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL :

30 mg/kg bw/day equalling

12mg Zn/kg bw/d

(anhydrate);

6.8mg Zn/kg bw/d

(heptahydrate);

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL :

30 mg/kg bw/day equalling

17mg Zn/kg bw/d

(anhydrate);

9.6 mg Zn/kg bw/d

(heptahydrate);

No discernible effects were seen on or maternal or foetal survival. A reduced number of implantations observed. No difference in number of abnormalities found in foetuses.

NOAEL :

200 mg/kg bw/day


NOAEL :

20 mg/kg bw/day


NOAEL :

13.6 mg/kg bw/day restrictions)

Key study

2 (reliable with restrictions)

Key study


Key study


Key study


Key study

CAS number:

1314-98-3

Reference

Research

Labs., Inc,

1973*

Food and

Drugs

Research

Labs., Inc,

1973*

EU RAR,

2004

Food and

Drugs

Research

Labs., Inc,

1973*

Food and

Drugs

Research

Labs., Inc,

1974*


EC number:


1314-98-3

Test substance*

Species Route Method Result Remark Reference

Zinc carbonate

Rat

Sprague

Dawley

Oral Females received daily doses of 0, 2.5, and 50 mg

Zn/kg bw (in form of

ZnCO

3

) in diet during days 1-

20 of gestation.


NOAEL :

50 mg/kg bw/day


Key study

Uriu-Hare,

1989

* ZnSO

4

form is unspecified. The NOAEL, expressed as Zn cation, has been calculation for both anhydrate- and heptahydrate forms.

Several prenatal toxicity studies are available that examined the developmental toxicity of various zinc compounds in rats, mice, rabbit or hamsters up to dietary exposure levels of 200 mg Zn/kg bw/day or 50 mg

Zn/kg bw/day by gavage (for details see Table 36). No developmental toxicity has been observed in these studies and there NOAEL’s have been established at the highest doses tested.

Although some developmental effects such as decreases in body weights or decrease in individual organ weights were observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al . (2007) at high exposure levels, these observations are, however, not suitable for risk assessment or hazard classifications as they were always accompanied with maternal toxicity. Moreover, no developmental toxicity was observed at non-maternally toxic doses in a teratogenicity study in which CF-1 albino mice were administered intraperitoneally 0, 12.5, 20.5 and 25 mg/kg on Day 11 of gestation (test 1) and at 20.5 mg/kg on

Days 8 -11 of gestation (test 2) (Chang et al ., 1977).


In establishing the Environmental Health Criteria for Zinc, the World Health Organisation has reviewed and summarised existing human studies examining the responses of women to zinc supplementation during pregnancy. None of the studies indicated any significant effects on the developing foetus (WHO, 2001). Two exemplar studies are summarised in the following:

A study was conducted on pregnant women to determine the effects of nutrients during pregnancy on maternal and fetal outcome. Four hundred fifty women were observed during pregnancy and postpartum. Forty-three variables including 12 laboratory indices of maternal nutrient status were assessed. Maternal plasma zinc levels were inversely correlated with fetal weight. Blood examinations revealed a significant association between the total occurrence of fetomaternal complications or fetal distress, and lowest quartile zinc/albumin and highest quartile folate. Under the study conditions, plasma zinc was determined to be a discriminator for fetomaternal complications only in women in the lowest quartile for plasma zinc (Mukherjee et al.

, 1984).

A double blind trial was conducted on pregnant women to determine the effects zinc supplementation during pregnancy on maternal and fetal outcome. 494 women booking before 20 week of gestation in a hospital were prescribed either 66 mg zinc sulphate (equivalent to 20 mg elemental zinc) capsules or placebo for once daily use, starting from day of booking till delivery. Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight. There were no differences between the mothers and neonates of the zinc supplemented and placebo group. Under the test conditions, zinc supplementation during pregnancy did not affect maternal or fetal outcome (Mahomed et al.

, 1989).

5.9.3. Summary and discussion of reproductive toxicity

Effects on fertility

The reproductive toxicity of zinc compounds has been investigated in one and two generation reproductive toxicity studies in which rats or mice were dosed by gavage or via the diet with soluble zinc compounds ( i.e

., zinc chloride, zinc sulphate) at exposure levels up to 14 mg Zn/kg bw/day (gavage) or 200 mg Zn/kg bw/day

(diet) (Khan et al., 2001, 2003, 2007). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maita et al.

(1981) and Edwards and Buckley (1995).

The available information suggests that high oral doses of zinc (i.e., exposure levels greater than 20 mg Zn/kg


EC number:


1314-98-3 bw/day) may adversely affect spermatogenesis and result in impaired fertility indicated by decreased number of implantation sites and increased number of resorptions (US EPA, 2005). However, these effects were only observed in the presence of maternal toxicity as seen in the one or two generation studies conducted by Khan et al., (2001, 2003, 2007) or, in case of the study conducted by Kumar et al ., (1976), when other study non-zinc relevant study specificities could have impacted the study outcome.

In a large number of controlled trials, dietary supplementation with zinc rate of 20 mg/day and 30 mg/day did not result in any adverse reproductive effects in healthy pregnant women as summarised in WHO (2001) and

ATSDR (2005).

Developmental toxicity

The developmental toxicity of zinc compounds can be assessed on the basis of prenatal toxicity studies that have been conducted with soluble zinc sulphate and zinc chloride and slightly soluble zinc carbonate in rats, mice, hamsters or rabbits. Moreover, a total of three one or two generation reproductive toxicity studies conducted by

Khan et al,.

(2001, 2003, 2007) provide further information on potential teratogenic effects of zinc compounds.

No prenatal toxicity was observed with either zinc sulphate, zinc chloride or zinc carbonate at exposure levels up to 50 mg Zn/kg bw/day by oral gavage or 200 mg Zn/kg bw/day if the zinc was dose via the diet. Established

NOAELs in these studies were typically at highest dose tested and systemically tolerated by the dams.

Developmental effects such as decrease in body or organ weights were, however, observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al . (2001, 2003,

2007). These studies are not considered suitable for the assessment of teratogenic effects for hazard classification or risk assessment purposes since they were always observed in the presence of maternal toxicity.

In studies with women receiving zinc supplementation during pregnancies at levels of approximately ≤ 0.3 mg

Zn/kg bw/day, no reproductive or developmental effects were observed (WHO, 2001; SCF, 2003). Evidence of zinc toxicity during human pregnancy has not been reported, but this may be due to the fact that very high exposures to zinc in human pregnancy are unusual. In contrast, zinc is necessary for normal growth and development (e.g., gene expression, vitamin metabolism) and therefore it is not surprising that zinc deficiency during pregnancy can cause a variety of adverse effects to the foetus or may result in reduced fertility or delayed sexual maturation in animals as well as in humans (EU RAR, 2004; WHO, 2001).

In conclusion, there is no experimental evidence that would justify a classification of zinc compounds for hazardous effects for reproductive or developmental toxicity under the Dangerous Substance Directive

67/548/EEC or Regulation (EC) 1272-2008 on the on classification, labelling and packaging of substances and mixtures. The available reproductive and developmental toxicity information has been exclusively generated with soluble zinc compounds zinc chloride or zinc sulphate which ensure maximum bioavailable concentration of zinc and hence, allow the use of the information also for the assessment of the slightly soluble zinc compounds and insoluble zinc metal on a read across basis. No experimental fertility data were identified for these compounds.

5.10. Other effects


5.10.1.1. Neurotoxicity

Zinc is an important trace element in the brain. A considerable amount of zinc is accumulated in the brain, particularly in the hippocampus, amygadala, cerebral cortex and olfactory cortex. Although some zinc in the brain firmly binds to metalloproteins or enzymes, a substantial amount of zinc (approximately 10%) forms free zinc ions or is loosely bound and detectable by staining using chelating reagents. Chelatable zinc is stored in the presynaptic vesicles of particular excitatory neurons and is secreted from vesicles to synaptic clefts with excitatory neurotransmitter glutamate during the neuronal excitation (Frederickson, 2000). Synaptically-released zinc is believed to play a crucial role in normal brain function. Therefore, zinc deficiency impairs brain development and capabilities of learning and memory.

Notwithstanding, recent studies have indicated excess zinc released in a pathological condition can have adverse effects on the central nervous system and that disruption of zinc homeostasis have been suggested to be implicated in several neurogenerative diseases including Alzheimer’s disease, prion disease, amyotrophic lateral sclerosis (ALS) and Wilson’s disease. However, the mechanisms underlying these diseases are complicated with a range of factors involved and only poorly understood. While the information suggests that metal-metal interactions and the disturbance of zinc homeostasis play a role in these type of diseases, the exact role and contribution of zinc in these processes is still undefined (Konoha et al ., 2006).


EC number:


1314-98-3

5.10.1.2. Immunotoxicity

Zinc affects multiple aspects of the immune system. It is crucial for normal development and function of cells, mediating innate immunity, neutrophils and NK cells. Macrophages, phagocytosis, intracelluar killing and cytokine production and the growth and function of T and B cells are adversely affected by zinc deficiency. The ability of zinc to function as an antioxidant and stabilize membranes suggests that it has a role in the prevention of free radical-induced injury during inflammatory processes (Prasad, 2008). The mechanistical basis of the role of zinc in the immune system has been reviewed and discussed by Hirano et al ., (2008).

The results of an exemplar experimental study on the effects of chronic zinc supplementation on circulating levels of peripheral blood leucocytes and lymphocytes in humans is summarised in the following table:

Table 37. Overview of experimental studies on immunotoxicity

Method Results Remarks

The effects of chronic Zn supplementation on circulating levels of peripheral blood leucocytes and lymphocyte subsets were studied in a double-blinded intervention trial in male subjects.

Human chronic (oral: feed)

30 mg Zn/d (nominal in diet)

Vehicle: unchanged (no vehicle)

Exposure: 14 wk

No effect of Zn supplementation was observed on circulating levels of peripheral blood leucocytes or on lymphocyte subsets. Cu status was also unaltered.

Independent of supplement, there appeared to be seasonal variations in selected lymphocyte subsets in both placebo and supplemented groups. Alterations in circulating levels of B cells

(cluster of differentiation

(CD) 19), memory T cells

(CD45RO) and expression of the intracellular adhesion molecule- 1 (CD54) on T cells were observed. No adverse effects of Zn supplementation were observed on immune status or

Cu status


Reference

Bonham M,

O’Connor JM,

Alexander HD,

Coulter J, Walsh

PM, McAnena

(2003)

5.10.1.3. Specific investigations: other studies

As discussed in various chapters in this chemical safety report, to maintain a healthy condition it is important to maintain the metal homeostasis. The following reports a study which has been conducted to examine the impact of high zinc diet on the iron balance and associated secondary effects.

A study was conducted in rats to elucidate the pathophysiology of zinc-induced iron deficiency anemia. Male

Sprague-Dawley rats were fed with a diet containing 0.005% (standard Zn diet group) and 0.2% (high Zn diet group) Zn. After 20 weeks, hematological parameters and histopathological changes in the bone marrow, spleen and liver were examined. The serum Zn concentration in the high Zn diet group was significantly higher than that in the standard diet group. On the other hand, the serum Fe concentration in the high Zn diet group was significantly lower than that in the standard diet group. The high Zn diet group exhibited Hb concentrations, Ht levels and MCV, MCH and MCHC values (microcytic hypochromic anemia) that were significantly lower than those in the standard diet group. On the other hand, the number of circulating reticulocytes was significantly elevated in the high Zn diet group relative to the standard diet group. However, there was no significant difference in the number of RBC between the 2 groups of rats. Serum EPO levels were significantly higher in the high Zn diet group than in the standard diet group. There were no substantial differences in the cellularity and the composition of hematopoietic cells between the bone marrow specimens obtained from the 2 groups of rats. Similarly, there was no obvious proliferation of hematopoietic cells in the liver specimens obtained from the 2 groups of rats, although mild degeneration of hepatocytes was observed in the high Zn diet group as compared with the standard diet group. While atrophy of white pulp and development of matured erythrocytes

(extra-medullary hematopoiesis) were observed in the spleens from the high Zn diet group, there were no significant histopathological changes in the spleens from the standard diet group. This extra-medullary


EC number:


1314-98-3 hematopoiesis was not observed at least up to 12 weeks after the start of dietary treatment. Under the test conditions, the long-term intake of a high Zn diet caused iron deficiency anemia most likely due to suppression of Fe absorption, accompanied by both reticulocytosis and extra-medullary erythropoiesis (Yanagisawa et al.

,

2009).


A study was conducted to determine the effects of chronic Zn supplementation on circulating levels of peripheral blood leucocytes and lymphocyte subsets. Male subjects (n=19) were given 30 mg Zn/d for 14 wk followed by 3 mg Cu/d for 8 wk to counteract adverse effects, if any, of Zn supplementation on immune status resulting from lowered Cu status. Placebo supplements were given to a control group (n=19). The study design was a double-blinded intervention trial. Dietary intakes of Zn approximated 10 mg/d. Blood samples, taken throughout the trial, were assessed for full blood profiles and flow cytometric analyses of lymphocyte subsets.

Putative indices of Cu status were also examined. No effect of Zn supplementation was observed on circulating levels of peripheral blood leucocytes or on lymphocyte subsets. Cu status was also unaltered. Independent of supplement, there appeared to be seasonal variations in selected lymphocyte subsets in both placebo and supplemented groups. Alterations in circulating levels of B cells (cluster of differentiation (CD) 19), memory T cells (CD45RO) and expression of the intracellular adhesion molecule- 1 (CD54) on T cells were observed. No adverse effects of Zn supplementation were observed on immune status or Cu status, under the test conditions

(Bonham et al.

, 2003).

A study was conducted to evaluate whether a daily high-dose calcium supplement perturbs the zinc status post menopausal women. 23 women (mean age: 63 yr) with low bone mineral density were administered daily oral calcium (1200 mg) during the first 4 wk. Daily co supplementation with calcium (1200 mg) and zinc (30 mg) was provided daily during subsequent 4 wk. Plasma and erythrocyte zinc concentrations plasma bone-specific alkaline phosphatase (BSAP) and 5 ′ -nucleotidase activities, and urinary zinc and calcium excretion were determined first at the end of first 4 wk period and were measured again at the end of the subsequent second 4 wk exposure period. Mean plasma and erythrocyte zinc concentrations after 4 wk of calcium alone were not significantly different from concentrations after co supplementation of calcium and zinc. Mean plasma BSAP activities before co-supplementation with zinc was significantly higher than that after zinc, whereas plasma 5 ′ nucleotidase activities were not affected by zinc supplementation. Urinary zinc excretion slightly, but significantly, increased after the supplementation of zinc, whereas calcium excretion remained similar. Daily calcium dose of 1200 mg had no detrimental effect on the zinc status in postmenopausal women with low bone mineral density, under the conditions of the test (Morgan et al.

, 2005).

5.10.3. Summary and discussion of specific investigations

Zinc is essential for growth and development, neurological function, wound healing and immunocompetence

(SCF, 2003). The main clinical manifestations of zinc deficiency are growth retardation, delay in sexual maturation or increased susceptibility to infections (SCF, 2003).

Important in this context is the maintenance of the physiological zinc homeostasis. Disturbance of this zinc homeostasis through for example excessive zinc exposure have been implicated with neurogenerative diseases like Alzheimer’s or Wilson’s disease undefined (Konoha et al ., 2006) or with immunosuppressive effects (Raqib et al., 2007), but the exact mechanisms have not been elucidated.

There is at this stage no evidence that zinc has any neurotoxicological or immunotoxicological effects under normal zinc exposure conditions and at recommended zinc intake levels. Zinc deficiency, however, adversely affects neurological function and immune competence.

5.11. Derivation of DNEL(s) / DMEL(s)

For the derivation of the derived no effect levels (DNEL(s)) it is of great importance to consider that occupational exposure limits have been established for soluble (i.e., represented by zinc chloride) as well as slightly soluble/insoluble zinc compounds (i.e., represented by zinc oxide) to manage workers risk in operations where zinc exposure might occur.

The following Tables 38 and 39 list the existing OELs for zinc chloride as well as zinc oxide

Table 38. OELs for zinc chloride

Country/organisation 8 hour-TWA 15 min-STEL References


EC number:


1314-98-3

USA

The Netherlands

UK

Sweden mg/m 3

1

1

1

1 b) mg/m 3

2

2 a)

ACGIH (1991)

SZW (1997)

HSE (1998)

National Board of

Occupational Safety and

Health,

Sweden (1993)

Arbejdstilsynet, 1992 Denmark a) This value is a 10 minutes-STEL b) This TWA is determined for dust

0.5

Table 39. OELs for zinc oxide

Country/organisation

USA

USA

The Netherlands

Germany

UK

8 hour-TWA mg/m 3

5 (fumes)

10 (dust)

5 (fumes)

15 (dust; total)

5 (dust; respirable)

5 (fumes)

5 (fumes)

6 (dust)

5 (fumes)

10 (dust)

5 (fumes)

15 min-STEL mg/m 3

10 (fumes)

(ceiling)

References

ACGIH (1991) (guidance values)

OSHA (1989) (legal limit values)

SZW (1997)

DFG (1997)

HSE (1998)

Sweden National Board of

Occupational Safety and

Health,

Sweden (1993)

Arbejdstilsynet (1992) Denmark 4 (fumes)

10 (dust)

Moreover, for the establishment of DNEL(s) for consumer exposure it is noteworthy that zinc is essential for human growth and development, neurological functions and immunocompetence. The main clinical manifestations of zinc deficiency are growth retardation, delay in sexual maturation or increased susceptibility to infections (WHO, 2001). Health specialists recommend supplementing the diet with zinc in case human diet is zinc deficient. The maximum allowable daily intake has been established to be 50 mg zinc per day.

5.11.1. Overview of typical dose descriptors for all endpoints

The human health endpoints that have been identified to be of concern for the various zinc compounds are

 Acute oral and inhalation toxicity

 Skin and eye irritation;

 Repeat dose toxicity humans (i.e., effect at LOAEL: reduced ESOD activity) and animals (i.e., effect at

LOAEL: pancreatic damage)

The soluble zinc compounds (i.e., zinc chloride, zinc sulphate, zinc bis(dihydrogen phosphate, diammonium tetrachlorozincate and triammonium pentachlorozincate) demonstrated higher acute toxicity via oral and inhalation routes of exposure compared to the slightly soluble and insoluble zinc compounds for which no classifications for this endpoint is required. Zinc chloride and zinc sulphate are classified as Xn; R22 and zinc chloride may be toxic by inhalation.

The soluble zinc compounds have also demonstrated severe irritant effects to the skin and eyes and respiratory tract and are classified as corrosive (i.e., zinc chloride) and severe eye irritant (i.e., zinc sulphate).

Since systemic effects are dependent on the systemic availability of zinc in form of the zinc cation following oral absorption, the repeat dose toxicity studies conducted in humans and animals serve as the basis to assess any systemic effects of zinc released from soluble, slightly soluble and insoluble zinc compounds.

The following Tables 40 and 41 list the relevant and available dose descriptors for soluble, slightly soluble as


EC number:


1314-98-3 well as insoluble zinc compounds:

Table 40. Available dose-descriptor(s) per endpoint for water soluble zinc compounds (i.e., zinc chloride, zinc sulphate, zinc bis(dihydrogen phosphate), diammonium tetrachlorozincate and triammonium pentachlorozincate).

Endpoint

Acute toxicity Oral

Quantitative dose descriptor

(appropriate unit) or qualitative assessment 1

N/A

Local Systemic

LD

50

=

300- 2000 mg/kg bw

Associated relevant effect

Mortality;

Remarks on study

Irritation/ corrosion

Sensitization

Repeated dose toxicity (subacute / subchronic / chronic)

Dermal

Inhalation

(animal)

Skin

Eye

Respiratory tract Insufficient information

Skin

Respiratory

Oral (human)

Oral (animal)

N/A

N/A

Non to severely irritating

Non to severely irritating

Not a skin sensitizer

No evidence for respiratory sensitization properties

N/A

N/A

LD

50

> 2,000 mg/kg bw

< 2 mg/L

N/A

N/A

N/A

N/A

N/A

Mortality;

Erythema, oedema, necrosis

Corneal opacity; iritis; effects on conjunctivae

Signs of respiratory distress

No effects

N/A

NOAEL = 0.83 mg/kg bw/day

At LOAEL of 2.5 mg Zn/kg bw/day decreased ESOD activity and effects as a result of copper imbalance

Lowest established At higher

Standard acute LD

50 studies on zinc chloride, zinc sulphate and zinc bis(dihydrogen phosphate)).; classification Xn, R22 required

Standard acute dermal toxicity study on zinc sulphate; no classification required

Acute LC

50

study on zinc chloride however, exposure duration very short – 10 min and particle size tested is not a true reflection of human exposure

In-conclusive information; zinc chloride classified as

C, R34; no classification of zinc sulphate;

In-conclusive information; zinc sulphate classified as

Xi, R41; no data, classification of zinc chloride

No information suggesting need for classification as Xi

R37

Negative LLNA and

GPMT justifies no classification

No information to suggest the need for classification as Xi,

R42

1 Pooled results from studies conducted on one or several soluble forms of zinc


EC number:

215-251-3

Endpoint

Mutagenicity

Inhalation

Dermal in vitro in vivo

Carcinogenicity Oral/dermal/ inhalation

Reproductive toxicity

(fertility impairment)

Oral/dermal/ inhalation zinc sulphide CAS number:

1314-98-3



Local Systemic

NOAEL = 13 mg

Zn/kg bw/day

N/A

N/A

-

-

N/A

N/A

N/A

N/A

-

-

N/A

NOAEL > 20 mg/kg bw/day

NOAEL (humans)

> 0.83 mg Zn/kg bw/day


Remarks on study exposure levels haematological & biochemical effects; pathological changes in kidneys, GI tract, thyroid & pancreas

N/A

N/A

Weight of evidence suggests absence of mutagenicity in bacterial and mammalian test systems; clastogenicity was found at high, often cytotoxic doses

Predominantly negative, but some conflicting results in chromosomal aberration assays;

There is no evidence for carcinogenic activity of zinc compounds in humans or experimental evidence

No adverse reproductive effects noted in pregnant women administered zinc at rates of 20-30 mg/day.

Zinc may impair fertility at high exposure levels.

In animal experiments these effects were always associated with maternal toxicity

Overall weight of evidence suggests that zinc compounds do not have a biologically relevant genotoxic activity; no classification for mutagenicity required

No evidence exists to justify classification of zinc compounds for reproductive toxicity


EC number:

215-251-3

Endpoint

Developmental toxicity


1314-98-3



Local Systemic

N/A NOAEL >50 mg/kg bw/day

NOAEL (humans)



No developmental effects seen in specifically designed developmental toxicity studies; some developmental effects seen in two generation reproductive toxicity study but only at maternally toxic doses


No evidence exists that would justify the classification of zinc compounds for developmental toxicity


EC number:


1314-98-3

Table 41. Available dose-descriptor(s) per endpoint for sparingly or insoluble soluble zinc compounds (i.e., zinc oxide, zinc hydroxide, zinc phosphate, zinc carbonate, zinc metal, zinc sulphide)

Endpoint

Acute toxicity Oral

Irritation/ corrosion

Sensitization

Repeated dose toxicity (subacute / subchronic / chronic)

Dermal

Inhalation

(humans)

Inhalation

(animal)

Skin

Eye



Systemic

N/A

Local

N/A

N/A



LD50 > 2,000 mg/kg bw

LD50 > 2,000 mg/kg bw

Mortality; Standard acute LD

50 studies on zinc oxide, zinc phosphate and zinc metal;

No data identified; read across from standard acute dermal toxicity study on zinc sulphate; & low acute oral toxicity; no classification required

LOAEL – 5 mg/m 3 Metal fume fever; Experience from workplace exposures; while a NOEL has not been determined, the effects following exposure at LOAEL disappear within 24hrs

N/A > 5.7 mg/L Mortality;

Not irritating

Non to minimally irritating

Respiratory tract Insufficient information

Skin

Respiratory

Oral (human)

Oral (animal)

Not a skin sensitizer

No evidence for respiratory sensitization properties

N/A

N/A

N/A

N/A

N/A

N/A

N/A

NOAEL = 0.83 mg/kg bw/day

Lowest established

NOAEL = 13 mg

Zn/kg bw/day

N/A

Corneal opacity; iritis; effects on conjunctivae

No signs of respiratory irritation in acute inhalation studies

No effects

N/A

At LOAEL of 2.5 mg Zn/kg bw/day decreased ESOD activity and effects as a result of copper imbalance

At higher exposure levels haematological & biochemical effects; pathological changes in kidneys, GI tract,

Acute LC

50

study on oxide; no classification required

Data on zinc oxide; no classification required;

Data on zinc oxide, zinc phosphate, and zinc metal; no classification required

No information suggesting need for classification as Xi

R37

Negative GPMT of zinc oxide; no classification required

No information suggesting need for classification as Xi,

R42

Read-across from dietary supplement studies with zinc sulphate;

Read across from studies with soluble zinc compounds

2 Pooled results from studies conducted on one or several soluble forms of zinc


EC number:

215-251-3

Endpoint

Inhalation

Mutagenicity

Dermal in vitro in vivo

Carcinogenicity Oral/dermal/ inhalation

Reproductive toxicity

(fertility impairment)

Oral/dermal/ inhalation

Developmental toxicity


1314-98-3



Local Systemic

N/A

N/A

-

-

N/A

N/A

N/A

NOAEL: 2.7 mg

ZnO/m³

N/A

-

-

N/A

NOAEL > 20 mg/kg bw/day

NOAEL (humans)


NOAEL >50 mg/kg bw/day

NOAEL (humans)



Remarks on study thyroid & pancreas

At highest dose total lung capacity decreased and wet lung weights were increased.

N/A

Weight of evidence suggests absence of mutagenicity in bacterial and mammalian test systems; clastogenicity was found at high, often cytotoxic doses

Predominantly negative, but some conflicting results in chromosomal aberration assays;

There is no evidence for carcinogenic activity of zinc compounds in humans or experimental evidence

No adverse reproductive effects noted in pregnant women administered zinc at rates of 20-30 mg/day.

Zinc may impair fertility at high exposure levels.

In animal experiments these effects were always associated with maternal toxicity

No developmental effects seen in specifically designed developmental toxicity studies; some developmental effects seen in two generation

Non-standard study,

5-day inhalation in guinea pigs not suitable for classification.

Overall weight of evidence suggests that zinc compounds do not have a biologically relevant genotoxic activity; no classification for mutagenicity required

Data suggests no evidence exists to justify the classification of zinc compounds for reproductive toxicity

No evidence exists that would justify the classification of zinc compounds for developmental toxicity


EC number:

215-251-3

Endpoint zinc sulphide



Local Systemic

Associated relevant effect reproductive toxicity study but only at maternally toxic doses

CAS number:

1314-98-3


5.11.2. Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific

DN(M)EL

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 derived from the 10 week oral human volunteer study by Yadrick et al.,

(1989) 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). Table below summarises the absorption rates of soluble and slightly soluble/insoluble zinc compounds as derived in section 5.1 ‘Toxicokinetics’.

Table 42. Summary of absorption rates through different routes of exposure

Oral

Exposure route Zinc compound category

Soluble zinc

Slightly soluble/insoluble zinc

Absorption rate

20%

12%

Dermal

Inhalation

Soluble zinc


Soluble zinc


2%

0.2%

40%

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. Table below provides an overview of the assessment factors under consideration for zinc compounds


EC number:


1314-98-3

Table 43.

Assessment factors (AF) for zinc compounds

Uncertainties

Interspecies

Assessment Factor

1

Intraspecies -worker

Intraspecies –general population

Exposure duration

Dose response and endpoint specific/severity issues

Quality of database

1

1

1

1

1

Justification

No AF required; NOAEL has been derived from human experience through food supplementation




No specific AF required; NOAEL is considered to be reliable.

No specific AF required; limitations of all available studies have been identified and accounted for.

According to the ECHA guidance on information requirements and chemical safety assessment, correction of the dose descriptor for systemic exposure is necessary if

 There is a dose descriptor for a given human exposure route and for the same route in experimental animals but for that particular exposure route there is a difference in bioavailability between experimental animals and humans at the relevant level of exposure;

 There is not a dose descriptor for a given human exposure route for the same route (in experimental animals or humans);

 There are differences in human and environmental exposure conditions;

 There are differences in respiratory volumes between experimental animals and humans.

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: o DNEL o DNEL oral sol Zn

= oral insol Zn

=

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

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., NOAEL mg Zn/day x 20% = 10 mg Zn/day); syst

= 50

 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


EC number:


1314-98-3 following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds following dermal exposure – 0.2%; o NOAEL dermal sol Zn

= 10 mg Zn/day / 2% = 500 mg Zn/day o 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: o DNEL dermal sol Zn

= 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day) o 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 mg Zn/day x 20% = 10 mg Zn/day); syst

= 50

 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%; o NOAEL inhal sol. Zn

= 10 mg Zn/day / 40% = 25 mg Zn/day o NOAEL inhal insol Zn

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

 Corrected dose descriptor for workers considering a breathing volume of 10m 3

8hr shift

per

 NOAEL inhal sol. Zn

= 25 mg Zn/day / 10m 3 /day = 2.5 mg/m 3

 NOAEL inhal insol. Zn

= 50 mg Zn/day / 10m 3 /day = 5 mg/m 3

 Corrected dose descriptor for consumers considering a breathing volume of 20m 3 day

per

 NOAEL inhal sol. Zn

= 25 mg Zn/day / 20m 3 /day = 1.3 mg/m 3

 NOAEL inhal insol. Zn

= 50 mg Zn/day / 20m 3 /day = 2.5 mg/m 3

 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: o DNEL o DNEL inhal sol Zn (worker)

= inhal insol Zn (worker)

=

2.5 mg/m 3 ;

5 mg Zn/m 3 ; o DNEL inhal sol Zn (consumer)

= 1.3 mg/m 3 ; o DNEL inhal insol Zn (consumer)

= 2.5 mg Zn/m 3 ;

The following Tables 44 and 45 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.


EC number:


1314-98-3

Table 44. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for workers

Endpoint


Oral

Dermal

Inhalation

Zinc compound category

Soluble

Slightly soluble/ insoluble

Soluble


Soluble


Most relevant quantitativ e external dose descriptor for systemic exposure

(NOEL)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

Corrected external dose descriptor for systemic exposure

Overall

Assessme nt factor

Endpointspecific

DNEL

(external dose)

Not required

Not required

500 mg Zn/day

(8.3 mg/kg bw/day)

5000 mg Zn/day

(83 mg/kg bw/day)

2.5 mg Zn/m 3

5 mg Zn/ m 3

1

1

1

1

1

1

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

500 mg Zn/day

(8.3 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)

2.5 mg Zn/m 3

5 mg Zn/ m 3

Table 45. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for consumers

Endpoint


Oral

Dermal

Zinc compound category

Soluble


Soluble


Most relevant quantitativ e dose descriptor for systemic exposure

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

Corrected dose descriptor for systemic exposure

Overall


Not required

Not required

500 mg Zn/day

(8.3 mg/kg bw/day)

5000 mg Zn/day

(83 mg/kg bw/day)

1

1

1

1


DNEL

(external dose)

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

500 mg Zn/day

(8.3 mg/kg bw/day)

5000 mg Zn/day

(83mg/kg bw/day)


EC number:

215-251-3

Endpoint Zinc compound category

Inhalation

Soluble

Slightly soluble/ insoluble zinc sulphide CAS number:

1314-98-3

Most relevant quantitativ e dose descriptor for systemic exposure

50 mg Zn/day

(0.83 mg/kg bw/day)

50 mg Zn/day

(0.83 mg/kg bw/day)

Corrected dose descriptor for systemic exposure

1.3 mg Zn/m 3

2.5 mg Zn/ m 3

Overall


1

1


DNEL

(external dose)

1.3 mg Zn/m 3

2.5 mg Zn/ m 3


EC number:


1314-98-3

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: o Oral

 DNEL oral sol Zn

=

 DNEL oral insol Zn

= o Dermal

 DNEL dermal sol Zn

=

50 mg Zn/day (i.e., 0.83 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, 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/m 3 for soluble and slightly soluble/insoluble zinc compounds respectively and consumer DNELs of

1.3 or 2.5 mg Zn/m 3 .

Table 38 and 39 provide an overview of existing OELs for soluble zinc compounds represented by zinc chloride (i.e., Table 38) as well as slightly soluble/insoluble zinc compounds represented by zinc oxide (i.e.,

Table 39). 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: o Inhalation - Worker

 DNEL inhal soluble Zn (worker)

=

 DNEL inhal insoluble Zn (worker)

=

1 mg Zn/m

5 mg Zn/m

3

3

;

; o Inhalation - Consumer

 DNEL inhal soluble Zn (consumer)

=

 DNEL inhal insoluble Zn (consumer)

=

1.3 mg Zn/m 3 ;

2.5 mg Zn/m 3 ;

6. HUMAN HEALTH HAZARD ASSESSMENT OF

PHYSICO-CHEMICAL PROPERTIES

6.1. Explosivity

Data waiving: see CSR section 1.3 Physico-chemical properties.

Classification according to GHS


EC number:


1314-98-3

Name: zinc sulphide


Classification according to DSD / DPD

Classification status: 67/548/EEC self classification (zinc sulphide)


6.2. Flammability




Name: zinc sulphide

Reason for no classification (Flammable gases): conclusive but not sufficient for classification

Reason for no classification (Flammable aerosols): conclusive but not sufficient for classification

Reason for no classification (Flammable liquids): conclusive but not sufficient for classification

Reason for no classification (Flammable solids): conclusive but not sufficient for classification




6.3. Oxidising potential



Name: zinc sulphide

Reason for no classification (Oxidising gases): conclusive but not sufficient for classification

Reason for no classification (Oxidising liquids): conclusive but not sufficient for classification

Reason for no classification (Oxidising solids): conclusive but not sufficient for classification





EC number:


1314-98-3

7. ENVIRONMENTAL HAZARD ASSESSMENT

General considerations

ZnS is insoluble in aqueous medium. Results from transformation/dissolution tests and acute aquatic toxicity testing demonstrate that ZnS has very limited solubility, which results in a release of zinc ions from ZnS below the hazard levels. As such, the substance is not classified for aquatic toxicity, and the results from eco-toxicity testing on soluble zinc compounds are not relevant for ZnS.

However, a basic assumption made in the hazard assessment of zinc compounds (in accordance to the same assumption made in the EU RA process) is that the ecotoxicity of zinc and zinc compounds is due to the

Zn ++ ion. Therefore, the PNECs as derived for the soluble zinc compounds (zinc ion related) are also relevant for the insoluble ZnS, because they are expressed as “zinc ion”, not as the test compound. It is emphasised that the aquatic toxicity test results obtained on soluble zinc compounds are not relevant for ZnS.

In this chapter 7, the aquatic toxicity data and transformation/dissolution data showing the insoluble character of

ZnS and its lack of environmental hazard, will be summarised. The PNECs as derived from test results on soluble zinc compounds will be mentioned. For detail on how these PNECs (all are “added “PNECs) were derived, reference is made to the zinc metal CSR.

Accordingly, the reference values derived from soluble zinc compounds for Zn++ classification are also applied to ZnS. For derivation of these latter values, reference is also made to the zinc metal CSR.

7.1. Aquatic compartment (including sediment)

7.1.1. Toxicity test results

The results of the transformation/dissolution tests (section 4.6, IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, some of the tests are waived (because no exposure to zinc ions is anticipated) and ZnS is not classified for aquatic toxicity.

The results on aquatic toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS.

7.1.1.1. Fish

7.1.1.1.1. Short-term toxicity to fish

The results are summarised in the following table:

Table 46. Overview of short-term effects on fish

Method Results

Brachydanio rerio (new name: Danio rerio)

LC50 (96 h): > 0.25 mg/L dissolved (meas. (arithm. mean)) freshwater static

OECD Guideline 203 (Fish, Acute

Toxicity Test)

Remarks sulphide

1 (reliable without restriction) key study experimental result

Test material (EC name): zinc

Reference

RCC (2003a)


EC number:


1314-98-3

Discussion

Zinc sulfide is an insoluble material. Fish tests, performed on an eluate of ZnS, and tested according to OECD

Guideline for testing of Chemicals, n° 203, show no toxicity of the ZnS for the fish.

According to these data, ZnS is not classified for aquatic toxicity.

The following information is taken into account for acute fish toxicity for the derivation of PNEC:

Tests performed on an undiluted filtrate of a supersaturated dispersion of ZnS-SACHTOLITH HD-S, according to standard OECD protocol show no short-term toxicity of ZnS to fish up to its solubility limit in test water.

7.1.1.1.2. Long-term toxicity to fish

Data waiving

Reason: exposure considerations

Justification: The results of the transformation/dissolution tests (IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the long term aquatic toxicity tests on fish is waived (because no exposure to zinc ions is anticipated).

Discussion

The following information is taken into account for long-term fish toxicity for the derivation of PNEC:

The results of the transformation/dissolution tests (section 4.6., IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the long term aquatic toxicity tests on fish is waived (because no significant exposure to zinc ions is anticipated).

The results on aquatic toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS.

7.1.1.2. Aquatic invertebrates

7.1.1.2.1. Short-term toxicity to aquatic invertebrates


Table 47. Overview of short-term effects on aquatic invertebrates

Method Results Remarks

Daphnia magna freshwater

LC50 (48 h): > 29 µg/L dissolved (meas. (arithm. mean)) based on: mortality

1 (reliable without restriction) key study static experimental result

OECD Guideline 202 (Daphnia sp.

Acute Immobilisation Test) Test material (EC name): zinc sulphide

Reference

RCC (2003b)

Discussion


EC number:


1314-98-3

Zinc sulfide is an insoluble material. Invertebrate tests, performed on an eluate of ZnS, and tested according to

OECD Guideline for testing of Chemicals n° 202, show no toxicity of the ZnS for the invertebrates.


The following information is taken into account for short-term toxicity to aquatic invertebrates for the derivation of PNEC:

Tests performed on an undiluted filtrate of a supersaturated dispersion of ZnS-SACHTOLITH HD-S, according to standard OECD protocol show no short-term toxicity of ZnS to invertebrates up to its solubility limit in test water.

7.1.1.2.2. Long-term toxicity to aquatic invertebrates

Data waiving


Justification: The results of the transformation/dissolution tests (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the long term aquatic toxicity tests on invertebrates is waived (because no exposure to zinc ions is anticipated).

Discussion

The following information is taken into account for long-term toxicity to aquatic invertebrates for the derivation of PNEC:

The results of the transformation/dissolution tests (4.6. ; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the long term aquatic toxicity tests on fish is waived (because no significant exposure to zinc ions is anticipated).

7.1.1.3. Algae and aquatic plants


Table 48. Overview of effects on algae and aquatic plants

Method Results

Scenedesmus subspicatus (new name:

Desmodesmus subspicatus) (algae) freshwater

EC50 (72 h): > 13 µg/L dissolved (meas. (arithm. mean)) based on: growth rate static

OECD Guideline 201 (Alga, Growth

Inhibition Test)

NOEC (72 h): >= 13 µg/L dissolved (meas. (arithm. mean)) based on: growth rate

Remarks

1 (reliable without restriction) key study experimental result

Test material (EC name): zinc sulphide

Reference

RCC (2003c)

Discussion

Effects on algae / cyanobacteria

Zinc sulfide is an insoluble material. Algae tests, performed on an eluate of ZnS, and tested according to OECD

Guideline for testing of Chemicals n° 201, show no toxicity of the ZnS for the algae.


EC number:


1314-98-3


The following information is taken into account for effects on algae / cyanobacteria for the derivation of PNEC: tests performed on an undiluted filtrate of a supersaturated dispersion of ZnS-SACHTOLITH HD-S, according to standard OECD protocol show no short-term toxicity of ZnS to algae up to its solubility limit in test water.

7.1.1.4. Sediment organisms

Data waiving


Justification: The results of the transformation/dissolution tests (section 4.6.: IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for sediment toxicity is waived, because no exposure to zinc ions is anticipated.

The results on sediment toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS.

Discussion

The following information is taken into account for sediment toxicity for the derivation of PNEC:

The results of the transformation/dissolution tests (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for sediment toxicity is waived, because no exposure to zinc ions is anticipated.

The results on sediment toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS.

7.1.1.5. Other aquatic organisms

In this section, whole ecosystem studies are summarised. In spite of the fact that ZnS is insoluble and as such not environmentally hazardhous, these studies indicate the effect of the zinc ion in whole ecosystems and are therefore mentioned as background information in this file, too. The results are summarised in the following table:

Table 49. Overview of effects on other aquatic organisms: communities

Method Results Remarks macroinvertebrate communities and families of Ephemeroptera, Plecoptera and Trichoptera were assessed.

freshwater

NOEC (wk): > 20 — < 27

µg/L dissolved (meas.

(arithm. mean)) based on: benthic macroinvertebrate structure and insect family richness

1 (reliable without restriction) key study field study with benthic macroinvertebrates and insects read-across based on grouping of substances (category approach)

Spatially matched measurements of benthic macroinvertebrate family richness and measured dissolved metal concentrations were compared over two sampling periods spanning all regions from England and Wales.

Test material

(IUPAC name): zinc (See endpoint summary for justification of

Reference

Crane M, Kwok

KWH, Wells C,

Whitehouse P and

Lui GCS. (2007)


EC number:


1314-98-3 microcosm/mesocosm freshwater flow-through

NOEC (4 wk): 22.8 µg/L dissolved (meas. (TWA)) based on: Phytoplakton: community abundance, richness and diversity

The study design and performance was based on SETAC workshop discussions in Potsdam (EWOFFT:

Hill et al. 1994), Lacanau (HARAP:

Campbell et al. 1998), and

Schmallenberg (CLASSIC: Giddings et al. 2002), which are summarized guidance documents.

NOEC (4 wk): > 60.4 µg/L dissolved (meas. (TWA)) based on: zooplankton: community abundance, richness and diversity read-across)

1 (reliable without restriction) key study read-across based on grouping of substances (category approach)

Test material (CAS name): zinc dichloride (See endpoint summary for justification of read-across)


Rand GM, Hoang

TC, Brausch JM.

(2010)

Rand GM, Hoang

TC, Brausch JM.

(2012) microcosm/mesocosm freshwater

NOEC (14 wk): 14 µg/L dissolved (meas. (TWA)) based on: chlorophyta eveness flow-through

The study design and performance was based on SETAC workshop discussions in Potsdam (EWOFFT:

Hill et al. 1994), Lacanau (HARAP:

Campbell et al. 1998), and

Schmallenberg (CLASSIC: Giddings et al. 2002), which are summarized guidance documents.

NOEC (14 wk): 14 µg/L dissolved (meas. (TWA)) based on: Zooplankton eveness

NOEC (14 wk): 21 µg/L dissolved (meas. (TWA)) based on: chlorophyll a in periphyton multispecies test read-across based on grouping of substances (category approach)

Test material (CAS name): zinc dichloride (See endpoint summary for justification of read-across)


Davies AG &

Sleep JA (1979) saltwater

NOEC (18 h): >= 7 — <=

13 µg/L dissolved

(estimated) based on: C fixation rate static key study

Photosynthetic inhibition (C fixation) test on phytoplancton communities in the field, designed for dose-response

LOEC (18 h): >= 10 — <=

15 µg/L dissolved

(nominal) based on: C fixation rate read-across based on grouping of substances (category approach)

Species of macro-algae, crustaceae, sponges, mollusca and annelids were introduced. Zoo- and phytoplankton and other macro invertebrates were introduced with the water and sediment.

saltwater static

No Observed Ecological

Adverse Effect

Concentration (83 d): 12

µg/L dissolved (meas.

(TWA)) based on: primary production, grwoth of

Littorina littorea

Test material


1 (reliable without restriction) key study read-across based on grouping of substances (category approach)

Foekema EM,

Kramer KJM,

Kaag NHBM,

Sneekes AC,

Bierman S,

Hoornsman (2012)

Test material (CAS


EC number:


1314-98-3

Custom-designed study. Each mesocosm study is designed to answer specific questions; nonetheless various guidance documents that describe the basic principles of this kind of studies when performed for risk assessment were used as general guidance.

Although these guiding documents concern fresh water mesocosm studies, the addressed issues were taken into account as much as possible during the marine mesocosm study that is described in this report. natural phytoplancton communities from field saltwater

NOEC (24 h): 1.45 µg/L dissolved (meas. (not specified)) based on: C fixation rate (growth) static

Field experiment on natural phytoplancton communities looking at

C fixation rates as the endpoint, designed for dose-response

LOEC (4 h): > 100 µg/L dissolved (meas. (not specified)) based on: C fixation rate name): zinc dichloride (See endpoint summary for justification of read-across)

Form: powder

2 (reliable with restrictions) supporting study read-across based on grouping of substances (category approach)

Wolter K, U.

Rabsch, P.

Krischker and A.

G. Davies (1984)

Test material

(IUPAC name): zinc dichloride (See endpoint summary for justification of read-across)

7.1.2. Calculation of Predicted No Effect Concentration (PNEC)

As indicated, ZnS is insoluble and not environmentally hazardhous; the zinc ion is not released in sufficient quantity from ZnS to cause aquatic toxicity. Still, the PNECs that were derived from soluble zinc compounds are considered relevant for the Zn contained in the ZnS, because they are Zn-ion, not zinc substance (ZnS) related. Therefore they are summarised below. For a detailed description on how the PNECs were derived, reference is made to the zinc metal CSR.

7.1.2.1. PNEC water

Table 50. PNEC water

PNEC Assessment factor

PNEC aqua

(freshwater): 20.6

µg/L

1

Remarks/Justification

Extrapolation method: statistical extrapolation

The following considerations are made on the uncertainty around the

HC5 and for determining the size of the assessment factor: •The number of chronic species NOECs (23) covers more than the requirements for taxonomic groups (8) and species (at least 10, preferably more than 15) set out in the guidance. •The large number of species in the SSD resulting in a low uncertainty on the HC5 value •The lognormal distribution giving a more conservative HC5 than the best fitting


EC number:


1314-98-3

PNEC aqua (marine water): 6.1 µg/L

1 distribution (extreme values distribution) •The chronic data are from tests performed in a variety of natural freshwaters, properly reflecting the range of abiotic conditions found in the European freshwaters •The general consideration that the bioavailability of metals under real life conditions is lower than the bioavailability in laboratory toxicity tests.

•The few specific NOEC values of the database that are below the HC5 can be explained by non-environmentally relevant conditions. •The inclusion of data obtained under very low background conditions into the

NOEC database which introduces a significant level of conservatism into the SSD and the PNEC derivation . •Predictions from the chronic Biotic

Ligand Model showing that the NOECs predicted for the realistic worst case conditions of EU waters, correspond well with the generic species mean NOEC values observed for the BLM organisms and used in the

SSD. •Comparison with reliable Mesocosm data, showing no evidence that the HC5 is not protective. •Evidence on the PNEC from a large scale field survey study, demonstrating that the PNEC for zinc should be in the range 20-27µg Zn dissolved/l The consideration of the elements above does not support the application of an additional assessment factor on the

HC5 for setting the PNEC.


The following considerations are made on the uncertainty around the

HC5: -The chronic NOEC database is very extensive and contains 39 species entries that cover much more than the requirements for taxonomic groups (8) and species (at least 10, preferably more than 15) set out in the guidance; -Sensitive life stages or long chronic exposure periods (a few months) are represented in each taxonomic group as set out in the guidance; -The large number of species in the SSD results in a low uncertainty on the HC5 value, as is shown by the small difference between the 50% confidence level and the 95% confidence limits found for the lognormal distribution: less than a factor of 2.5; -The lognormal distribution that was used for PNEC derivation resulted in an HC5 of

6.09 µg/l, which is markedly lower than the HC5 value calculated from the Weibull distribution (8.5 µg/l), which provided the best fit. So the

HC5 that is used for the PNEC derivation is a conservative value; -The

HC5 value from the log-normal SSD is protective for mesocosm data; -

There is no indication for a particular sensitive group in the SSD. In addition, whenever an SSD includes > 20 data points, the chance of having a value below the HC5 is significant. So, having one or more values below the HC5 is inherent to bigger datasets and is not an issue as such; Based on these observations, there is no need for an assessment factor higher than 1. The PNEC saltwater for zinc is thus of 6.09 µg/L.

Intermittent release is not applicable for zinc.

7.1.2.2. PNEC sediment

Table 51. PNEC sediment


PNEC sediment

(freshwater): 117.8 mg/kg sediment dw

1



It is emphasized that the reported PNEC for freshwater sediments is an added PNEC, i.e. natural background needs to be taken into account when characterizing the risks from monitored data. The following


EC number:


1314-98-3

PNEC sediment

(marine water): 56.5 mg/kg sediment dw

1 considerations are made on the uncertainty around the HC5 and for determining the size of AF: •The 7 available chronic single-species tests are among the most important taxonomic groups for the sediment ecosystems and as such reflect a broader difference in sensitivity among species (7.5 instead of 2.5 in the Zn RAR). •The sediment chronic database covers long term (3 to 8 weeks) lethal and sub-lethal endpoints that are all relevant for potential effects at population level. •The lognormal distribution gives a more conservative HC5 than the best fit distribution ( logistic distribution) •The proposed PNECadd, sediment is lower than all other sediment quality guidelines/values proposed in various jurisdictions around the world (see e.g. Chapman et al. 1999,

MacDonald et al. 2000) •Field data demonstrate that the proposed

PNECadd, sediment is protective for ecosystems. The consideration of the elements above does not support the application of an additional assessment factor on the HC5 for setting the PNEC.

Extrapolation method: partition coefficient

It is emphasized that the reported PNEC for saltwater sediments is an added PNEC, i.e. natural background needs to be taken into account when characterizing the risks from monitored data. The following considerations are made on the uncertainty around the HC5 and for determining the size of AF: • Lowest reported NOEC value (A. marina; emergence; 207 mg/kg d.w.) is higher than the proposed EqP PNEC •

The proposed marine EqP PNEC is lower than all other sediment quality guidelines/values proposed in various jurisdictions around the world (see e.g. Chapman et al. 1999) • The HC5 based on combined freshwater and seawater data derived from the lognormal distribution gives a value of

106 mg/kg d.w, which divided by AF2 gives a PNEC of 53 mg/kg. This value is close to the EqP PNEC • Marine sediment PNEC in the Zn RA is based on the freshwater sediment PNEC of 49 mg/kg which is in the same range • Using the AF approach gives a low PNEC value (14.6 mg/kg d.w.) which is in the lower percentiles of the natural background concentrations for zinc and is therefore not relevant

7.2. Terrestrial compartment

7.2.1. Toxicity test results

The results of the transformation/dissolution tests in aqueous media (4.6. ; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions from ZnS in the pore water is anticipated to be insignificant. ZnS is very stable, also in soils, where it is the chemical endpoint form under which zinc is occurring mainly in nature. The results on soil toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS.

7.2.1.1. Toxicity to soil macro-organisms

Data waiving

Information requirement: Toxicity to soil macro-organisms except arthropods


Justification: The results of the transformation/dissolution tests in aqueous media (4.6. ; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the


EC number:


1314-98-3 pore water is anticipated to be insignificant.

Information requirement: Toxicity to terrestrial arthropods


Justification: The results of the transformation/dissolution tests in aqueous media (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

Discussion of effects on soil macro-organisms except arthropods

ZnS is very stable also in soils, it is the chemical endpoint form under which zinc is occurring mainly in nature.

The results on soil toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for ZnS

The following information is taken into account for effects on soil macro-organisms except arthropods for the derivation of PNEC:

The results of the transformation/dissolution tests in aqueous media (4.6. ; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

Discussion of effects on soil arthropods



The following information is taken into account for effects on soil arthropods for the derivation of PNEC:

The results of the transformation/dissolution tests in aqueous media (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

7.2.1.2. Toxicity to terrestrial plants

Data waiving


Justification: The results of the transformation/dissolution tests in aqueous media (4.6. IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of

ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

Discussion


The results on soil toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant


EC number:


1314-98-3 for ZnS

The following information is taken into account for toxicity on terrestrial plants for the derivation of PNEC:

The results of the transformation/dissolution tests in aqueous media (4.6. ; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

7.2.1.3. Toxicity to soil micro-organisms

Data waiving


Justification: The results of the transformation/dissolution tests in aqueous media (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of

ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

Discussion



The following information is taken into account for toxicity on soil micro-organisms for the derivation of

PNEC:

The results of the transformation/dissolution tests in aqueous media (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be insignificant.

7.2.1.4. Toxicity to other terrestrial organisms

No data

7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil)

As indicated, ZnS is insoluble and not environmentally hazardhous; the zinc ion is not released in sufficient quantity from ZnS to cause aquatic toxicity. Still, the PNECs that were derived from soluble zinc compounds are considered relevant for the Zn contained in the ZnS, because they are Zn-ion, not zinc substance (ZnS) related. Therefore it is summarised below. For a detailed description on how the PNECs were derived, reference is made to the zinc metal CSR.

Table 52. PNEC soil

PNEC

PNEC soil: 35.6 mg/kg soil dw

Assessment factor

1




EC number:


1314-98-3

The given value is the generic PNECadd, i.e. it has to be added to the natural background concentration of zinc. This generic PNECadd, should as a rule be multiplied with a factor 3 to take into account "lab-to-field" differences in toxicity. As such, the generic corrected PNECadd is 107 mg Zn/kg dw. Soil-specific PNEC values can further be calculated when the characteristics of the soil are documented. The following considerations are made on the uncertainty around the HC5: i) The chronic NOEC database is very extensive and largely fulfills the requirements for taxonomic groups (8) and species (at least 10, preferably more than 15) set out in the guidance; ii) the database covers ecologically relevant endpoints and full chronic studies ; iii) the

NOECS/EC10 were obtained by testing on soils covering the variability of soil characteristics all over the EU; iv) the log-normal distribution was accepted at all sigificance levels; v) considering all individual NOEC levels, the HC5 is protective; vi) comparison with field /mesocosm studies demonstrates that the HC5 is protective. The consideration of the elements above does not support the application of an additional assessment factor on the HC5 for setting the PNEC.

7.3. Atmospheric compartment

The EU risk assessment concluded on this compartment: “ A quantitative risk characterisation for exposure of organisms to airborne zinc is not possible. This because there are no useful data on the effects of airborne zinc on environmental organisms and thus no PNEC for air could be derived. The PECs in air will be used for the risk assessment of man indirectly exposed via the environment”.

In accordance to the EU risk assessment, this compartment was not further assessed.

7.4. Microbiological activity in sewage treatment systems

7.4.1. Toxicity to aquatic micro-organisms

Data waiving


Justification: The results of the transformation/dissolution tests (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the aquatic toxicity tests on microorganisms is waived (because no exposure to zinc ions is anticipated).

Discussion

The following information is taken into account for effects on aquatic micro-organisms for the derivation of

PNEC:

The results of the transformation/dissolution tests (4.6.; IUCLID 5.6.) and of the aquatic toxicity tests documented in this section all consistently demonstrate the very limited solubility of ZnS. For this reason, the aquatic toxicity tests on microorganisms is waived (because no exposure to zinc ions is anticipated).

7.4.2. PNEC for sewage treatment plant


EC number:


1314-98-3

As indicated, ZnS is insoluble and not environmentally hazardhous; the zinc ion is not released in sufficient quantity from ZnS to cause aquatic toxicity. Still, the PNECs that were derived from soluble zinc compounds are considered relevant for the Zn contained in the ZnS, because they are Zn-ion, not zinc substance (ZnS) related. Therefore it is summarised below. For a detailed description on how the PNECs were derived, reference is made to the zinc metal CSR.

Table 53. PNEC sewage treatment plant

Value Assessment factor


PNEC STP: 100

µg/L

1 Extrapolation method: assessment factor

Considering that the nitrification inhibition test is most sensitive of the data available, the PNEC is derived from the NOEC (100 µg Zn/l ;

Juliastuti et al. 2003) divided by AF 1 to give the PNEC-STP of 100µg

Zn/l.

7.5. Non compartment specific effects relevant for the food chain

(secondary poisoning)

The EU risk assessment concluded the following related to this issue: “Based on the ICDZ data (Cleven et al.,

1993) on bioaccumulation of zinc in animals and on biomagnification (i.e. accumulation and transfer through the food chain), it is concluded that secondary poisoning is considered to be not relevant in the effect assessment of zinc. Major decision points for this conclusion are the following. The accumulation of zinc, an essential element, is regulated in animals of several taxonomic groups, for example in molluscs, crustaceans, fish and mammals. In mammals, one of the two target species for secondary poisoning, both the absorption of zinc from the diet and the excretion of zinc, are regulated. This allows mammals, within certain limits, to maintain their total body zinc level (whole body homeostasis) and to maintain physiologically required levels of zinc in their various tissues, both at low and high dietary zinc intakes. The results of field studies, in which relatively small differences were found in the zinc levels of small mammals from control and polluted sites, are in accordance with the homeostatic mechanism. These data indicate that the bioaccumulation potential of zinc in both herbivorous and carnivorous mammals will be low.

Based on the above data, secondary poisoning and the related issues bioaccumulation and biomagnification are not further discussed in this report” (EU risk assessment, ECB 2008).

7.5.1. Toxicity to birds

Data waiving

Information requirement: Toxicity to birds


Justification: zinc is an essential element which is regulated throughout the food chain. It does not bioaccumulate/biomagnify. Therefore testing of long-term toxicity to birds is considered not relevant.

Discussion

The aim of avian toxicity tests is to provide data for secondary poisoning, if the chemical safety assessment demonstrates the need for such a study (notably relevant for substances with a potential to bioaccumulate and high mammalian toxicity). Zinc is an essential element that is regulated throughout the food chain and does not bioaccumulate/biomagnify. For this reason, the potential for secondary poisoning is not considered relevant (EU risk assessment, ECB 2008), and testing of long-term toxicity to birds is considered not relevant.


EC number:


1314-98-3

The following information is taken into account for effects on birds for the derivation of PNEC: zinc is an essential element which is regulated throughout the food chain. It does not bioaccumulate/biomagnify.

Therefore testing of long-term toxicity to birds is considered not relevant.

7.5.2. Toxicity to mammals

See 7.5.1.

7.5.3. Calculation of PNECoral (secondary poisoning)

Table 53. PNEC oral


No potential for bioaccumulation


Zinc is an essential element that is actively regulted within the body of all organisms. Due to the general lack of increased whole body and tissue concentrations at higher exposure levels, the zinc BCF data show generally an inverse relationship to exposure concentrations (McGeer et al 2003). The physiological basis for the inverse relationship of BCF to zinc exposure concentration arises from Zn uptake and control mechanisms. At low environmental zinc levels, organisms are able to sequester and retain Zn in tissues for essential functions. When Zn exposure is higher, aquatic organisms are able to control uptake. There is clear evidence that many species actively regulate their body Zn concentrations, including crustaceans, oligochaetes, mussels, gastropods, fish, amphipods, chironomids by different mechanisms (McGeer et al

2003). The bioaccumulation potential in mammals is also considered low. Based on this, the EU risk assessment concludes that secondary poisoning is considered to be not relevant in the effect assessment for zinc.

7.6. Conclusion on the environmental hazard assessment and on classification and labelling

Environmental classification justification

7.6.1. Classification under Annex I dangerous substances directive 67/548/EEC

Zinc sulphide was not classified under Directive 67/548/EEC, and does not figure in.Annex 1 of Directive

67/548/EEC (ECB 2008).

7.6.2. Classification under

2nd Adaptation to Technical Progress (ATP) to the CLP

Regulation (2 nd ATP CLP)

The results of the transformation/dissolution test (section 4.6.) demonstrate that ZnS is practically insoluble.

Zinc is released from the ZnS only in a very limited way. The observed levels of zinc released in the medium after 7days are at all loadings below the reference concentrations for aquatic ecotoxicity at the pH range tested

(reference values for acute aquatic zinc toxicity are 413 µg Zn/l and 136 µg Zn/l at pH 6 and pH 8 respectively).

The observed zinc concentration after 28 days at pH 6 at 1mg/l loading is also smaller than the lowest reference value for chronic aquatic toxicity (19µg Zn/l at pH 8). Considering this latter result, testing over 28 days at pH 8


EC number:


1314-98-3 was not considered relevant since a) the T/D rate and extent is lower at pH 8 than at pH 6, and b) the reference value for chronic aquatic zinc toxicity is higher at pH 6.

Based on these observations, ZnS is not classified for environmental effects.

General discussion

Results from transformation/dissolution tests and acute aquatic toxicity testing demonstrate that ZnS has very limited solubility. As such, the substance is not classified for aquatic toxicity, and the results from eco-toxicity testing on soluble zinc compounds are not relevant for ZnS.

However, a basic assumption made in the hazard assessment of zinc compounds (in accordance to the same assumption made in the EU RA process) is that the ecotoxicity of zinc and zinc compounds is due to the

Zn ++ ion. Therefore, the PNECs as derived for the soluble zinc compounds (zinc ion related) are also relevant for the insoluble ZnS, because they are expressed as “zinc ion”, not as the test compound. It is emphasised that the aquatic toxicity test results obtained on soluble zinc compounds are not relevant for ZnS.

8. PBT AND VPVB ASSESSMENT

According to regulation (EC) 1907/2006 (REACH) a PBT and vPvB assessment shall usually be conducted as foreseen in Article 14 (3) (d) in conjunction with Annex I Section 4 and according to the criteria laid down in

Annex XIII. However, according to Annex XIII a PBT and vPvB assessment shall not be conducted for inorganic substances. ZnS is an inorganic substance, thus a PBT and vPvB assessment is not required.

Still, the points below are raised:

8.1. Assessment of PBT/vPvB Properties

8.1.1. Summary and overall conclusions on PBT or vPvB properties

Zinc is a natural, essential element, which is needed for the optimal growth and development of all living organisms, including man. All living organisms have homeostasis mechanisms that actively regulate zinc uptake and absorption/excretion from the body; due to this regulation, zinc and zinc compounds do not bioaccumulate or biomagnify.

Zinc is an element, and as such the criterion “persistence” is not relevant for the metal and its inorganic compounds in a way as it is applied to organic substances. The removal of inorganic substances from the water column has been discussed as a surrogate for persistence. In section 4.6., the rapid removal of zinc from the water column is documented. So, zinc does not meet this criterion, neither.

Considering the above, zinc and zinc compounds are not PBT or vPvB.

9. EXPOSURE ASSESSMENT

Not applicable. This substance is not classified.

10. RISK CHARACTERISATION

Not applicable. This substance is not classified.


EC number:


1314-98-3

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EC number:

215-251-3

Milieubeheer, VRPM/DGM/AMS 361346 zinc sulphide CAS number:

1314-98-3


EC number:


1314-98-3

ANNEX 1: Exposure scenario building and environmental release estimation for the waste life stage of the manufacture and the use of zinc and zinc compounds


EC number:


1314-98-3

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