CHEMICAL SAFETY REPORT
Substance Name: Slags, lead-zinc smelting
EC Number: 297-907-9
CAS Number: 93763-87-2
Registrant's Identity:
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
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 ...................................................................................................................... 5
2.1. Manufacture ............................................................................................................................................. 5
2.2. Identified uses .......................................................................................................................................... 7
2.3. Uses advised against .............................................................................................................................. 11
3. CLASSIFICATION AND LABELLING ..................................................................................................... 12
3.1. Classification and labelling according to CLP / GHS ............................................................................ 12
3.2. Classification and labelling according to DSD / DPD ........................................................................... 14
3.2.1. Classification and labelling in Annex I of Directive 67/548/EEC .................................................. 14
3.2.2. Self classification(s) ........................................................................................................................ 14
3.2.3. Other classification(s) ..................................................................................................................... 15
4. ENVIRONMENTAL FATE PROPERTIES ................................................................................................ 15
4.1. Degradation ........................................................................................................................................... 16
4.1.1. Abiotic degradation ........................................................................................................................ 16
4.1.1.1. Hydrolysis ................................................................................................................................ 16
4.1.1.2. Phototransformation/photolysis ............................................................................................... 17
4.1.1.2.1. Phototransformation in air ................................................................................................ 17
4.1.1.2.2. Phototransformation in water ............................................................................................ 17
4.1.1.2.3. Phototransformation in soil ............................................................................................... 17
4.1.2. Biodegradation ................................................................................................................................ 17
4.1.2.1. Biodegradation in water ........................................................................................................... 17
4.1.2.1.1. Estimated data ................................................................................................................... 17
4.1.2.1.2. Screening tests .................................................................................................................. 17
4.1.2.1.3. Simulation tests (water and sediments) ............................................................................. 17
4.1.2.1.4. Summary and discussion of biodegradation in water and sediment .................................. 17
4.1.2.2. Biodegradation in soil .............................................................................................................. 17
4.1.3. Summary and discussion of degradation ........................................................................................ 18
4.2. Environmental distribution .................................................................................................................... 18
4.2.1. Adsorption/desorption .................................................................................................................... 20
4.2.2. Volatilisation................................................................................................................................... 20
4.2.3. Distribution modelling .................................................................................................................... 20
4.2.4. Summary and discussion of environmental distribution ................................................................. 20
4.3. Bioaccumulation .................................................................................................................................... 21
4.3.1. Aquatic bioaccumulation ................................................................................................................ 21
4.3.2. Terrestrial bioaccumulation ............................................................................................................ 22
4.3.3. Summary and discussion of bioaccumulation ................................................................................. 23
4.4. Secondary poisoning .............................................................................................................................. 24
4.5. Natural background ............................................................................................................................... 24
4.6. Additional information on environmental fate and distribution ............................................................ 25
5. HUMAN HEALTH HAZARD ASSESSMENT .......................................................................................... 29
5.1. Toxicokinetics ....................................................................................................................................... 32
5.1.1. Non-human information ................................................................................................................. 32
5.1.2. Human information ......................................................................................................................... 36
5.1.3. Summary and discussion of toxicokinetics ..................................................................................... 42
5.2. Acute toxicity ........................................................................................................................................ 43
5.2.1. Non-human information ................................................................................................................. 43
5.2.1.1. Acute toxicity: oral .................................................................................................................. 43
5.2.1.2. Acute toxicity: inhalation ......................................................................................................... 45
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
5.2.1.3. Acute toxicity: dermal ............................................................................................................. 46
5.2.1.4. Acute toxicity: other routes ...................................................................................................... 46
5.2.2. Human information ......................................................................................................................... 47
5.2.3. Summary and discussion of acute toxicity ...................................................................................... 48
5.3. Irritation ................................................................................................................................................. 49
5.3.1. Skin ................................................................................................................................................. 49
5.3.1.1. Non-human information........................................................................................................... 49
5.3.1.2. Human information .................................................................................................................. 50
5.3.2. Eye .................................................................................................................................................. 51
5.3.2.1. Non-human information........................................................................................................... 51
5.3.2.2. Human information .................................................................................................................. 52
5.3.3. Respiratory tract .............................................................................................................................. 52
5.3.3.1. Non-human information........................................................................................................... 52
5.3.3.2. Human information .................................................................................................................. 52
5.3.4. Summary and discussion of irritation ............................................................................................. 52
5.4. Corrosivity ............................................................................................................................................. 53
5.4.1. Non-human information ................................................................................................................. 53
5.4.2. Human information ......................................................................................................................... 53
5.4.3. Summary and discussion of corrosion ............................................................................................ 53
5.5. Sensitisation ........................................................................................................................................... 53
5.5.1. Skin ................................................................................................................................................. 53
5.5.1.1. Non-human information........................................................................................................... 53
5.5.1.2. Human information .................................................................................................................. 54
5.5.2. Respiratory system .......................................................................................................................... 54
5.5.2.1. Non-human information........................................................................................................... 54
5.5.2.2. Human information .................................................................................................................. 55
5.5.3. Summary and discussion of sensitisation........................................................................................ 55
5.6. Repeated dose toxicity ........................................................................................................................... 55
5.6.1. Non-human information ................................................................................................................. 55
5.6.1.1. Repeated dose toxicity: oral ..................................................................................................... 55
5.6.1.2. Repeated dose toxicity: inhalation ........................................................................................... 58
5.6.1.3. Repeated dose toxicity: dermal ................................................................................................ 60
5.6.1.4. Repeated dose toxicity: other routes ........................................................................................ 60
5.6.2. Human information ......................................................................................................................... 60
5.6.3. Summary and discussion of repeated dose toxicity ........................................................................ 63
5.7. Mutagenicity .......................................................................................................................................... 64
5.7.1. Non-human information ................................................................................................................. 64
5.7.1.1. In vitro data .............................................................................................................................. 64
5.7.1.2. In vivo data ............................................................................................................................... 67
5.7.2. Human information ......................................................................................................................... 69
5.7.3. Summary and discussion of mutagenicity ...................................................................................... 69
5.8. Carcinogenicity ...................................................................................................................................... 70
5.8.1. Non-human information ................................................................................................................. 70
5.8.1.1. Carcinogenicity: oral ................................................................................................................ 70
5.8.1.2. Carcinogenicity: inhalation ...................................................................................................... 71
5.8.1.3. Carcinogenicity: dermal ........................................................................................................... 71
5.8.1.4. Carcinogenicity: other routes ................................................................................................... 71
5.8.2. Human information ......................................................................................................................... 71
5.8.3. Summary and discussion of carcinogenicity ................................................................................... 73
5.9. Toxicity for reproduction ....................................................................................................................... 73
5.9.1. Effects on fertility ........................................................................................................................... 73
5.9.1.1. Non-human information........................................................................................................... 73
5.9.1.2. Human information .................................................................................................................. 76
5.9.2. Developmental toxicity ................................................................................................................... 76
5.9.2.1. Non-human information........................................................................................................... 76
5.9.2.2. Human information .................................................................................................................. 77
5.9.3. Summary and discussion of reproductive toxicity .......................................................................... 78
5.10. Other effects..................................................................................................................................... 79
5.10.1. Non-human information ........................................................................................................... 79
5.10.1.1. Neurotoxicity ......................................................................................................................... 79
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
5.10.1.2. Immunotoxicity ...................................................................................................................... 79
5.10.1.3. Specific investigations: other studies ..................................................................................... 80
5.10.2. Human information ....................................................................................................................... 80
5.10.3. Summary and discussion of specific investigations ...................................................................... 81
5.11. Derivation of DNEL(s) / DMEL(s) ..................................................................................................... 81
5.11.1. Overview of typical dose descriptors for all endpoints ................................................................. 82
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 ..................................................... 87
5.11.3. Selection of the critical DNEL(s) for critical health effects .......................................................... 92
6. HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES .................... 93
6.1. Explosivity ............................................................................................................................................. 93
6.2. Flammability .......................................................................................................................................... 93
6.3. Oxidising potential ................................................................................................................................ 94
7. ENVIRONMENTAL HAZARD ASSESSMENT ........................................................................................ 94
7.1. Aquatic compartment (including sediment) ........................................................................................... 95
7.1.1. Toxicity test results ......................................................................................................................... 95
7.1.1.1. Fish .......................................................................................................................................... 95
7.1.1.1.1. Short-term toxicity to fish ................................................................................................. 95
7.1.1.1.2. Long-term toxicity to fish ................................................................................................. 96
7.1.1.2. Aquatic invertebrates ............................................................................................................... 97
7.1.1.2.1. Short-term toxicity to aquatic invertebrates ...................................................................... 97
7.1.1.2.2. Long-term toxicity to aquatic invertebrates ...................................................................... 97
7.1.1.3. Algae and aquatic plants .......................................................................................................... 98
7.1.1.4. Sediment organisms ................................................................................................................. 98
7.1.1.5. Other aquatic organisms .......................................................................................................... 99
7.1.2. Calculation of Predicted No Effect Concentration (PNEC) .......................................................... 101
7.1.2.1. PNEC water ........................................................................................................................... 101
7.1.2.2. PNEC sediment ...................................................................................................................... 102
7.2. Terrestrial compartment ....................................................................................................................... 103
7.2.1. Toxicity test results ....................................................................................................................... 103
7.2.1.1. Toxicity to soil macro-organisms .......................................................................................... 103
7.2.1.2. Toxicity to terrestrial plants ................................................................................................... 104
7.2.1.3. Toxicity to soil micro-organisms ........................................................................................... 105
7.2.1.4. Toxicity to other terrestrial organisms ................................................................................... 106
7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil) ................................................... 106
7.3. Atmospheric compartment................................................................................................................... 106
7.4. Microbiological activity in sewage treatment systems ........................................................................ 106
7.4.1. Toxicity to aquatic micro-organisms ............................................................................................ 106
7.4.2. PNEC for sewage treatment plant ................................................................................................. 107
7.5. Non compartment specific effects relevant for the food chain (secondary poisoning) ........................ 107
7.5.1. Toxicity to birds ............................................................................................................................ 108
7.5.2. Toxicity to mammals .................................................................................................................... 108
7.5.3. Calculation of PNECoral (secondary poisoning) .......................................................................... 108
7.6. Conclusion on the environmental hazard assessment and on classification and labelling ................... 109
8. PBT AND VPVB ASSESSMENT ............................................................................................................. 109
8.1. Assessment of PBT/vPvB Properties ................................................................................................... 109
8.1.1. Summary and overall conclusions on PBT or vPvB properties .................................................... 109
9. EXPOSURE ASSESSMENT ..................................................................................................................... 110
10. RISK CHARACTERISATION ................................................................................................................ 110
REFERENCES ................................................................................................................................................... 111
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 ........................................................................................ 128
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
List of Tables
Table 1. Substance identity ..................................................................................................................................... 2
Table 2. Constituents .............................................................................................................................................. 2
Table 3. Overview of physico-chemical properties ................................................................................................ 3
Table 4. Overview of quantities (in tonnes/year) .................................................................................................... 5
Table 5. Waste types, amounts and waste treatment processes for zinc and zinc compounds from manufacturing
................................................................................................................................................................................ 6
Table 6. Uses by workers in industrial settings ...................................................................................................... 8
Table 7. Waste types, amounts and waste treatment processes for zinc from identified uses .............................. 11
Table 8. Waste types, amounts and treatment of waste from service life sated subsequent to the identified uses
for zinc from identified uses ................................................................................................................................. 11
Table 9. Classification according to Directive 67/548/EEC criteria ..................................................................... 14
Table 10. (taken from the RA zinc, ECB 2008): Possible chemical forms (speciation) of dissolved zinc in
seawater (Cleven et al., 1993)............................................................................................................................... 18
Table 11. Overview of studies on aquatic bioaccumulation ................................................................................. 21
Table 12. Overview of studies on terrestrial bioaccumulation ............................................................................. 22
Table 13. Summary of the measured metal concentration after 7-day T/D testing of slags, lead-zinc smelting
under standard T/D protocol conditions. .............................................................................................................. 25
Table 14. Overview of experimental studies on acute toxicity after oral administration...................................... 29
Table 15. Overview of experimental studies on acute toxicity after dermal administration ................................. 29
Table 16. Overview of experimental studies on skin irritation ............................................................................. 29
Table 17. Overview of experimental studies on eye irritation .............................................................................. 30
Table 18. Overview of experimental in vitro genotoxicity studies ....................................................................... 30
Table 19. Water solubility values of the eleven zinc compounds covered in this CSR ........................................ 31
Table 20. Grouping based on water solubility ...................................................................................................... 32
Table 21. Dermal absorption of Zn (% of dose) through pig skin in vitro within 72 hours .................................. 33
Table 22. Deposition fractions for oral breathers and for oronasal augmenters, using a polydisperse particle
distribution (MMAD 15.2 m, GSD 4.0) ............................................................................................................. 38
Table 23. Assumptions used for estimating the inhalation absorption ................................................................. 39
Table 24. Percentage estimations for inhalation absorption of soluble, slightly soluble and insoluble zinc
compounds ............................................................................................................................................................ 39
Table 25. Elimination data obtained following thirty humans dosed with 18 to 900 moles of 65Zn .................. 41
Table 26. Overview of experimental studies on acute toxicity after oral administration according to decreasing
water solubility of zinc compounds ...................................................................................................................... 43
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Table 27. Re-calculation of oral LD50 rat values................................................................................................... 45
Table 28. Overview of experimental studies on acute toxicity after inhalation exposure according to decreasing
water solubility of zinc compounds ...................................................................................................................... 45
Table 29. Overview of experimental studies on acute toxicity after dermal exposure ......................................... 46
Table 30. Overview of experimental studies on skin irritation according to decreasing water solubility of zinc
compounds ............................................................................................................................................................ 49
Table 31. Overview of experimental studies on eye irritation according to decreasing water solubility of zinc
compounds ............................................................................................................................................................ 51
Table 32. Overview of experimental studies on skin sensitisation according to decreasing water solubility of
zinc compounds .................................................................................................................................................... 53
Table 33. Overview of experimental studies on repeated dose toxicity after oral administration ........................ 55
Table 34. Overview of experimental studies on repeated dose toxicity after inhalation ...................................... 58
Table 35. Overview of experimental in vitro genotoxicity studies according to decreasing water solubility ...... 64
Table 36. Overview of experimental in vivo genotoxicity studies according to decreasing water solubility ....... 68
Table 37. Overview of experimental studies on fertility ...................................................................................... 73
Table 38. Overview of experimental studies on developmental toxicity .............................................................. 76
Table 39. Overview of experimental studies on immunotoxicity ......................................................................... 79
Table 40. OELs for zinc chloride ......................................................................................................................... 81
Table 41. OELs for zinc oxide .............................................................................................................................. 81
Table 42. 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). .............................................................................................................................................. 82
Table 43. 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) .............................................. 85
Table 44. Summary of absorption rates through different routes of exposure ...................................................... 87
Table 45. Assessment factors (AF) for zinc compounds ...................................................................................... 88
Table 46. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for workers ........................ 90
Table 47. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for consumers .................... 90
Table 48. Overview of information on explosivity ............................................................................................... 93
Table 49. Overview of information on flammability ............................................................................................ 93
Table 50. Overview of short-term effects on fish ................................................................................................. 95
Table 51. Overview of short-term effects on aquatic invertebrates ...................................................................... 97
Table 52. Overview of long-term effects on aquatic invertebrates ....................................................................... 97
Table 53. Overview of effects on algae and aquatic plants................................................................................... 98
Table 54. Overview of effects on other aquatic organisms: communities ............................................................ 99
Table 55. PNEC water ........................................................................................................................................ 101
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Table 56. PNEC sediment................................................................................................................................... 102
Table 57. Overview of effects on soil macro-organisms .................................................................................... 103
Table 58. Overview of effects on terrestrial plants ............................................................................................. 104
Table 59. PNEC soil ........................................................................................................................................... 106
Table 60. Overview of effects on micro-organisms ............................................................................................ 107
Table 61. PNEC sewage treatment plant ............................................................................................................ 107
Table 62. PNEC oral ........................................................................................................................................... 108
List of Figures
Figure 1. Transformation /dissolution results for slags, lead-zinc smelting at pH 6, for 7days. ........................... 26
Figure 2. Base case total zinc removal from the water column using EUSES model parameters. The initial total
zinc concentration in the water column (C0) is 413 μg/L. The horizontal dashed line represents C/C0 = 0.3 or
70% removal of zinc (from Mutch Associates 2010b). ........................................................................................ 28
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
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
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Part B
1. IDENTITY OF THE SUBSTANCE AND PHYSICAL
AND CHEMICAL PROPERTIES
1.1. Name and other identifiers of the substance
The substance Slags, lead-zinc smelting is a UVCB (origin: inorganic) having the following characteristics and
physical–chemical properties (see the IUCLID dataset for further details).
Table 1. Substance identity
EC number:
297-907-9
EC name:
Slags, lead-zinc smelting
CAS number (EC inventory): 93763-87-2
IUPAC name:
Slags, lead-zinc smelting
Description:
Oxidic inert material remaining after pyrometallurgical treatment of Zincbearing (secondary) materials
Molecular formula:
not applicable
Molecular weight range:
n.a.
Structural formula:
1.2. Composition of the substance
Name: Slags, lead-zinc smelting
Description: Oxidic inert material remaining after pyrometallurgical treatment of Zinc-bearing (secondary)
materials
Degree of purity: 100 % (w/w)
Table 2. Constituents
Constituent
Typical concentration
Concentration range
Remarks
zinc
6.22 % (w/w)
>= 1.0 — < 12.0 % (w/w) mainly as (FeZn)2O4
33.5 % (w/w)
> 1.0 — < 45.0 % (w/w)
17.8 % (w/w)
>= 1.0 — < 30.0 % (w/w)
2.17 % (w/w)
> 0.0 — < 3.0 % (w/w)
7.62 % (w/w)
> 0.0 — < 15.0 % (w/w)
EC no.: 231-175-3
iron
EC no.: 231-096-4
calcium oxide
EC no.: 215-138-9
Aluminium oxide
EC no.: 215-691-6
silicon dioxide
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
EC no.: 231-545-4
Manganese oxide
7.24 % (w/w)
> 0.0 — < 8.0 % (w/w)
0.67 % (w/w)
>= 0.0 — < 1.0 % (w/w)
< 0.2 % (w/w)
>= 0.0 — < 1.5 % (w/w)
0.29 % (w/w)
>= 0.0 — < 0.5 % (w/w)
EC no.: 215-695-8
copper
EC no.: 231-159-6
chromium
EC no.: 231-157-5
lead
EC no.: 231-100-4
1.3. Physico-chemical properties
Table 3. Overview of physico-chemical properties
Property
Results
Value used for CSA / Discussion
Physical state at
20°C and 1013 hPa
The physical state of the substance is solid
heterogeneous grainy material, its clour is
black - ochra, it is odourless (Outotec,
2010)
Value used for CSA: solid
Melting / freezing
point
In nitrogen, the substance starts melting at
1262°C. Decomposition occurs in nitrogen
at 875°C and around 1040°C in air
(Outotec, 2010).
Relative density
The density of the substance is 4.14 g/cm3
(Outotec, 2010)
Water solubility
The sample indicated high solubility in the
preliminary test. In the actual flask test, the
experimentally determined average
solubility of Zn was 1.2 mg/l. However, the
solubility of the substance reflects the
solubility of the pregnant liquor as the
substance is considered insoluble.
Flammability
the substance has no flammability,
explosiveness or auto-inflammability
properties (Outotec, 2010; Ibexu, 2009).
Value used for CSA: 4.14 at 20°C
Explosive properties the substance has no flammability,
explosiveness or auto-inflammability
properties (Outotec, 2010; Ibexu, 2009).
Self-ignition
temperature
the substance has no flammability,
explosiveness or auto-inflammability
properties (Outotec, 2010; Ibexu, 2009).
Granulometry
The D50 of the substance is 2248 µm, the
D80 is 4934 µm (Outotec, 2010).
Data waiving
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
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: Surface tension
Reason: other justification
Justification: endpoint is not relevant for solid powder
Information requirement: Partition coefficient n-octanol/water (log value)
Reason: other justification
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)
Information requirement: Flash point
Reason: other justification
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
Reason: other justification
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
Reason: other justification
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: Self-ignition temperature
Reason: other justification
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: Oxidising properties
Reason: other justification
Justification: The substance has no oxidizing properties, the compound is stable
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Information requirement: Stability in organic solvents and identity of relevant degradation products
Reason: other justification
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
Reason: study scientifically unjustified
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 scientifically unjustified
Justification: The endpoint viscosity is relevant for liquids, only. The substance is solid.
Discussion of physico-chemical properties
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
2.1. Manufacture
Quantities
Table 4. Overview of quantities (in tonnes/year)
Year
Total tonnage
2013-05-27 CSR-PI-5.2.1
Own use Used for article
Used as intermediate
CHEMICAL SAFETY REPORT
Used for
5
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
under strictly controlled research
conditions
purposes
2007
Manufactured: 0.0
Imported: 0
0.0
Imported in article: 0.0
Used in production of
article: 0.0
Transported: 0.0
Imported: 0.0
0.0
2008
Manufactured: 0.0
Imported: 0
0.0
Imported in article: 0.0
Used in production of
article: 0.0
Transported: 0.0
Imported: 0.0
0.0
2009
Manufactured: 0.0
Imported: 0
0.0
Imported in article: 0.0
Used in production of
article: 0.0
Transported: 0.0
Imported: 0.0
0.0
Manufacturing process
Description of activities/process(es):
• During the recovery of Zinc units, by fuming, the enriched Zinc Flue Dust is collected and recovered in
baghouse filters and an inert slag is continuously discharged, quenched by spraying water or in a waterpool.
• Additional equipment may be used to classify the slag and/or control the final moisture of the product,
according the specifications,
• Further transfer of the slag to protected slag yard or storage silo’s or through especially designed transfer units,
i.e. special containers, …
WASTE (cfr Annex 1, Arche, 2012) :
Table 5. 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
Manufactu
re
Sludge from
on-site
WWTP
06 05 02*
19 02 05*
Range: 0 –
22,000 t/y.
Median:
2,500 t/y
Range: 250 –
300,0000
mg
Zn/kg
dw.
Median: 8,700
mg Zn/kg dw
General dust
10 05 03*
10 05 05*
10 10 09*
10 10 11*
12 01 03
12 01 04
10 05 01
10 10 03
Range: 0 –
36 t/y.
Median: 11
t/y
Range: 700 –
800,000
mg
Zn/kg dw.
Median: 400,000
mg Zn/kg dw.
Range: 0 –
135,000 t/y.
Median:
49,500 t/y
Range: 12,000 –
450,000
mg
Zn/kg dw.
Median: 49,500
mg Zn/kg dw.
Slags
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
Waste
treatment
process/
recycling
Internal or
external
landfilling
Recycling
internally
Incineration
Recycled in
other
applications
Recycled
internally or
externally
(e.g. ZnSO4
production)
Information
source
In
house
questionnaire
2011
Internal or
external
landfilling.
Recycled in
another
application
(road
constructio
n, profiling,
6
EC number:
297-907-9
Slags, lead-zinc smelting
Sludges from
zinc
hydrometallur
gy (Jarosite,
goethite, …)
Cadmium
cake/sponge
11 02 02*
Range: 0 –
230,000 t/y.
Median:
101,500 t/y
10 05 06*
11 01 09*
Range: 0 –
1,000 t/y.
Median:
670 t/y
Cement
Copper
Not
considered
as waste
100%
recycled
10 05 06*
06 04 04*
Range: 0 –
4,000 t/y.
Median:
1,450 t/y
11 02 07*
Range: 0 –
4857 t/y.
Median:
3,000 t/y
Range: 550 –
300,000
mg
Zn/kg dw.
Median: 5,000
mg Zn/kg dw.
Range: 0 –
40,000 t/y.
Median:
24,767 t/y
Range: 25 –
200,000
mg
Zn/kg dw.
Median: 30,000
mg Zn/kg dw.
Range: 745 –
950,000
mg
Zn/kg dw.
Median: 825,000
mg Zn/kg dw.
Hg residue/
sludge/
calomel
Anodic
sludge/
mud/
sludge
Pb
leach
cell
Mn
sludge/
Range: 0 –
100 t/y.
Median: 20
t/y
Casting/smelti
ng residues:
Zn skimming,
drosses and
ashes
10 05 11
10 05 03*
11 02 03
Range: 0 –
4,000 t/y.
Median:
2,400 t/y
Other wastes:
slimes,
sludges, leach
residues, solid
wastes
lead
silver anode,
precipitates,
salts,
adsorbents,
packaging
materials,
spoilt
products,
soaps,
refractories
…
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 –
150,000 t/y.
Median:
190 t/y
Range: 27,000 –
100,000
mg
Zn/kg dw.
Median: 30,000
mg Zn/kg dw.
Range: 30,000 –
200,000
mg
Zn/kg dw.
Median: 160,000
mg Zn/kg dw.
Range: 50,000 –
125,000
mg
Zn/kg dw.
Median: 79,000
mg Zn/kg dw.
Range: 100 –
9000 mg Zn/kg
dw.
Median: 550 mg
Zn/kg dw.
Range: 592 –
600,000
mg
Zn/kg dw.
Median: 50,000
mg Zn/kg dw.
CAS number:
93763-87-2
covering
layer, zinc
recyclers)
Internal or
external
landfilling
Recycled
internally
Internal or
external
landfilling
Recycled in
copper
production
Landfilled in
special
concrete
bunkers,
eventually
stabilization
prior
to
landfilling.
Internal or
external
landfilling
Recycled in
other
applications
Recycled in
lead or lead
alloy
production
Recycled
internally or
externally
Recycled in
another
application
Recycled
internally
Recycled in
other
applications
Internal or
external
landfilling/
mine filling
Incineration
2.2. Identified uses
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
7
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Table 6. Uses by workers in industrial settings
Confidential
IU number
Identified Use
(IU) name
Substance
supplied to
that use
Use descriptors
1
Zn Waelz slag
production
as such
(substance
itself)
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 19: Intermediate
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 14: Manufacture of basic metals, including alloys
Subsequent service life relevant for that use?: yes
4
2013-05-27 CSR-PI-5.2.1
Additive for
production of
construction
materials
as such
(substance
itself)
in a mixture
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 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)
PROC 7: Industrial spraying
PROC 8a: Transfer of substance or preparation (charging/discharging) from/to vessels/large
CHEMICAL SAFETY REPORT
8
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
containers at non-dedicated facilities
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 10: Roller application or brushing
PROC 13: Treatment of articles by dipping and pouring
PROC 14: Production of preparations or articles by tabletting, compression, extrusion, pelletisation
PROC 15: Use as laboratory reagent
PROC 17: Lubrication at high energy conditions and in partly open process
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 9b: Fillers, putties, plasters, modelling clay
PC 20: Products such as ph-regulators, flocculants, precipitants, neutralisation agents
Environmental release category (ERC):
ERC 2: Formulation of preparations
ERC 3: Formulation in materials
ERC 5: Industrial use resulting in inclusion into or onto a matrix
ERC 10a: Wide dispersive outdoor use of long-life articles and materials with low release
ERC 11a: Wide dispersive indoor use of long-life articles and materials with low release
Sector of end use (SU):
SU 10: Formulation [mixing] of preparations and/or re-packaging (excluding alloys)
SU 13: Manufacture of other non-metallic mineral products, e.g. plasters, cement
Subsequent service life relevant for that use?: yes
Article category related to subsequent service life (AC):
AC 4: Stone, plaster, cement, glass and ceramic articles
5
2013-05-27 CSR-PI-5.2.1
Additive as
as such
fluxing agent in (substance
pyrometallurgic itself)
al processes
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 5: Mixing or blending in batch processes for formulation of preparations and articles
CHEMICAL SAFETY REPORT
9
EC number:
297-907-9
Slags, lead-zinc smelting
in a mixture
CAS number:
93763-87-2
(multistage and/or significant contact)
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
Market sector by type of chemical product:
PC 19: Intermediate
PC 20: Products such as ph-regulators, flocculants, precipitants, neutralisation agents
Environmental release category (ERC):
ERC 1: Manufacture of substances
ERC 5: Industrial use resulting in inclusion into or onto a matrix
ERC 6a: Industrial use resulting in manufacture of another substance (use of intermediates)
Sector of end use (SU):
SU 10: Formulation [mixing] of preparations and/or re-packaging (excluding alloys)
SU 14: Manufacture of basic metals, including alloys
Subsequent service life relevant for that use?: yes
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
10
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
WASTE (cfr Annex 1, Arche, 2012) :
Table 7. Waste types, amounts and waste treatment processes for zinc from identified uses
Waste from
Type of waste
Suitable
waste
code
Amount
(t/y)
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*
…
0.7% from
the
Zndownstre
am
use
tonnage
ends up in
hazardous
waste
Compo
sition
Waste
treatment
process/
recycling
Treated as
hazardous
waste
Information
source
Reck 2008
Waste stream
profiles
EC
2010
Waste report
ARCHE 2011
Table 8. Waste types, amounts and treatment of waste from service life sated subsequent to the identified
uses for zinc from identified uses
Waste
from
Type
waste
of
Suitable
waste
code
Amount
(t/y)
Composition
Municipal
waste and
EoL
Solid
municipal
waste:
Paper/cardboard,
Metal,
Glass,
Plastics,
Textile,
Organic
matter,
Other
20 01 34
20 01 40
20 03 01
20 03 07
179,430
ktonnes
dry weight
Average
concentration:
71 mg Ni/kg dw
Waste
treatment
process/
recycling
Municipal waste
landfill
Municipal waste
incineration
Recycling
Information
source
EUROSTAT
2009
Waste report
ARCHE 2011
Most common technical function of substance (what it does):
construction material
2.3. Uses advised against
None
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
11
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
3. CLASSIFICATION AND LABELLING
3.1. Classification and labelling according to CLP / GHS
Name: slags, lead-zinc smelting
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:
Reason for no classification: conclusive but not sufficient for classification
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:
Reason for no classification: conclusive but not sufficient for classification
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:
Reason for no classification: conclusive but not sufficient for classification
Substances and
mixtures which in
contact with water
emits flammable
gases:
Reason for no classification: conclusive but not sufficient for classification
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
Corrosive to metals: Reason for no classification: conclusive but not sufficient for classification
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
12
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
 for health hazards:
Acute toxicity - oral: Reason for no classification: conclusive but not sufficient for classification
Acute toxicity dermal:
Reason for no classification: conclusive but not sufficient for classification
Acute toxicity inhalation:
Reason for no classification: conclusive but not sufficient for classification
Skin
corrosion/irritation:
Reason for no classification: conclusive but not sufficient for classification
Serious damage/eye
irritation:
Reason for no classification: conclusive but not sufficient for classification
Respiration
sensitization:
Reason for no classification: conclusive but not sufficient for classification
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:
Reason for no classification: conclusive but not sufficient for classification
Reproductive
Toxicity: Effects on
or via lactation:
Reason for no classification: conclusive but not sufficient for classification
Germ cell
mutagenicity:
Reason for no classification: conclusive but not sufficient for classification
Carcinogenicity:
Reason for no classification: conclusive but not sufficient for classification
Specific target organ Reason for no classification: conclusive but not sufficient for classification
toxicity - single:
Specific target organ Reason for no classification: conclusive but not sufficient for classification
toxicity - repeated:
 for environmental hazards:
Hazards to the
Reason for no classification: conclusive but not sufficient for classification
aquatic environment
(acute/short- term):
Hazards to the
Reason for no classification: conclusive but not sufficient for classification
aquatic environment
(long-term):
Hazardous to the
atmospheric
Reason for no classification: data lacking
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
13
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
environment:
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: slags, lead-zinc smelting
Table 9. Classification according to Directive 67/548/EEC criteria
Endpoints
Reason for no
classification
Justification for
(non) classification
can be found in
section
Explosiveness
conclusive but not
sufficient for
classification
6.1
Oxidising properties
conclusive but not
sufficient for
classification
6.3
Flammability
conclusive but not
sufficient for
classification
6.2
Thermal stability
conclusive but not
sufficient for
classification
Acute toxicity
conclusive but not
sufficient for
classification
5.2
Acute toxicity- irreversible
damage after single
exposure
conclusive but not
sufficient for
classification
5.2
Repeated dose toxicity
conclusive but not
sufficient for
classification
5.6
Irritation / Corrosion
conclusive but not
sufficient for
classification
5.3.4 and 5.4.3
Sensitisation
conclusive but not
sufficient for
classification
5.5.3
Carcinogenicity
conclusive but not
sufficient for
classification
5.8.3
Mutagenicity - Genetic
conclusive but not
5.7.3
2013-05-27 CSR-PI-5.2.1
Classification
CHEMICAL SAFETY REPORT
14
EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Toxicity
sufficient for
classification
Toxicity to reproductionfertility
conclusive but not
sufficient for
classification
5.9.3
Toxicity to reproductiondevelopment
conclusive but not
sufficient for
classification
5.9.3
Toxicity to reproduction breastfed babies
conclusive but not
sufficient for
classification
5.9.3
Environment
conclusive but not
sufficient for
classification
7.6
3.2.3. Other classification(s)
----------------------------------------------------------------------------------------------------------------------------- ---------
4. ENVIRONMENTAL FATE PROPERTIES
General introduction to chapters 4, 5, 6 and 7.
Slags, lead-zinc smelting are highly insoluble. In standard transformation/dissolution testing, only zinc is
released from the substance in a very limited way. The rate and extent of zinc release is not sufficient to trigger
classification. Still, some fate and distribution characteristics of zinc are considered relevant and reported in this
section.
Under Regulation 793/93/CEE, an extensive risk assessment on Zinc and 5 zinc compounds
(ZnO, ZnCl2, ZnSO4, 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 slags, lead-zinc
smelting are insoluble and do not have any hazard for the environment, the general data
related to the zinc ion its fate and distribution are considered relevant for slags, lead-zinc
smelting, 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.
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
2013-05-27 CSR-PI-5.2.1
CHEMICAL SAFETY REPORT
15
EC number:
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Slags, lead-zinc smelting
CAS number:
93763-87-2
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 may be 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
Reason: study scientifically unjustified
Justification: Waived: According to Annex IX of REACH Regulation, information on hydrolysis is not
2013-05-27 CSR-PI-5.2.1
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EC number:
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Slags, lead-zinc smelting
CAS number:
93763-87-2
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
Reason: other justification
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
Reason: other justification
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).
4.1.2.1.4. Summary and discussion of biodegradation in water and sediment
Discussion (screening testing)
Discussion (simulation testing)
4.1.2.2. Biodegradation in soil
2013-05-27 CSR-PI-5.2.1
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EC number:
297-907-9
Slags, lead-zinc smelting
CAS number:
93763-87-2
Data waiving
Reason: other justification
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).
4.1.3. 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 zinc
metal
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 zinc from the water column (given under 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 5.6.: "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
Zinc 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.
Table 10. (taken from the RA zinc, ECB 2008): Possible chemical forms (speciation) of
dissolved zinc in seawater (Cleven et al., 1993).
Percentage of total zinc
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Zn species
Zn2+
ZnCln2-n (n:1-4)
ZnOH+, ZN(OH)2
ZnCO3
ZnHCO+3
ZnOHCl
ZnSO4
Slags, lead-zinc smelting
Reference 1
17
11.4
62.2
6
0.7
4
Reference 2
16.1
63.7
2.3
3.3
0.3
12.5
1.9
CAS number:
93763-87-2
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).
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CAS number:
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4.2.1. Adsorption/desorption
Data waiving
Reason: study scientifically unjustified
Justification: For metals, adsorption/sdesorption 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 coeficients is given under 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 coeficients are given under 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) was estimated in the RAR from that for
particulate matter, as follows: Kpsed= Kpsusp/ 1.5, based on the average difference in concentrations of zinc and
other metals in both media. For zinc this results in a Kp sedof 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
(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
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CAS number:
93763-87-2
different fractions. Information on these partition coefficients is given under 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) was estimated in the RAR from that for
particulate matter, as follows: Kpsed= Kpsusp/ 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 11. Overview of studies on aquatic bioaccumulation
Method
Results
Remarks
Reference
Palaemon elegans (crustaceae)
BCF: 28960 (whole body d.w.)
(steady state)
2 (reliable with
restrictions)
Rainbow PS and
White SL. (1989)
BCF: 2558 (whole body d.w.)
(steady state)
key study
aqueous (saltwater)
semi-static
Total uptake duration: 28 d
Total depuration duration: 1 min
BCF: 843 (whole body d.w.)
(steady state)
BCF: 277 (whole body d.w.)
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read-across based on
grouping of
substances (category
approach)
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The decapod Palaemon elegans
was exposed to sublethal
concentrations of zinc over 28
days time period; total zinc
accumulation was measured.
Echinogammarus pirloti
aqueous (saltwater)
semi-static
Total uptake duration: 21 d
Total depuration duration: 1 min
Slags, lead-zinc smelting
(steady state)
BCF: 38 (whole body d.w.)
(steady state)
Test material
(IUPAC name):
zinc chloride (See
endpoint summary
for justification of
read-across)
BCF: 60960 (whole body d.w.)
(steady state)
2 (reliable with
restrictions)
BCF: 5658 (whole body d.w.)
(steady state)
key study
BCF: 123 (whole body d.w.)
(steady state)
BCF: 2024 (whole body d.w.)
(steady state)
BCF: 819 (whole body d.w.)
The amphipod Echinogammarus (steady state)
pirloti was exposed to sublethal
concentrations of zinc over 21
BCF: 328 (whole body d.w.)
days time period; total zinc
(steady state)
accumulation was measured.
BCF: 116 (whole body d.w.)
(steady state)
various wildlife species
feed and aqueous (freshwater)
field study
CAS number:
93763-87-2
BAF: 4060 (whole body d.w.)
(steady state) (aquatic
invertebrates: control water)
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
BAF: 2600 (whole body d.w.)
(steady state) (snails, control
water)
BAF: 779 (whole body d.w.)
(steady state) (snails,
contaminated water)
Rainbow PS and
White SL. (1989)
read-across based on
grouping of
substances (category
approach)
Test material
(IUPAC name):
zinc chloride (See
endpoint summary
for justification of
read-across)
2 (reliable with
restrictions)
key study
Pascoe GA,
Blanchet RJ and
Linder G (1996)
read-across based on
grouping of
substances (category
approach)
Test material
(IUPAC name):
zinc (See endpoint
summary for
justification of
read-across)
BAF: 177 (whole body w.w.)
(steady state) (fish, contaminated
water)
4.3.2. Terrestrial bioaccumulation
The results of terrestrial bioaccumulation studies are summarised in the following table:
Table 12. Overview of studies on terrestrial bioaccumulation
Method
Results
Remarks
Reference
various wildlife species
BCF: 3.3 (whole body d.w.)
(steady state) (grasshoppers,
control soil)
2 (reliable with
restrictions)
Pascoe GA,
Blanchet RJ and
Linder G (1996)
food chain analysis in a
contaminated natural
environment
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BCF: 0.14 (whole body d.w.)
(steady state) (grasshoppers,
key study
read-across based on
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Slags, lead-zinc smelting
contaminated soil)
BCF: 1.84 (whole body d.w.)
(steady state) (earthworms,
control soil)
BCF: 0.54 (whole body d.w.)
(steady state) (earthworms,
contaminated soil)
BCF: 0.015 (whole body d.w.)
(steady state) (small mammals,
contaminated soil)
CAS number:
93763-87-2
grouping of
substances (category
approach)
Test material
(IUPAC name):
zinc (See endpoint
summary for
justification of
read-across)
BCF: 0.27 (whole body d.w.)
(steady state) (above ground
fodder, control soil)
BCF: 0.11 (whole body d.w.)
(steady state) (above ground
fodder, contaminated soil)
BCF: 0.66 (whole body d.w.)
(steady state) (below ground
fodder, control soil)
BCF: 0.21 (whole body d.w.)
(steady state) (below ground
fodder, contaminated soil)
BCF: 0.73 (whole body d.w.)
(steady state) (above ground
grasses, control soil)
BCF: 0.079 (whole body d.w.)
(steady state) (above ground
grasses, contaminated soil)
BCF: 1.5 (whole body d.w.)
(steady state) (below ground
grasses, control soil)
BCF: 0.45 (whole body d.w.)
(steady state) (below ground
grasses, contaminated soil)
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
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
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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
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 Kpsusp 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.
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CAS number:
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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 slags, lead-zinc smelting transformation/dissolution tests have been performed. Based on these test results, it
was concluded that slags, lead-zinc smelting are insoluble and should not be classified for environmental effect.
The results are summarised below.
Slags, lead-zinc smelting powder was tested for its capacity to release zinc (and other metal) ions in aqueous
medium, according to standardised protocols.
In this study, 100 mg/L of “slags, lead-zinc smelting” was agitated at 100 rpm in a pH buffered aqueous medium
at pH 6 and at pH 8 for 7 days. The solutions were sampled at specific time intervals and the concentrations of
dissolved zinc, lead, cadmium, copper and nickel in water were determined. The test at pH 6 was extended with
2 additional replicate test vessels to further address the variability of the results. The results are summarised in
table below.
Table 13. Summary of the measured metal concentration after 7-day T/D testing of slags, lead-zinc
smelting under standard T/D protocol conditions.
Loading @ pH 6
100 mg/L zinc Waelz slag
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X µg/L Zn
± σ µg/L Zn
7-day endpoint
166 ± 114
CAS number:
93763-87-2
X µg/L Pb
± σ µg/L Pb
X µg/L Cd
± σ µg/L Cd
X µg/L Cu
± σ µg/L Cu
X µg/L Ni
± σ µg/L Ni
<2.00
<0.200
<4.00
1.48 ± 1.30
Loading @ pH 8
100 mg/L zinc Waelz slag
X µg/L Zn
± σ µg/L Zn
7-day endpoint
17.7 ± 2.3
X µg/L Pb
± σ µg/L Pb
X µg/L Cd
± σ µg/L Cd
X µg/L Cu
± σ µg/L Cu
X µg/L Ni
± σ µg/L Ni
<2.00
<0.200
<4.00
<1.00
X = average of 5 (pH6) and 3 (pH8) test vessels (3 samples per test vessel)
σ = standard deviation
The results demonstrate that slags, lead-zinc smelting are practically insoluble. Zinc is released from the slags,
lead-zinc smelting only in a very limited way. The observed levels of zinc released in the medium after 7days
are at 100 mg/l loadings below the reference concentrations for aquatic toxicity at both the pH values of 6 and 8
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).
In the tests at pH 6, it was not possible to keep the pH constant, even when the CO2 flow rate for pH buffering
was increased to a maximum. The pH evolved to ~=pH 6.6 at the end of the test. This variability in pH most
probably explains the higher variability observed on the results. The number of replicates was increased from 3
to 5 to address this variability, but the variability remained high. It is noted that in spite of this high variability,
the zinc concentration released from the slag did in none of the distinct tests reach the reference value for acute
aquatic toxicity of zinc at pH 6 of 413µg Zn/l (observed range of test results after 7 days: 26.1-305µg Zn/l). This
pH effect is an intrinsic characteristic of the slag which is a basic material, containing high amounts of CaO.
The release of other metal ions (Cu, Ni, Cd, Pb) was negligible at both pH values tested.
Extrapolation of the results obtained after 7 days at 100mg/l loading to 28 days loading of 1mg/l of the
substance, results in an estimated zinc concentration of 6.6 µg/l (linear extrapolation of 100mg/l loading rate
results to 28 days: 660µg/l, divided by 100, see figure below).
Figure 1. Transformation /dissolution results for slags, lead-zinc smelting at pH 6, for 7days.
At pH 8, a plateau is reached after 96 hrs. The value observed after 28 days is thus similar to the one observed
after 7 days.
Both the estimated values at 1mg/l loading after 28 days (6.5µg Zn/l at pH 6, 0.2µg Zn/l at pH 8) are far below
the reference values for chronic aquatic toxicity (82µg/l and 19µg/l zinc, resp.)
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CAS number:
93763-87-2
Conclusion
Because of the results mentioned above, it is concluded that according to standard testing, zinc ions are released
from slags, lead-zinc smelting in aqueous medium in only a very limited way. The amount of zinc released is
not sufficient to reach the reference values for acute aquatic ecotoxicity over the whole pH range at 100mg/l
loading of the substance.
The observations mentioned above are confirmed by the systematic absence of ecotoxic effects observed in
standard acute aquatic toxicity testing with slags, lead-zinc smelting on fish, invertebrates and algae (IUCLID
section 6) at loading rates of 100mg /l of the substance.
As a consequence, slags, lead-zinc smelting should not be 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. Finally, some “real world” experimental evidence is discussed.
The removal of zinc in the base case is described in figure below.
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1.2
1
C/C0
0.8
0.6
0.4
0.2
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28
Time (days)
TICKET-UWM
30% Remaining
Figure 2. Base case total zinc removal from the water column using EUSES model
parameters. The initial total zinc concentration in the water column (C0) is 413 μg/L. The
horizontal dashed line represents C/C0 = 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 KD 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 KD 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
KD values is lower than the zinc risk assessment document value of 5.04. As a result of the generally
lower log KD (and associated lower fPart 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
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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
The results of experimental studies specific for Slags, lead-zinc smelting are summarised in the following tables:
Table 14. Overview of experimental studies on acute toxicity after oral administration
Method
Results
Remarks
Reference
rat (Wistar) female
LD50: > 2000 mg/kg bw
(female) based on: test mat.
2 (reliable with
restrictions)
Alvarez Luque N
(2007a)
oral: unspecified
key study
A study was conducted to evaluate
the acute oral toxicity of the test
material in rats. The rats were
exposed to a dose of 2.000mg/kg bw
and observed during a period of 14
days
experimental result
Test material (EC
name): Slags, leadzinc smelting
Table 15. Overview of experimental studies on acute toxicity after dermal administration
Method
Results
Remarks
Reference
rat (Wistar) female
LD50: > 2000 mg/kg bw
(female) based on: test mat.
2 (reliable with
restrictions)
Alvarez Luque N
(2007a)
A study was conducted to evaluate
the acute dermal toxicity of the test
material in rats. The rats were
exposed to a dose of 2.000mg/kg bw
of the tes material and observed
during a period of 14 days
key study
experimental result
Test material (EC
name): Slags, leadzinc smelting
Table 16. Overview of experimental studies on skin irritation
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Method
Results
Remarks
Reference
rabbit (New Zealand
White)
not irritating
2 (reliable with
restrictions)
Alvarez Luque N
(2007)
Erythema score:
Coverage: open (shaved)
0 of max. 4 (mean) (Time point: 24,
48, 72h)
A study was conducted to
evaluate the skin
Edema score:
irritation of the test
0 of max. 4 (mean) (Time point: 24,
material in rabbits. The
48, 72h)
rabbits were exposed to a
single dose and observed
during a period up to 72
hours
key study
experimental result
Test material (EC
name): Slags, leadzinc smelting
Table 17. Overview of experimental studies on eye irritation
Method
Results
Remarks
Reference
rabbit (New Zealand
White)
not irritating
2 (reliable with
restrictions)
Alvarez Luque N
(2007b)
Cornea score:
A study was conducted to
0 of max. 4 (mean) (Time point: 24,
evaluate the eye irritation
48, 72h)
of the test material in
rabbits. The rabbits were Iris score:
exposed to a dose of
1 of max. 2 (mean) (Time point: 24,
2.000mg/kg bw and
48, 72h)
observed during a period
of 14 days
Conjunctivae score:
key study
experimental result
Test material (EC
name): Slags, leadzinc smelting
0 of max. 3 (mean) (Time point: 24,
48, 72h)
Chemosis score:
1 of max. 4 (mean) (Time point: 24,
48, 72h)
Table 18. Overview of experimental in vitro genotoxicity studies
Method
Results
Remarks
Reference
bacterial gene mutation assay
(gene mutation)
Evaluation of results:
2 (reliable with
restrictions)
Alvarez Luque N
(2007c)
negative
S. typhimurium TA 1535, TA
Test results:
1537, TA 98 and TA 100 and
negative (in vitro gene
Escherichia coli wp2 uvrA (met.
mutation) for S. typhimurium
act.: with and without)
TA 1535, TA 1537, TA 98 and
TA 100 and Escherichia coli
Doses: 312; 625; 1250; 2500 and
wp2 uvrA(all strains/cell types
5000 µg/plate
tested); met. act.: with and
without
Bacterial gene mutation assay
was used to test Ferrosita for
reversion of his- auxotrophs of
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Salmonella Thyphimurium in the
strains TA1535, TA1537, TA98
and TA100 and tryp of
Escherichia Coli wp2 uvrA
The specific data on Slags, lead-zinc smelting demonstrate low level of acute oral/dermal toxicity and negative
results for the endpoints: skin/eye irritation and in vitro genotoxicity.
Given the fact that slag, lead- zinc smelting is highly insoluble and therefore is categorised in the group of
insoluble zinc compounds (as Zinc sulphide), the following health hazard assessment on insoluble zinc
compounds is applicable.
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-Zn3(PO4)2; zinc carbonate-ZnCO3; zinc sulphide-ZnS;
zinc sulphate-ZnSO4; zinc chloride–ZnCl2; diammonium tetrachlorozincate–ZnCl2/2NH4Cl; triamonium
pentachlorozincate-ZnCl2/3NH4Cl; zinc bis(dihydrogen phosphate)-Zn(H3PO4)2).
The zinc compounds have been grouped into three categories on the basis of their water solubility as described
in Table below:
Table 19. Water solubility values of the eleven zinc compounds covered in this CSR
Water solubility in mg/L2
Ranking of solubility
ZnCl2
ZnSO4
Zn(H3PO4)2
ZnCl2/2NH4Cl
ZnCl2/3NH4Cl
Zn(OH)2
ZnO
Water solubility
in mg/L1
4.3 x106
0.22x106
>1x104
>1x104
>1x104
1.6
1.6
0.851x106
0.210x106
>1 x106
0.291 x106
0.155 x106
648
2.9
Soluble
Soluble
Soluble
Soluble
Soluble
Slightly soluble
Slightly soluble
Zn 3(PO4)2
ZnCO3
Zn metal
ZnS
0.1
<0.2
<0.1
<10
2.7
1.3
0.1
0.00045x10-3
Slightly soluble
Slightly soluble
Slightly soluble
Insoluble
Zinc compound
1Values
2Values
are taken from ESIS database http://ecb.jrc.ec.europa.eu/esis/; ATSDR 2005; EU RARs (EU RAR, 2004a-f)
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).
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.
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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 20052009 (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 20. Grouping based on water solubility
Zinc compound
Ranking of solubility
ZnCl2
ZnSO4
Zn(H3PO4)2
ZnCl2/2NH4Cl
ZnCl2/3NH4Cl
ZnO
Zn(OH)2
Zn3(PO4)2
ZnCO3
Zn metal
ZnS
Soluble
Soluble
Soluble
Soluble
Soluble
Slightly soluble
Slightly soluble
Slightly soluble
Slightly soluble
Slightly soluble
Insoluble
Solubility-based
grouping
ZnCl2
ZnSO4
Zn(H3PO4)2
ZnCl2/2NH4Cl
ZnCl2/3NH4Cl
ZnO
Zn(OH)2
Zn3(PO4)2
ZnCO3
Zn metal
ZnS
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 ZnSO4 (16 mg formulation/cm2; 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
receptor medium and cutaneous bioavailability. It never exceeded 2%. The percentages for the absorption of
zinc from ointments containing ZnO and ZnSO4 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 ZnSO4 and ZnCl2 (in 20 mg formulation/cm2) 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).
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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 ZnSO4) 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/cm2 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 21. Dermal absorption of Zn (% of dose) through pig skin in vitro within 72
hours
Receptor fluid
Horny layer
Residual skin
Potentially absorbed dose
a
Soluble ZnSO4a
0.3 %
1.3 %
0%
1.6%
Slightly soluble ZnOa
0.03 %
12.3 %
2.6 %
14.9%
Corrected for background levels of zinc in receptor fluid and skin.
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 ZnSO4 monohydrate and a suspension of ZnO in this in vitro system may amount to
1.6% and 14.9%, respectively (Grötsch, 1999).
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 65ZnCl2 (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
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 65Zn as ZnCl2 (n=15), ZnCO3 (n=15) or Zn5(OH)8Cl2H2O (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 Zn5(OH)8Cl2H2O, ZnCl2 and ZnCO3, respectively (GalvezMorros et al., 1992).
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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)/m3 (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 2O3 aerosol
occurred with a half-life of about 34 hours. It was not clear whether the clearance of Zn particles from the lungs
was affected by the pathological condition of the lungs (Oberdörster et al., 1980).
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 65ZnCl2 by the dorsal skin of the guinea pig was estimated by monitoring the
decline of radioactivity emitted by 65ZnCl2 in at least 10 trials for each concentration tested ranging from 0.8 to
4.87 M ZnCl2 (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 65Zn) were topically applied to
shaved skin on the back of rabbits. Each application consisted of 2.5 mg zinc compound containing 5 Ci 65Zn.
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 65Zn in skin treated with 4 different zinc compounds. High concentrations of 65Zn were
observed in the cortical and cutical zones of the hair shaft, being the highest in the keratogenous zone.
Accumulation of 65Zn 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
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weight were seen. It was therefore suggested that the major mode of 65Zn uptake in skin is by diffusion through
the hair follicles due to the heavy localization of 65Zn primarily in the hair shaft and hair follicles. According to
the author, this emphasizes that chemical differences in the compounds may not play a very important role in the
skin uptake of 65Zn. No data were given on systemic absorption (Kapur et al., 1974).
The dermal absorption of 65Zn from ZnCl2 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 65Zn-activity in carcass, liver, gastrointestinal
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 ZnCl2 in acidic solution (pH = 1). Less acidic solutions with
ZnCl2 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 ZnCl2 solutions with pH = 1
on dermal integrity (Hallmans and Lidén, 1979).
Topical application of ZnCl2 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/cm2) 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/cm2) 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 ZnSO4 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 65Zn 2+ as ZnCl2 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 2-macroglobulin
only in the liver (Henkin et al., 1974).
Excretion
After a single oral dose of 86 – 130 g of 65Zn as ZnCl2, ZnCO3 or Zn5(OH)8Cl2H2O, male rats eliminated 65Zn
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/kg feed or
100 mg Zn5(OH)8Cl2H2O/kg feed for 14 days, the radioactivity from a subcutaneous dose of 37 kBq of 65ZnCl2
disappeared from the body with a rate of approximately 1% during the period 5 to 14 days post dosing (GalvezMorros et al., 1992).
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
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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 et 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 65ZnCl2 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 65ZnCl2 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 65Zn 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 65Zn 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 65Zn (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
ZnSO4 (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 65Zn 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
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 ZnCl2. The authors stated that “patients were given 3 to 18 Ci carrier free 65Zn”, therefore for the
calculation of the dose of 65Zn 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
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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 ZnSO4 was performed. Gelatine capsules containing 45
mg zinc as ZnSO4 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 (tmax). There was evidence of an enteral recirculation, the first rebound effect appeared
after 1.4 hours during the absorption phase before t 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 ZnSO4 was 0.4 hours (Nève
et al., 1991).
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
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
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corresponding to a breathing rate of 19 m3 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 22. Deposition fractions for oral breathers and for oronasal augmenters, using a
polydisperse particle distribution (MMAD 15.2 m, GSD 4.0)
Inhalability
Adjustment
Oral
Off
Oronasal
Off
Oronasal
On
Tidal
volume
(mL)
1100
1700
1100
1700
1100
1700
Breaths
(min-1)
Head
20
23
20
23
20
23
0.638
0.676
0.927
0.804
0.519
0.585
Deposition region
TracheoPulmonary
bronchial
0.071
0.139
0.100
0.101
0.011
0.021
0.064
0.064
0.011
0.021
0.063
0.064
Total
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
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
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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 23. Assumptions used for estimating the inhalation absorption
Soluble zinc compounds
Fraction absorbed in
airway region
Fraction cleared to GI
tract, followed by oral
uptake kinetics
Slightly soluble to insoluble zinc
compounds
(e.g., Zn; ZnO; Zn3(PO4)2)
0% head
0% tracheobronchial
100% pulmonary
100% head x 12%
100% tracheobronchial x 12%
0% pulmonary
(e.g., ZnCl2, ZnSO4)
20% head
50% tracheobronchial
100% pulmonary
80% head x 20%
50% tracheobronchial x 20%
0% pulmonary
By applying the above assumptions to the deposition fractions (Table 23), 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 24. Percentage estimations for inhalation absorption of soluble, slightly soluble
and insoluble zinc compounds
Inhalability
Oral
off
Oronasal
off
Tidal
volume
(mL)
Breaths
Soluble zinc compounds
(min-1)
(e.g., ZnCl2, ZnSO4)
Slightly soluble to insoluble
zinc compounds
(e.g., Zn; ZnO; Zn3(PO4)2)
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
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
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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/cm2/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 65Zn (as zinc chloride) was determined in adult male Wistar rats after intraperitoneal
injection of 15 Ci 65Zn. 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).
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).
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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 65Zn, half-lives ranged from 100 to 500 days (Elinder, 1986).
Sixteen healthy adult human volunteers were given oral administration of 92 mol of 65Zn (as ZnCl2) 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 65Zn. Table below shows the elimination data following 10 to 60 days postdosing.
Table 25. Elimination data obtained following thirty humans dosed with 18 to 900
moles of 65Zn
Dose group
(moles; (mg))
18 (1.2)
45 (2.9)
90 (5.8)
180 (11.6)
450 (29)
900 (58)
a significantly
Excretion rate
(% of remaining Zn/day )
0.44
0.62
0.37
0.49
0.37
0.74a
Biological half-life
(days)
157
111
186
141
186
93
different from the 18 moles group
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 65Zn (i.e., approximately 0.4 to
1.2 ng zinc) as ZnCl2 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 ZnSO4 (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 65Zn 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 65Zn
(half-life ca. 230 days) which was significantly different (P>0.001) from half-life values during placebo
treatment. Accelerated loss of 65Zn 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 65Zn 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 65Zn” for the calculation of the dose of 65Zn in
terms of nanogram zinc, it has been assumed that all zinc administered was 65Zn (Aamodt et al. 1982).
In ten of the patients from the study described above (Aamodt et al. 1982), the kinetics of 65Zn was studied in
more detail by Babcock et al. (1982). These patients received a fixed diet containing 8 – 13 mg Zn per day for 4
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to 7 days before and after the single 65Zn 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 ZnSO4) 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
ZnSO4) and to an increase in the urinary elimination rate (about 2-fold upon administration of ZnSO4 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 ZnCO3.
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, Zn3(PO4)2, ZnCO3, 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
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.
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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. Non-human information
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 26. Overview of experimental studies on acute toxicity after oral administration
according to decreasing water solubility of zinc compounds
Test
Substance
Zinc chloride
Study
Type
Acute
oral
Species
Endpoint
Exposure
Result
LD50
1,100
mg/kg
bw
Remarks
Reference
Rat
LD50
Single dose
2 (reliable with
restrictions)
key study
Single dose
1,260
mg/kg
bw
2 (reliable with
restrictions)
key study
LD50
50, 100,
1,000 or
3,000
mg/kg bw
920
mg/kg
bw
Mouse
LD50
No
information
available
926
mg/kg
bw
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 e)
2 (reliable with
restrictions)
key study
Domingo J L,
Llobet J M,
Paternain J L
and Corbella
J (1988a)
Domingo J L,
Llobet J M,
Paternain J L
and Corbella
J (1988b)
Litton
bionetics
(1974)
Zinc chloride
Acute
oral
Mouse
LD50
Zinc sulphate
Acute
oral
Rat
Zinc sulphate
Acute
oral
Zinc sulphate
Acute
oral
Rat
LD50
200- 2000
mg/kg bw
Zinc sulphate
Acute
oral
Rat
LD50
Single dose
1,000
–
2,000
mg/kg
bw
1,710
mg/kg
bw
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 e)
2 (reliable with
restrictions)
key study
Zinc sulphate
Acute
Mouse
LD50
No further
1,891
2 (reliable with
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CHEMICAL SAFETY REPORT
Domingo J L,
Llobet J M,
Paternain J L
and Corbella
J (1988b)
Sanders A
(2001b)
Domingo J L,
Llobet J M,
Paternain J L
and Corbella
J (1988a)
Courtois Ph,
43
EC number:
297-907-9
Test
Substance
Slags, lead-zinc smelting
Study
Type
oral
Species
Zinc sulphate
Acute
oral
Rat
Zinc sulphate
Acute
oral
Zinc sulphate
Endpoint
Exposure
CAS number:
93763-87-2
information
available
Result
LD50
mg/kg
bw
Remarks
Reference
restrictions)
supporting study
Guillard O,
Pouyollon M,
Piriou A and
Warnet J-M,
(1978)
LD50
No further
information
available
2,280
mg/kg
bw
Rat
LD50
Single dose;
>
2,000
mg/kg
bw
Acute
oral
Rat
LD50
No further
information
available
2,949
mg/kg
bw
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 e)
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 e)
2 (reliable with
restrictions)
supporting study
Lorke D
(1983)
Zinc
bis(dihydrogen
phosphate)
Acute
oral
Rat
LD50
Single dose
Zinc oxide
Acute
oral
Rat
LD50
Single; dose
3002000
mg/kg
bw
>5,000
mg/kg
bw
1 (reliable
without
restriction)
key study
2 (reliable with
restrictions)
key study
Zinc oxide
Acute
oral
Mouse
LD50
No further
information
available
ca.
7,950
mg/kg
bw
4 (not
assignable)
supporting study
Zinc oxide
Acute
oral
Rat
LD50
Single dose
>
15,000
mg/kg
bw
Zinc
phosphate
Acute
oral
Rat
LD50
Single dose;
>
5,000
mg/kg
bw
Zinc metal
Acute
oral
Rat
LD50
Single dose
>2,000
mg/kg
bw
Zinc sulfide
Acute
oral
Rat
LD50
No
information
available
>
15,000
mg/kg
bw
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 b)
2 (reliable with
restrictions)
supporting study
used in RAR,
(EU 2004 d)
2 (reliable with
restrictions)
key study
used in RAR,
(EU 2004 d)
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)
Klein and
Glaser (1989)
Prinsen MK
(1996)
Sachtleben
Chemie
GmbH (2000
a)
The acute oral toxicity studies with zinc sulphate do not specifically state which hydrated form of the zinc
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sulphate was tested. As this impacts the LD50 value, all available LD50 values were re-calculated to provide an
understanding the range of LD50 values of currently marketed zinc sulphate products (i.e., mono-, hexa-, and
heptahydrate). Table below summarises the results of this re-calculation
Table 27. Re-calculation of oral LD50 rat values
Reported for
Zinc sulphate
form
LD50
(mg/kg bw)
Dihydrate
1,710
LD50 (mg/kg bw) recalculated for
Mono
Hexa
Hepta
1,554
2,334
Reference
2,490
2,280
2,949
1,423
2,137
2,280
1,840 1
2,764 1
2,9491
2,949 2
4,429 2
4,7252
1
1
920
574
862
9201
Unspecified
920 2
1,382 2
1,4742
> 2,500
> 1,665
> 2,500
> 2,667
Hexahydrate
1,000 < LD50 <
624 < LD50 <
937 < LD50 <
1000 < LD50 <
Heptahydrate
2,000
1,248
1,875
2,000
1 Assumes testing of the heptahydrate (worst case) ; 2 Assumes testing of the monohydrate
Heptahydrate
Unspecified
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 28. Overview of experimental studies on acute toxicity after inhalation exposure
according to decreasing water solubility of zinc compounds
Test
substance
Study
type
Specie
s
Endpoint
Exposure
time
Result
(mg/L)
LC50
(4hrs)
(mg/L)
Not
applicable
Zinc
chloride
Acute
inhalation
Rat
LC50
10 min
<2
Zinc oxide
Acute
inhalation
Mouse
LC50
No
informati
on
available
2.5
Not known-
Zinc oxide
Acute
inhalation
Rat
LC50
4 hours
>5.7
>5.7
Zinc metal
Acute
inhalation
Rat
LC50
4 hours
>5.41
>5.41
Remarks
Reference
2 (reliable
with
restrictions)
key study
Karlsson
N, Cassel
G,
Fangmark
I and
Bergman
F (1986)
RTECS,
(1991)
4 (not
assignable)
supporting
study
used in RAR,
(EU 2004 b)
2 (reliable
with
restrictions)
key study
used in RAR,
(EU 2004 b)
2 (reliable
with
restrictions)
key study
used in RAR,
(EU 2004 a)
Klimisch
H-J,
Hildebrand B
and
Freisberg
KO (1982)
Arts,
MHE
(1996)
Additional inhalation data
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Male Syrian hamsters were exposed via inhalation to zinc sulphate aerosols in doses of 1.3 to 34.2 mg /m 3 (1.17.3 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/m3 (0.2 mg Zn) (Skornik and Brain, 1983).
In anesthetized dogs the pulmonary mechanics were not significantly changed after inhalation exposure to
submicron aerosols of ZnSO4 up to 17.3 mg/m3 for 7.5 minutes. Also an exposure of 4 hours to 4.1 to 8.8 mg/m 3
ZnSO4 to anesthetized dogs showed no effect on breathing mechanics, hemodynamic, or on arterial blood gases
(Sackner et al., 1981).
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/m3 (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/m3 (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/m3 (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
Table 29. Overview of experimental studies on acute toxicity after dermal exposure
Test
substance
Zinc
sulphate
Study
Type
Acute
dermal
Species
Endpoint
Exposure
Result
Rat
LD50
Single
application;
24 hours;
semiocclusive
>2,000
mg/kg
bw
Study Reliability
(Klimisch Score)
2 (reliable with
restrictions)
key study
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 ZnCl2 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 2/kg bw. At higher dose
levels, a dose-related intra-alveolar oedema was observed (Richards et al., 1989)
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
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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).
5.2.2. Human information
Soluble zinc compounds
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
ZnSO4/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/m3 zinc chloride aerosol a metallic taste was detected. Experimental exposure to zinc
chloride for 2 minutes resulted in slight nausea and some cough at 80 mg/m 3 in the majority of human subjects,
whereas at 120 mg/m3 irritation of the nose, throat and chest were noted (Cullumbine, 1957). Exposure to 4,800
mg/m3 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
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/m3) 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/m3 for metal fume fever can be derived.
Occupational exposure (6-8 hours) to zinc oxide fume generated during welding operations was investigated.
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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)/m3, 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/m3. 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/m3 for groups lavaged after 3, 8, and 22 hours, respectively, resulting in an exposure
of 20-170 mg zinc/m3 (equal to 25-212 mg ZnO/m3; calculation based on a 30-min exposure to the reported
exposure range of 0.6-5.1 g.min/m3). 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/m3 (3.4-46 mg ZnO/m3) for a
period of 15 to 120 minutes (cumulative zinc exposure 165-1110 mg.min/m3). 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 (r2=0.58) and IL-8 (r2=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/m3 expressed as zinc (625 mg.min/m3 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
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/m3 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
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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/m3). 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 LD50 values consistently exceeding 2,000 mg/kg bw, slightly soluble or insoluble zinc compounds such as,
zinc oxide (LD50 ranges between 5,000 and 15,000mg/kg bw), zinc phosphate (LD 50 is >5,000mg/kg bw), zinc
metal (LD50 >2,000mg/kg bw) or zinc sulphide (LD50 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/m3) 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
5.3.1. Skin
5.3.1.1. Non-human information
Table 30. Overview of experimental studies on skin irritation according to decreasing
water solubility of zinc compounds
Test
substance
Zinc
chloride
Study
type
Skin
irritation
Species
Endpoint
Exposure
Result
Zinc
chloride
Zinc
Guinea-pig
Erythema,
eschar and
oedema
formation
Skin
irritation
Rabbit
Erythema,
eschar and
oedema
formation
Skin
Rabbit
Erythema,
Daily; 0.5
mL of 1%
solution;
open-patch; 5
days
Daily; 0.5
mL of 1%
solution;
open-patch; 5
days
Daily; 0.5
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Remarks
Reference
Moderately
irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Severely
irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Severely
2 (reliable with
Lansdown
49
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Test
substance
chloride
Study
type
irritation
Species
Endpoint
Exposure
eschar and
oedema
formation
mL of 1%
solution;
occluded; 5
days
Daily; 0.5
mL of 1%
solution;
open-patch; 5
days
0.5g;
moistened
substance;
semiocclusive; 4
hours
Daily; 0.5
mL; openpatch; 5 days
Zinc
chloride
Skin
irritation
Mouse
Erythema,
eschar and
oedema
formation
Zinc
sulphate
Skin
irritation
Rabbit
Erythema,
eschar and
oedema
formation
Zinc
sulphate
Skin
irritation
Rabbit
Zinc
sulphate
Skin
irritation
Guinea Pig
Zinc
sulphate
Skin
irritation
Mouse
Zinc oxide
Skin
irritation
Rabbit
Zinc oxide
Skin
irritation
Rabbit
Zinc oxide
Skin
irritation
Rabbit
Zinc oxide
Skin
irritation
Guinea-pig
Zinc oxide
Skin
irritation
Mouse
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
Erythema,
eschar and
oedema
formation
CAS number:
93763-87-2
Result
Remarks
Reference
irritating
restrictions)
key study
ABG,
(1991)
Severely
irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Not irritating
2 (reliable with
restrictions)
key study
Van
Huygevoort
AHBM
(1999b)
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Daily; 0.5
mL; openpatch; 5 days
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Daily; 0.5
mL; openpatch; 5 days
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
500 mg;
occlusive; 24
hours
Not irritating
2 (reliable with
restrictions)
key study
Löser,
(1977)
Daily; 0.5
mL;
occlusive; 5
days
Daily; 0.5
mL; open
patch; 5 days
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Daily; 0.5
mL; open
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
Daily; 0.5
mL; open
Not irritating
2 (reliable with
restrictions)
key study
Lansdown
ABG,
(1991)
5.3.1.2. Human information
Slightly soluble and insoluble zinc compounds
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 2) was placed on
the human skin for 48 hours (Agren, 1990).
A patient who was treated with 40% zinc oxide ointment (15 g on 150 cm2) 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
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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
5.3.2.1. Non-human information
The results of experimental studies on eye irritation are summarised in the following table:
Table 31. Overview of experimental studies on eye irritation according to decreasing
water solubility of zinc compounds
Test substance
Study
type
Occular
irritation
Species
Endpoint
Exposure
Rabbit
Diammonium
tetrachlorozincate
Occular
irritation
Rabbit
Effects on
iris, cornea
and
conjunctiv
ae
Effects on
iris, cornea
and
conjunctivae
Zinc oxide
Occular
irritation
Rabbit
Effects on
iris, cornea
and
conjunctivae
Zinc oxide
Occular
irritation
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
Zinc oxide
Occular
irritation
Rabbit
Effects on
iris, cornea
and
conjunctivae
50 mg neat
product
instilled into
one eye
slightly
irritating
Zinc phosphate
Occular
irritation
Rabbit
Effects on
iris, cornea
and
conjunctivae
100 mg neat
product
instilled into
one eye;
unrinsed
Not irritating
Zinc dust
Occular
irritation
Rabbit
Effects on
iris, cornea
and
conjunctivae
100 mg
instilled into
one eye;
Median
particle
diameter
4µm; rinsed
after 24
Minimally
irritating
Zinc sulphate
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Result
Severely
irritating
Moderately
irritating
Remarks
Reference
2 (reliable with
restrictions)
key study
used in RAR,
(EU 2004 e)
4 (not
assignable)
supporting
study
Van
Huygevoort
(1999 f)
E.I.Dupont
de Nemours
and Co
(1992)
Not irritating
1 (reliable
without
restriction)
key study
used in RAR,
(EU 2004 b)
Van
Huygevoort
AHBM
(1999 e)
Not irritating
2 (reliable with
restrictions)
supporting
study
used in RAR,
(EU 2004 b)
2(reliable with
restrictions)
supporting
study
used in RAR,
(EU 2004 a)
1(reliable
without
restriction)
key study
used in RAR,
(EU 2004 d)
2 (reliable with
restrictions)
key study
used in RAR,
(EU 2004 a, b)
Thijssen J
(1978)
Löser E
(1977)
Mirbeau T,
Guillaumat
PPO and
Pelcot C
(1999)
Van
Huygevoort
AHBM
(1999 c)
51
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Test substance
Zinc powder
Slags, lead-zinc smelting
Study
type
Species
Endpoint
Rabbit
Effects on
iris, cornea
and
conjunctivae
Occular
irritation
Exposure
hours
100 mg neat
product
instilled into
one eye;
Median
particle
diameter
150µm;
unrinsed
CAS number:
93763-87-2
Result
Minimally
irritating
Remarks
Reference
2 (reliable with
restrictions)
key study
used in RAR,
(EU 2004 a, b)
Van
Huygevoort
AHBM
(1999 d)
5.3.2.2. Human information
Soluble zinc compounds
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).
Slightly soluble and insoluble zinc compounds
Zinc sulphide is not irritating to human eyes (Sachtleben Chemie GmbH, 2000c).
5.3.3. Respiratory tract
5.3.3.1. Non-human information
Soluble zinc compounds
Rats exposed to zinc chloride in single exposure studies exhibited signs of respiratory distress and oedema (see
acute inhalation toxicity).
Slightly soluble and insoluble zinc compounds
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).
5.3.3.2. Human information
No information available
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.
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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
5.4.1. Non-human information
Refer to section 5.3
5.4.2. Human information
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
5.5.1.1. Non-human information
The results of experimental studies on skin sensitisation are summarised in the following table:
Table 32. Overview of experimental studies on skin sensitisation according to
decreasing water solubility of zinc compounds
Test substance
Method
Results
Remarks
Reference
Zinc sulphate
Mouse local lymph node
assay
Negative
2 (reliable with
restrictions)
key study
Ikarashi Y,
Tsuchiya T and
Nakamura A
(1992)
Zinc sulphate
Guinea pig (DunkinHartley) female
Guinea pig maximization
test
Negative
2 (reliable with
restrictions)
supporting study
used in RAR, (EU
2004 e)
Van Huygevoort
(1999 i)
Zinc oxide
Guinea pig maximization
test
Negative
1 (reliable without
restriction)
key study
used in RAR, (EU
2004 b)
Van Huygevoort
AHBM (1999 g)
Zinc oxide
Guinea pig maximization
test
Ambiguous
1 (reliable without
restriction)
key study
Van Huygevoort
AHBM (1999h1)
Van Huygevoort
AHBM (1999h2)
Zinc sulphate (ZnSO4•7 H2O) 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.
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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 (ZnSO4•7 H2O) 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).
5.5.1.2. Human information
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
5.5.2.1. Non-human information
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
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and zinc compounds considered in this chemical safety report.
5.5.2.2. Human information
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. Non-human information
5.6.1.1. Repeated dose toxicity: oral
The results of experimental studies are summarised in the following table:
Table 33. Overview of experimental studies on repeated dose toxicity after oral
administration
Test substance
Zinc sulphate
Species
Mouse
ICR
Method
90-Day oral feeding in male/female
ICR mice;
Similar to OECD Guideline 408;
Results
NOAEL:
458 mg ZnSO4/kg
bw/day; equalling
104 mg Zn/kg bw/day
Remarks
Reference
2 (reliable with Maita K, Hirano
restrictions) M, Mitsumori K,
key study
Takashi K and
Shirasu Y (1981)
Dietary doses: 0, 300, 3,000, 30,000
At LOEL of 30,000ppm
ppm; equivalent to:
blood and biochemical
42.7/46.4, 458/479, 4927/4,878 mg
effects noted.
ZnSO4/kg bw/day (males/females)
Pathological and
histopathological
changes observed in
kidneys, thyroid, GI
tract and pancreas
Zinc sulphate
Rats
Wistar
90-Day oral feeding in male/female
rats;
Similar to OECD Guideline 408;
NOAEL:
234 mg ZnSO4/kg
bw/day; equalling
53.5 mg Zn/kg bw/day
2 (reliable with Maita K, Hirano
restrictions) M, Mitsumori K,
key study
Takashi K and
Shirasu Y (1981)
Dietary doses: 0, 300, 3,000, 30,000
At LOEL of 2,486 mg
ppm; equivalent to:
ZnSO4/kg bw/day blood
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effects and pancreatic
23.2/24.5, 234/243, and 2,514/2,486
damage noted;
mg/kg bw/day (males/females)
Zinc
Rats
monoglycerolate Sprague
Dawley
90-Day oral feeding in male/female
SD rats;
Similar to OECD Guideline 408;
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
2 (reliable with Edwards K and
restrictions) Buckley P (1995)
key study
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;
ICR mice (12/sex/group) were given daily doses of 300, 3000 or 30000 mg ZnSO 4•7 H2O/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 ZnSO4•7 H2O/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 H2O/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
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 4•7
H2O/kg bw/day for males and females, respectively (equivalent to approximately 53.5 mg Zn/kg bw) (Maita et
al., 1981).
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
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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 4 (unspecified)/l drinking water for 1 year. This
exposure equals approximately 100 mg ZnSO4/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 ZnCl2/kg bw/day) for 4 consecutive weeks. A control group was included. The body
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
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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
The results of experimental studies are summarised in the following table:
Table 34. 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/m3
Exposure: 16 weeks (5
hrs/day for 3 days/week)
Zinc oxide
Guinea pigs 5day inhalation in guinea
Hartley
pigs;
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;
Reference
2 (reliable with Wallenborn JG,
restrictions)
Evansky P,
supporting study Shannahan JH,
Vallanat B,
Ledbetter AD,
(2008)
No NOAEL identified;
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
Exposure: 5 days (3hrs/day)
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
Ultrafine particle (0.05 µm)
‘nose only’ exposure
concentrations of 0, 2.7, and
7 mg ZnO/m3;
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restrictions)
LC, Ainsworth
supporting study D, Peoples S
and Amdur MO
(1988)
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at peak concentrations: 25 —
34 mg/m³ air (analytical)
(male) (Wet-lung
weight/Body weight ratio and
Wet-lung weight/Dry-lung
weight ratio)
Zinc oxide
Guinea pigs 6 day inhalation in guinea
Hartley
pigs;
Decreased Vital capacity,
functional residual capacity,
alveolar volume and single
Ultrafine particle (0.05 µm)
breath diffusing capacity for
‘nose only’ exposure
carbon monoxide and
concentrations of 0 and 5
elevated lung weights due to
mg ZnO/m3;
inflammation
Exposure: 6 days (3hrs/day)
2(reliable with Lam HF,
restrictions)
Conner MW,
supporting study Rogers AE,
Fitzgerald S
and Amdur MO
(1985)
Animal examination at 24,
48, and 72 hours post
exposure;
Zinc oxide
Guinea pigs 1, 2, or 3 day inhalation in
Hartley
guinea pigs;
Marginal LOAEL: 2.3 mg
ZnO/m3;
Ultrafine particle (0.05 µm)
‘nose only’ exposure
concentrations of 0, 2.3, 5.9
and 12.1 mg ZnO/m3;
Morphological damage and
increase of inflammation
markers and enzymes in
pulmonary lavage fluid at
dose levels of 5.9 and 12.1 mg
Exposure: 1, 2, or 3
ZnO/m3; minimal changes in
consecutive days (3hrs/day);
enzyme levels in lavage fluid
Microscopical examination but no morphological changes
in lung tissue 2.3 mg ZnO/m3;
of lung tissue as well as
examination of pulmonary ;
lavage fluid;
2 (reliable with
restrictions)
supporting study
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/m3 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 βDglucosaminidase, γ-glutamyl transferase) in bronchoalveolar lavage fluid, indicating minimal pulmonary
effect. In the heart, cytosolic glutathione peroxidase activity decreased, while mitochondrial ferritin levels
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/m3 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/m3 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
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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/m3. Minimal changes in neutrophils and
activities of lactate dehydrogenase and alkaline phosphatase were seen in the pulmonary fluid at the lowest dose
level of 2.3 mg/m3 after 3 exposures but no morphologic changes were observed at this dose level. Based on
these results 2.3 mg ZnO/m3 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.
5.6.2. Human information
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
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 7th 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.
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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
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
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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 (1013%) 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
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
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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
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.
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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/m3 (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.
5.7. Mutagenicity
5.7.1. Non-human information
5.7.1.1. In vitro data
The results of experimental studies are summarised in the following table:
Table 35. Overview of experimental in vitro genotoxicity studies according to
decreasing water solubility
Test substance
Zinc chloride
Endpoint
Bacillus
subtilis
recombination
assay (DNA
repair)
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Species
Bacillus
subtilis
Method
Bacillus
subtilis
recombination
assay
Results
Negative
CHEMICAL SAFETY REPORT
Remarks
2 (reliable
with
restrictions)
supporting
study
Reference
Kada et al.,
(1980)
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Test substance
Zinc chloride
Endpoint
Bacterial
assay (gene
mutation)
Species
E. coli
(strain WP2s
())
Zinc chloride
Eukaryotic
assay (gene
mutation)
Mouse
lymphoma
cells
Zinc chloride
Cytogenetic
assay
(chromosomal
aberrations)
Human
dental pulp
cells (D824
cells)
Zinc chloride
Cytogenetic
assay
(chromosomal
aberrations)
Human
lymphocytes
Zinc chloride
Cytogenetic
assay
(chromosomal
aberrations)
Human
lymphocytes
Zinc chloride
Cell
transformation
assay
Zinc sulphate
CAS number:
93763-87-2
Method
Other:
induction of λ
prophage
(adaptation of
McCarroll et
al. 1981);
conc. 3200
μmol/l; m.a.
unknown
Unknown:
without m.a.
Results
Ambiguous
(two-fold
increase of
λ prophage
induction)
Remarks
4 (not
assignable)
supporting
study
Reference
Rossman et al.,
(1984)
Negative
Amacher and
Paillet (1980)
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)
Negative
2 (reliable
with
restrictions)
key study
2 (reliable
with
restrictions)
supporting
study
Deknudt and
Deminatti
(1978)
Syrian
hamster
embryo cells
Unknown; up
to 20 μg /ml
Negative
Bacterial test
(gene
mutation)
S.
typhimurium
(5 strains)
Negative
Zinc sulphate
Bacterial test
(gene
mutation)
S.
typhimurium
(1 strain)
Ames test:
with and
without m.a. ;
5 doses, up to
3600 µg/plate
Other:
without m.a.;
up to 3000
nM/plate
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
used in
RAR (EU
2004 c)
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
key study
Marzin and Phi
(1985)
Zinc sulphate
Eukaryotic
assay (gene
mutation)
S. cerevisiae
(1 strain)
Other:
without m.a.;
single
concentration
(0.1 mol/L
screening
assay
Weakly
positive
(no details
given)
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
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Ambiguous
Negative
Negative
CHEMICAL SAFETY REPORT
Someya et al.,
(2008)
Deknudt (1982)
Di Paolo and
Casto (1979)
Gocke et al.,
(1981)
Singh, (1983)
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Test substance
Zinc sulphate
Endpoint
Eukaryotic
assay (gene
mutation)
Species
S. cerevisiae
(1 strain)
Zinc sulphate
Cytogenetic
assay
Human
embryonic
lung
cells:WI-38
Zinc
bis(dihydrogen
phosphate)
Bacterial test
(gene
mutation)
Zinc oxide
CAS number:
93763-87-2
Method
Unknown:
m.a.
Unknown;
1000 and
5000 ppm
Unknown:
without m.a.;
0.1, 1.0 and
10 µg/plate
Results
Negative
Ames test:
with and
without m.a;
505000µg/plate
Negative
Bacterial test
(gene
mutation)
S.
typhimurium
(4 strains)
and E. coli
(strain WP2
uvrA)
S.
typhimurium
(4 strains)
Ames test;
1000 – 5000
μg/plate
Negative
Zinc oxide
Bacterial test
(gene
mutation)
S.
typhimurium
(3 strains)
Ames test
Negative
Zinc oxide
Eukaryotic
assay (gene
mutation)
Mouse
lymphoma
cells
Unknown:
with and
without m.a.
Positive
Zinc oxide
Cytogenetic
assay (sister
chromatide
exchange)
Syrian
hamster
embryo cells
Unknown;
m.a. unknown
Ambiguous
Zinc oxide
Cytogenetic
assay
(chromosomal
aberrations)
Human
dental pulp
cells (D824
cells)
Positive
Zinc oxide
Cytogenetic
assay
(chromosomal
aberrations)
Syrian
hamster
embryo
cells)
Zinc oxide
Unscheduled
DNA
synthesis
Syrian
hamster
embryo cells
Doses:
Concentration
in (uM)
30 100, 300
(met. act.:
without)
Doses:
Concentration
in (uM)
0, 60, 120,
180(met. act.:
without
Unknown:
without m.a.;
0.3, 1, 3, 10
and 30 µg/mL
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Remarks
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
1 (reliable
without
restriction)
key study
Reference
Siebert et al.,
(1970)
2 (reliable
with
restrictions)
key study
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
used in
RAR (EU
2004 b)
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
Crebelli et al.,
(1985)
Positive
2 (reliable
with
restrictions)
supporting
study
Hikiba et al.,
(2005)
Positive 
1 μg/mL
2 (reliable
with
restrictions)
supporting
study
Suzuki (1987)
Negative
CHEMICAL SAFETY REPORT
Litton Bionetics
(1974)
Research
Institute of
Organic
Synthesis inc.,
CETA (2010)
Litton Bionetics
(1976)
Cameron (1991)
Suzuki (1987)
Someya et al.,
(2008)
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Test substance
Zinc oxide
Endpoint
Cell
transformation
assay
Species
Syrian
hamster
embryo cells
Method
Unknown:
without m.a.;
0, 1, 3 μg
ZnO/ mL
Results
Positive 1
and 3
μg/mL
Remarks
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
Reference
Suzuki (1987)
Zinc
monoglycerolate
Bacterial test
(gene
mutation)
S.
typhimurium
(4 strains)
Negative
Zinc
monoglycerolate
Eukaryotic
assay (gene
mutation)
Mouse
lymphoma
cells
Zinc
monoglycerolate
Cytogenetic
assay
(chromosomal
aberrations)
Human
lymphocytes
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
(toxic at 15
μg/mL)
with m.a. 130 μg/mL
(toxic at 30
μg/mL)
According to
OECD
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:
without
m.a. from
10 μg/mL
with m.a.
from 15
μg/mL
2 (reliable
with
restrictions)
supporting
study
Adams and
Kirkpatrick
(1994)
Positive in
the
presence of
m.a. at 30
and 40
μg/mL
2 (reliable
with
restrictions)
supporting
study
Akhurst and
Kitching (1994)
Jones and Gant,
(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
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
The results of experimental studies are summarised in the following table:
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Table 36. Overview of experimental in vivo genotoxicity studies according to decreasing
water solubility
Test substance
Zinc chloride
Endpoint
Cytogenetic
assay
(chromosomal
aberrations)
Species
Mouse
Method
Other: 0.5%
zinc in
calciumdeficient
(0.03% Ca) or
standard diet
(1.1% Ca) for
30 days
Zinc chloride
Cytogenetic
assay
(chromosomal
aberrations)
Mouse
Zinc chloride
Drosophila
SLRL test
Drosophila
melanogaster
Other; single
i.p. injections
of 0, 7.5, 10 or
15 mg
ZnCl2/kg bw
and repeated
i.p. injections
every other
day of 2 and 3
mg ZnCl2/kg
bw for 8, 16 or
24 days.
Unknown;
0.247 mg/mL
adult feeding
Zinc sulphate
Cytogenetic
assay
(chromosomal
aberrations)
Rat
Zinc sulphate
Micronucleus
Mouse
Zinc sulphate
HostMediated
Assay
Mouse
Zinc sulphate
Dominant
lethal assay
Rat
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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
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
Remarks
2 (reliable
with
restrictions)
supporting
study
Reference
Deknudt
(1982)
2 (reliable
with
restrictions)
supporting
study
Gupta et
al., (1991)
Negative
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
Carpenter
and Ray
(1969)
Negative
2 (reliable
with
restrictions)
key study
Gocke et
al. (1981)
Weakly
positive
2 (reliable
with
restrictions)
supporting
study
Litton
Bionetics
(1974)
Negative
2 (reliable
with
restrictions)
supporting
study
Litton
Bionetics
(1974)
Negative
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Bionetics
(1974)
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Test substance
Zinc sulphate
Endpoint
Drosophila
SLRL test
Species
Drosophila
melanogaster
Zinc oxide
Cytogenetic
assay
(chromosomal
aberrations)
Rat
Zinc
monoglycerolate
Micronucleus
Rat
Method
other; 5 mM
(in 5%
saccharose)
adult feeding
method
Other: 5
months
inhalation of
0.1 to 0.5
mg/m3
Other:
resembling
OECD
guideline No.
474; 0.05%,
0.2%, and 1%
in purified diet
over a 13 week
period
CAS number:
93763-87-2
Results
Negative
Slight
increases of
chromosomal
aberrations
were seen;
primarily
hyperdiploid
cells were
seen.
Negative
Remarks
2 (reliable
with
restrictions)
supporting
study
2 (reliable
with
restrictions)
supporting
study
Reference
Gocke et
al., (1981)
2 (reliable
with
restrictions)
supporting
study
Windebank
et al.,
(1995)
Voroshilin
et al.,
(1978)
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
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).
5.7.2. Human information
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
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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
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. Non-human information
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
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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
Presently information is unavailable.
5.8.1.4. Carcinogenicity: other routes
Presently information is unavailable.
5.8.2. Human information
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
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 0.92.3) 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
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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
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;
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(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
(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
5.9.1.1. Non-human information
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 37. Overview of experimental studies on fertility
Test substance Method
Results
Zinc chloride
As of 3.5 mg Zn/kg bw/day:
2 (reliable with
Khan et al.,
P - Mortality; body weight
restrictions)
2001
gain; fertility indext; thymus supporting study
atrophy
F1 - litter size (non
significant); number of
surviving pubs (non
significant);
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
Remarks
Reference
As of 7.2 mg Zn/kg bw/day:
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P – hemosidosis of spleen;
lymphocyte deficiency
F1 - number of surviving pubs
; BW gain (PND 21)
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
HNO3/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);
2 (reliable with
Khan et al.,
restrictions)
2001
supporting study
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
via the oral route.
Application procedure
not specified but likely
oral gavage. Exposure
started 77 days prior to
mating.
As of 3.5 mg Zn/kg bw/day:
P - Mortality; body weight
gain; abs/rel liver/kidney
weight; lesions in GI tract,
inflammation in prostate
F1 - Mortality; body weight
gain; abs/rel
brain/prostate/spleen weight;
F2 – no effects
2 (reliable with
Khan et al.,
restrictions)
2007
supporting study
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
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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.
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P – Zn-concentration in testis and restrictions)
1986
sperm; sperm mobility;
supporting study
number of pregnancies
F1 – number of live births
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 37, some additional studies
indicating high oral doses of zinc (i.e., exposures greater that 25 mg day/kg bw/day) to impair fertility as
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).
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5.9.1.2. Human information
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
5.9.2.1. Non-human information
The following table summarizes the key studies addressing the developmental toxicity of zinc compounds in
experimental animals:
Table 38. Overview of experimental studies on developmental toxicity
Test
substance*
Zinc
sulphate
Species
Route Method
Result
Remark
Reference
Mouse
CD-1
Oral
Females
received daily
doses of 0, 0.3,
1.4, 6.5 and 30
mg ZnSO4
(unspecified)/k
g bw by oral
gavage during
days 6-15 of
gestation.
2 (reliable
with
restrictions)
Key study
Food and
Drugs
Research
Labs., Inc,
1973*
Zinc
sulphate
Rat
Wistar
Oral
Females
received daily
doses of 0, 0.4,
2.0, 9.1 and
42.5 mg ZnSO4
(unspecified)/k
g bw by oral
gavage during
days 6-15 of
gestation.
2 (reliable
with
restrictions)
Key study
Food and
Drugs
Research
Labs., Inc,
1973*
Zinc
sulphate
Rat
Charles
Foster
Oral
Females
received daily
doses of 0, and
200 mg Zn/kg
bw (in form of
ZnSO4) in diet
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
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
2 (reliable
with
restrictions)
Key study
EU RAR,
2004
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Test
substance*
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Species
Route Method
during days 118 of gestation
Zinc
sulphate
Hamster Oral
Zinc
sulphate
Rabbit
Dutch
Zinc
carbonate
Rat
Oral
Sprague
Dawley
Oral
Females
received daily
doses of 0, 0.9,
4.1, 19, and 88
mg ZnSO4
(unspecified)/k
g bw by oral
gavage during
days 6-10 of
gestation.
Females
received daily
doses of 0, 0.6,
2.8, 13 and 60
mg ZnSO4
(unspecified)/k
g bw during
days 6-18 of
gestation.
Females
received daily
doses of 0, 2.5,
and 50 mg
Zn/kg bw (in
form of
ZnCO3) in diet
during days 120 of gestation.
Result
CAS number:
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Remark
Reference
2 (reliable
with
restrictions)
Key study
Food and
Drugs
Research
Labs., Inc,
1973*
No discernible effects
were seen on or
maternal or foetal
survival. No
difference in number
of abnormalities found
in foetuses.
NOAEL:
13.6 mg/kg bw/day
2 (reliable
with
restrictions)
Key study
Food and
Drugs
Research
Labs., Inc,
1974*
No discernible effects
were seen on or
maternal or foetal
survival. No
difference in number
of abnormalities found
in foetuses.
NOAEL:
50 mg/kg bw/day
2 (reliable
with
restrictions)
Key study
Uriu-Hare,
1989
observed. No
difference in number
of abnormalities found
in foetuses.
NOAEL:
200 mg/kg bw/day
No discernible effects
were seen on or
maternal or foetal
survival. No
difference in number
of abnormalities found
in foetuses.
NOAEL:
20 mg/kg bw/day
* ZnSO4 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 38). 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).
5.9.2.2. Human information
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
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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
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
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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. Non-human information
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).
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 39. Overview of experimental studies on immunotoxicity
Method
Results
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
2 (reliable with
supplementation was
restrictions)
observed on circulating levels supporting study
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
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Reference
Bonham M,
O’Connor JM,
Alexander HD,
Coulter J, Walsh
PM, McAnena
(2003)
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Remarks
Reference
adverse effects of Zn
supplementation were
observed on immune status or
Cu status
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
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).
5.10.2. Human information
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
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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 40 and 41 list the existing OELs for zinc chloride as well as zinc oxide
Table 40. OELs for zinc chloride
Country/organisation
USA
The Netherlands
UK
Sweden
8 hour-TWA
mg/m3
1
1
1
1b)
Denmark
15 min-STEL
mg/m3
2
2 a)
0.5
References
ACGIH (1991)
SZW (1997)
HSE (1998)
National Board of
Occupational Safety and
Health,
Sweden (1993)
Arbejdstilsynet, 1992
a) This value is a 10 minutes-STEL
b) This TWA is determined for dust
Table 41. OELs for zinc oxide
Country/organisation
USA
USA
The Netherlands
Germany
UK
Sweden
Denmark
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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/m3
10 (fumes)
(ceiling)
4 (fumes)
10 (dust)
CHEMICAL SAFETY REPORT
References
ACGIH (1991) (guidance
values)
OSHA (1989) (legal limit
values)
SZW (1997)
DFG (1997)
HSE (1998)
National Board of
Occupational Safety and
Health,
Sweden (1993)
Arbejdstilsynet (1992)
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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 42 and 43 list the relevant and available dose descriptors for soluble, slightly soluble as
well as insoluble zinc compounds:
Table 42. 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
Quantitative dose descriptor
(appropriate unit) or qualitative
assessment1
Local
Systemic
Associated
relevant effect
Oral
N/A
LD50 =
300- 2000
mg/kg bw
Mortality;
Dermal
N/A
LD50 > 2,000
mg/kg bw
Inhalation
(animal)
N/A
< 2 mg/L
Mortality;
Remarks
on study
Standard acute LD50
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 LC50 study on
zinc chloride however,
exposure duration
very short – 10 min
and particle size tested
is not a true reflection
of human exposure
1 Pooled results from studies conducted on one or several soluble forms of zinc
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Endpoint
Irritation/
corrosion
Sensitization
Repeated dose
toxicity (subacute / subchronic /
chronic)
Mutagenicity
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Quantitative dose descriptor
(appropriate unit) or qualitative
assessment1
Local
Systemic
Associated
relevant effect
Skin
Non to severely
irritating
N/A
Erythema,
oedema, necrosis
Eye
Non to severely
irritating
N/A
Corneal opacity;
iritis; effects on
conjunctivae
Respiratory tract
Insufficient
information
N/A
Signs of
respiratory
distress
Skin
Not a skin
sensitizer
N/A
No effects
Respiratory
N/A
N/A
Oral (human)
No evidence
for respiratory
sensitization
properties
N/A
NOAEL = 0.83
mg/kg bw/day
Oral (animal)
N/A
Lowest established
NOAEL = 13 mg
Zn/kg bw/day
Inhalation
Dermal
in vitro
N/A
N/A
-
N/A
N/A
-
in vivo
-
-
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,
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;
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Remarks
on study
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
Overall weight of
evidence suggests that
zinc compounds do
not have a biologically
relevant genotoxic
activity; no
classification for
mutagenicity required
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Endpoint
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Quantitative dose descriptor
(appropriate unit) or qualitative
assessment1
Local
Systemic
Associated
relevant effect
Carcinogenicity
Oral/dermal/
inhalation
N/A
N/A
There is no
evidence for
carcinogenic
activity of zinc
compounds in
humans or
experimental
evidence
Reproductive
toxicity
(fertility
impairment)
Oral/dermal/
inhalation
N/A
NOAEL > 20
mg/kg bw/day
Developmental
toxicity
Oral/dermal/
inhalation
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
reproductive
toxicity study but
only at maternally
toxic doses
NOAEL (humans)
> 0.83 mg Zn/kg
bw/day
N/A
NOAEL >50
mg/kg bw/day
NOAEL (humans)
> 0.83 mg Zn/kg
bw/day
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Remarks
on study
No evidence exists to
justify classification of
zinc compounds for
reproductive toxicity
No evidence exists
that would justify the
classification of zinc
compounds for
developmental
toxicity
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Table 43. 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
Irritation/
corrosion
Sensitization
Repeated dose
toxicity (subacute / subchronic /
chronic)
Quantitative dose descriptor
(appropriate unit) or qualitative
assessment2
Local
Systemic
Associated
relevant effect
Oral
N/A
LD50 > 2,000
mg/kg bw
Mortality;
Dermal
N/A
LD50 > 2,000
mg/kg bw
Inhalation
(humans)
N/A
LOAEL – 5 mg/m3
Metal fume fever;
Inhalation
(animal)
N/A
> 5.7 mg/L
Mortality;
Skin
Not irritating
N/A
N/A
Eye
Non to
minimally
irritating
N/A
Corneal opacity;
iritis; effects on
conjunctivae
Respiratory tract
Insufficient
information
N/A
Skin
Not a skin
sensitizer
N/A
No signs of
respiratory
irritation in acute
inhalation studies
No effects
Respiratory
N/A
N/A
Oral (human)
No evidence
for respiratory
sensitization
properties
N/A
NOAEL = 0.83
mg/kg bw/day
Oral (animal)
N/A
Lowest established
NOAEL = 13 mg
Zn/kg bw/day
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,
Remarks
on study
Standard acute LD50
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
Experience from
workplace exposures;
while a NOEL has not
been determined, the
effects following
exposure at LOAEL
disappear within 24hrs
Acute LC50 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
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Endpoint
Quantitative dose descriptor
(appropriate unit) or qualitative
assessment2
Local
Systemic
Inhalation
N/A
NOAEL: 2.7 mg
ZnO/m³
Dermal
in vitro
N/A
-
N/A
-
in vivo
-
-
Carcinogenicity
Oral/dermal/
inhalation
N/A
N/A
Reproductive
toxicity
(fertility
impairment)
Oral/dermal/
inhalation
N/A
NOAEL > 20
mg/kg bw/day
Developmental
toxicity
Oral/dermal/
inhalation
Mutagenicity
NOAEL (humans)
> 0.83 mg Zn/kg
bw/day
N/A
NOAEL >50
mg/kg bw/day
NOAEL (humans)
> 0.83 mg Zn/kg
bw/day
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Associated
relevant effect
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
Remarks
on study
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
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Endpoint
Slags, lead-zinc smelting
Quantitative dose descriptor
(appropriate unit) or qualitative
assessment2
Local
Systemic
CAS number:
93763-87-2
Associated
relevant effect
Remarks
on study
reproductive
toxicity study but
only at maternally
toxic doses
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 44. Summary of absorption rates through different routes of exposure
Exposure route
Oral
Dermal
Inhalation
Zinc compound category
Absorption rate
Soluble zinc
20%
Slightly soluble/insoluble zinc
12%
Soluble zinc
2%
Slightly soluble/insoluble zinc
0.2%
Soluble zinc
40%
Slightly soluble/insoluble zinc
20%
To derive the endpoint specific NOAELs for workers and consumers on the basis of the established NOAEL of
50 mg zinc/day (0.83 mg/kg bw/day based on a woman’s body weight of 60 kg), the NOAEL has to be
corrected by assessment factors to account for the uncertainties of the database that led to the establishment of
the NOAEL. As the toxicity of zinc compounds is well understood and the NOAEL has been based on human
experience and data following chronic exposure to zinc through food supplementation, the assessment factors to
be used for zinc compounds are relatively small. Table below provides an overview of the assessment factors
under consideration for zinc compounds
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Table 45. Assessment factors (AF) for zinc compounds
Uncertainties
Interspecies
Assessment Factor
1
Intraspecies -worker
1
Intraspecies –general population
1
Exposure duration
1
Dose response and endpoint
specific/severity issues
Quality of database
1
1
Justification
No AF required; NOAEL has been derived
from human experience through food
supplementation
No AF required; NOAEL has been derived
from human experience through food
supplementation
No AF required; NOAEL has been derived
from human experience through food
supplementation
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
DNELoral sol Zn =
50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)
o
DNELoral insol Zn =
50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day)
This setting of the DNEL is fully in line with the approach and result that was concluded in the EU Risk
Assessment- part II Human Health (EU RAR 2004).
Derivation of the dermal DNEL (workers, consumers)
The derivation of a dermal DNEL on the basis of an oral NOAEL of 50 mg Zn/day derived from human
volunteer studies requires a route to route extrapolation. In this process, the follow steps are required

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of
soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAEL syst = 50
mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a dermal exposure to a soluble or slightly soluble/insoluble zinc compound that results
in a systemic exposure of 10 mg Zn/day; assumption: bioavailability of soluble zinc compounds
following dermal exposure – 2%; bioavailability of slightly soluble/insoluble zinc compounds
following dermal exposure – 0.2%;
o
NOAELdermal sol Zn = 10 mg Zn/day / 2% = 500 mg Zn/day
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o


CAS number:
93763-87-2
NOAELdermal insol Zn = 10 mg Zn/day / 0.2% = 5000 mg Zn/day
No assessment factor is considered to be required as the original dose descriptor has been derived from
appropriate human volunteer studies; hence the DNELs are as follows:
o
DNELdermal sol Zn = 500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day)
o
DNELdermal insol Zn = 5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day)
No further differentiation between worker and consumer DNELs is considered necessary.
Derivation of the inhalatory DNEL (workers, consumers)
The oral NOAEL of 50 mg Zn/day is also the basis for the derivation of the inhalatory DNEL. Hence, the
derivation of the inhalatory DNEL requires a route to route extrapolation as described in the following:

Derivation of the systemic exposure reflecting the oral NOAEL considering the bioavailability of
soluble zinc compounds which have been used in the human volunteer studies (i.e., NOAEL syst = 50
mg Zn/day x 20% = 10 mg Zn/day);

Calculation of a inhalatory exposure to a soluble or slightly soluble/insoluble zinc compound that
results in a systemic exposure of 10 mg Zn/day; the following assumptions are made: bioavailability of
soluble zinc compounds following inhalatory exposure – 40%; bioavailability of slightly
soluble/insoluble zinc compounds following inhalatory exposure – 20%;
o
NOAELinhal sol. Zn = 10 mg Zn/day / 40% = 25 mg Zn/day
o
NOAELinhal insol Zn = 10 mg Zn/day / 20% = 50 mg Zn/day



Corrected dose descriptor for workers considering a breathing volume of 10m3 per
8hr shift

NOAELinhal sol. Zn = 25 mg Zn/day / 10m3/day = 2.5 mg/m3

NOAELinhal insol. Zn = 50 mg Zn/day / 10m3/day = 5 mg/m3
Corrected dose descriptor for consumers considering a breathing volume of 20m3 per
day

NOAELinhal sol. Zn = 25 mg Zn/day / 20m3/day = 1.3 mg/m3

NOAELinhal insol. Zn = 50 mg Zn/day / 20m3/day = 2.5 mg/m3
No assessment factor is considered to be required as the original dose descriptor has been derived from
appropriate human volunteer studies; hence the DNELs are as follows:
o
o
DNELinhal sol Zn (worker) =
DNELinhal insol Zn (worker) =
2.5 mg/m3;
5 mg Zn/m3;
o
o
DNELinhal sol Zn (consumer) =
DNELinhal insol Zn (consumer) =
1.3 mg/m3;
2.5 mg Zn/m3;
The following Tables 46 and 47 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.
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Table 46. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for
workers
Endpoint
Repeated
dose
toxicity
Zinc
compound
category
Oral
Dermal
Most
relevant
quantitativ
e external
dose
descriptor
for
systemic
exposure
(NOEL)
Corrected
Overall Endpointexternal dose Assessme specific
descriptor for nt factor
DNEL
systemic
(external
exposure
dose)
Soluble
50 mg Zn/day
(0.83 mg/kg
bw/day)
Not required
1
50 mg Zn/day
(0.83 mg/kg
bw/day)
Slightly soluble/
insoluble
50 mg Zn/day
(0.83 mg/kg
bw/day)
50 mg Zn/day
(0.83 mg/kg
bw/day)
Not required
1
500 mg Zn/day
(8.3 mg/kg bw/day)
1
50 mg Zn/day
(0.83 mg/kg
bw/day)
500 mg Zn/day
(8.3 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)
5000 mg Zn/day
(83 mg/kg bw/day)
1
5000 mg Zn/day
(83mg/kg bw/day)
2.5 mg Zn/m3
1
2.5 mg Zn/m3
5 mg Zn/ m3
1
5 mg Zn/ m3
Soluble
Slightly soluble/
insoluble
Inhalation
Soluble
Slightly soluble/
insoluble
Table 47. Corrected dose descriptor(s) per endpoint and endpoint-specific DNELs for
consumers
Endpoint
Repeated
dose
toxicity
Oral
Dermal
Zinc
compound
category
Most
relevant
quantitativ
e dose
descriptor
for
systemic
exposure
Corrected
Overall
dose
Assessme
descriptor for nt factor
systemic
exposure
Endpointspecific
DNEL
(external
dose)
Soluble
50 mg Zn/day
(0.83 mg/kg
bw/day)
Not required
1
50 mg Zn/day
(0.83 mg/kg
bw/day)
Slightly soluble/
insoluble
50 mg Zn/day
(0.83 mg/kg
bw/day)
50 mg Zn/day
(0.83 mg/kg
bw/day)
Not required
1
500 mg Zn/day
(8.3 mg/kg bw/day)
1
50 mg Zn/day
(0.83 mg/kg
bw/day)
500 mg Zn/day
(8.3 mg/kg
bw/day)
50 mg Zn/day
(0.83 mg/kg
bw/day)
5000 mg Zn/day
(83 mg/kg bw/day)
1
Soluble
Slightly soluble/
insoluble
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5000 mg Zn/day
(83 mg/kg bw/day)
90
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Endpoint
Inhalation
Zinc
compound
category
Most
relevant
quantitativ
e dose
descriptor
for
systemic
exposure
Corrected
Overall
dose
Assessme
descriptor for nt factor
systemic
exposure
Endpointspecific
DNEL
(external
dose)
Soluble
50 mg Zn/day
(0.83 mg/kg
bw/day)
50 mg Zn/day
(0.83 mg/kg
bw/day)
1.3 mg Zn/m3
1
1.3 mg Zn/m3
2.5 mg Zn/ m3
1
2.5 mg Zn/ m3
Slightly soluble/
insoluble
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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
o
Oral

DNELoral sol Zn =
50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);

DNELoral insol Zn =
50 mg Zn/day (i.e., 0.83 mg Zn/kg bw/day);
DNELdermal sol Zn =
500 mg Zn/day (i.e., 8.3 mg Zn/kg bw/day);
Dermal

 DNELdermal insol Zn =
5000 mg Zn/day (i.e., 83 mg Zn/kg bw/day);
These DNEL’s appropriately protect workers and consumers for the most sensitive health endpoint, i.e. reduced
ESOD activity, observed in humans following repeated exposure to zinc compounds.
With regard to establishing the critical DNELs for inhalatory exposure of workers or consumers to zinc
compounds, two approaches are considered suitable:
a. the derivation of the DNEL on the basis of existing oral human dietary supplement studies requiring
route to route extrapolation as illustrated in chapter 5.11.2
and
b. the use of existing OELs as the respective DNELs for worker exposure.
With regard to the latter, the guidance on information requirements and chemical safety assessment states that
the OELs and/or the underlying information used for setting the OELs can be used to derive the DNELs for
workers (ECHA, 2008).
As presented in chapter 5.11.2, existing data from human supplementary studies results in worker DNELs of 2.5
or 5 mg Zn/m3 for soluble and slightly soluble/insoluble zinc compounds respectively and consumer DNELs of
1.3 or 2.5 mg Zn/m3.
Table 40 and 41 provide an overview of existing OELs for soluble zinc compounds represented by zinc
chloride (i.e., Table 40) as well as slightly soluble/insoluble zinc compounds represented by zinc oxide (i.e.,
Table 41). 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


o
DNELinhal soluble Zn (worker) =
DNELinhal insoluble Zn (worker) =
1 mg Zn/m3;
5 mg Zn/m3;
Inhalation - Consumer


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DNELinhal soluble Zn (consumer) =
DNELinhal insoluble Zn (consumer) =
1.3 mg Zn/m3;
2.5 mg Zn/m3;
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6. HUMAN HEALTH HAZARD ASSESSMENT OF
PHYSICO-CHEMICAL PROPERTIES
6.1. Explosivity
The available information on explosivity is summarised in the following table:
Table 48. Overview of information on explosivity
Method
Results
Remarks
Reference
EN-14034-1:2004:
Bestimmung der
Explsionskenngrossen
von Staub/LuftGemischen, Teil 1:
maximalen
Explosionsdruckes ;
teil 2 (EN-14034-2:
2006): maximalen
zeitlichen
Druckanstieg; teil 3
(EN-14034-3: 2006):
untere
Explosionsgrenze
Evaluation of results: non explosive
1 (reliable without
restriction)
Flemming F
(2009a)
Study results:
Explosive under influence of flame: no
key study
experimental result
Test material (EC
name): Slags, leadzinc smelting
Data waiving: see CSR section 1.3 Physico-chemical properties.
The following information is taken into account for any hazard / risk assessment:
the substance has no flammability, explosiveness or auto-inflammability properties (Outotec, 2010; Ibexu,
2009).
Classification according to GHS
Name: Slags, lead-zinc smelting
Reason for no classification: conclusive but not sufficient for classification
Classification according to DSD / DPD
Classification status: (slags, lead-zinc smelting)
Reason for no classification: conclusive but not sufficient for classification
6.2. Flammability
The available information on flammability is summarised in the following table:
Table 49. Overview of information on flammability
Method
Results
Remarks
Reference
VDI-Richtlinie 2263,
blatt 1
Study results:
1 (reliable without
restriction)
Flemming F
(2009b)
Ignition on contact with air: no
key study
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experimental result
Test material (EC
name): Slags, leadzinc smelting
Data waiving: see CSR section 1.3 Physico-chemical properties.
The following information is taken into account for any hazard / risk assessment:
the substance has no flammability, explosiveness or auto-inflammability properties (Outotec, 2010; Ibexu,
2009).
Data waiving: see CSR section 1.3 Physico-chemical properties.
Classification according to GHS
Name: Slags, lead-zinc smelting
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
Classification according to DSD / DPD
Classification status: (slags, lead-zinc smelting)
Reason for no classification: conclusive but not sufficient for classification
6.3. Oxidising potential
Data waiving: see CSR section 1.3 Physico-chemical properties.
Classification according to GHS
Name: Slags, lead-zinc smelting
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
Classification according to DSD / DPD
Classification status: (slags, lead-zinc smelting)
Reason for no classification: conclusive but not sufficient for classification
7. ENVIRONMENTAL HAZARD ASSESSMENT
General considerations
Slag, lead-zinc smelting is insoluble in aqueous medium. Results from transformation/dissolution tests (section
4.6) and acute aquatic toxicity testing (section 7.1) demonstrate that slag, lead-zinc smelting has very limited
solubility, which results in a release of zinc (and other metal) ions below the hazard levels. As such, the
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substance should not be classified for aquatic toxicity, and the results from eco-toxicity testing on soluble zinc
compounds are not relevant for Slag, lead-zinc smelting.
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 slag, lead-zinc smelting, 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 slag,
lead-zinc smelting.
In this chapter 7, the aquatic toxicity data showing the insoluble character of slag, lead-zinc smelting and its lack
of environmental hazard, will be summarised. The transformation/dissolution data are summarised under section
4.6. 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 slag, lead-zinc smelting. 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 slag, lead-zinc smelting.
For this reason, some of the tests are waived (because no exposure to zinc ions is anticipated) and slag, lead-zinc
smelting is not classified for aquatic toxicity.
The results on aquatic toxicity obtained with soluble or slightly soluble zinc compounds are not considered
relevant for slag, lead-zinc smelting.
7.1.1.1. Fish
7.1.1.1.1. Short-term toxicity to fish
The results are summarised in the following table:
Table 50. Overview of short-term effects on fish
Method
Results
Remarks
Reference
Brachydanio rerio (new name: Danio
rerio)
LC50 (96 h): > 100 mg/L
test mat. (nominal)
1 (reliable without
restriction)
Hydrotox (2009a)
freshwater
key study
static
experimental result
OECD Guideline 203 (Fish, Acute
Toxicity Test)
Test material (EC
name): Slags, leadzinc smelting
Leuciscus idus
freshwater
static
OECD Guideline 203 (Fish, Acute
Toxicity Test)
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LC50 (96 h): > 100 g/L test 2 (reliable with
mat. (nominal)
restrictions)
supporting study
Institüt fur
BaustoffForschung (2004)
experimental result
Test material (EC
name): Slags, leadzinc smelting
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Discussion
Slag from lead-zinc smelting is insoluble material. Fish tests, performed on an eluate of the slag made according
to DIN 384141 part 4, and tested according to OECD 203, show no toxicity of the slag for the fish.
According to these data, slag lead-zinc smelting should not be classified for aquatic toxicity.
The following information is taken into account for acute fish toxicity for the derivation of PNEC:
tests performed on eluate of slag, lead-zinc smelting according to standard OECD protocol show no short-term
toxicity of the substance to fish.
7.1.1.1.2. Long-term toxicity to fish
Data waiving
Reason: exposure considerations
Justification: Slags have been tested for a) acute ecotoxicity on algae, daphnids and fish, and b) chronic
toxicity on daphnids and algae. All the test results demonstrated the lack of aquatic toxicity of this substance,
also according to EU classification criteria.
Transformation/dissolution testing on slag according to OECD standard protocol showed that the substance
releases not sufficient zinc ions to exceed classification levels for acute and chronic toxicity at pH 6 and pH 8.
Finaly, fish are as a rule less sensitive to the zinc ion than the invertebrates and algae, as observed in the
datasets on soluble zinc compounds. For these reasons, chronic testing of slag on fish was not considered
relevant and is waived.
Discussion
Slags, lead-zinc smelting have been tested for a) acute ecotoxicity on algae, daphnids and fish, and b) chronic
toxicity on daphnids and algae. All the test results demonstrated the lack of aquatic toxicity of this substance,
also according to EU classification criteria.
Transformation/dissolution testing on slag according to OECD standard protocol showed that the substance
releases not sufficient zinc ions to exceed classification levels for acute and chronic toxicity at pH 6 and pH 8.
Finaly, fish are as a rule less sensitive to the zinc ion than the invertebrates and algae, as observed in the datasets
on soluble zinc compounds.
For these reasons, chronic testing of slag, lead-zinc smelting on fish (vertebrates) is not considered relevant and
is waived.
The following information is taken into account for long-term fish toxicity for the derivation of PNEC:
Slags, lead-zinc smelting have been tested for a) acute ecotoxicity on algae, daphnids and fish, and b) chronic
toxicity on daphnids and algae. All the test results demonstrate the lack of aquatic toxicity of this substance, also
according to EU classification criteria.
Transformation/dissolution testing on slag according to OECD standard protocol showed that the substance
releases not sufficient zinc ions to exceed classification levels for acute and chronic toxicity at pH 6 and pH 8.
Finaly, fish are as a rule less sensitive to the zinc ion than the invertebrates and algae, as observed in the datasets
on soluble zinc compounds. For these reasons, chronic testing of slag on fish was not considered relevant and is
waived.
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7.1.1.2. Aquatic invertebrates
7.1.1.2.1. Short-term toxicity to aquatic invertebrates
The results are summarised in the following table:
Table 51. Overview of short-term effects on aquatic invertebrates
Method
Results
Remarks
Reference
Daphnia magna
EC50 (48 h): > 100 mg/L
test mat. (nominal) based
on: mobility
1 (reliable without
restriction)
Hydrotox (2009b)
freshwater
static
experimental result
OECD Guideline 202 (Daphnia sp.
Acute Immobilisation Test)
Daphnia magna
freshwater
static
key study
Test material (EC
name): Slags, leadzinc smelting
EC50 (48 h): > 100 g/L test 2 (reliable with
mat. (nominal) based on:
restrictions)
mobility
supporting study
experimental result
OECD Guideline 202 (Daphnia sp.
Acute Immobilisation Test)
Institüt fur
Baustoff
Forschung
Duisburg,
germany (2004)
Test material (EC
name): Slags, leadzinc smelting
Discussion
Slag from lead-zinc smelting is insoluble material. Daphnid tests, performed on an eluate of the slag made
according to DIN 384141 part 4, and tested according to OECD 202, show very limited toxicity of the slag for
the daphnids.
According to these data, slag, lead-zinc smelting should not be classified for aquatic toxicity.
The following information is taken into account for short-term toxicity to aquatic invertebrates for the derivation
of PNEC:
tests performed on eluate of slag, lead-zinc smelting according to standard OECD protocol show no short-term
toxicity to Daphnids.
7.1.1.2.2. Long-term toxicity to aquatic invertebrates
The results are summarised in the following table:
Table 52. Overview of long-term effects on aquatic invertebrates
Method
Results
Remarks
Reference
Daphnia magna
NOEC (21 d): 70 g/L test
mat. (nominal) based on:
immobilisation
2 (reliable with
restrictions)
Hygiene-Institüt
des Ruhrgebiets
(1999a)
freshwater
static
OECD 202 was mentioned as protocol.
Both the mobility and the reproduction
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key study
experimental result
Test material (EC
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capacity of the daphnids was evaluated
CAS number:
93763-87-2
name): Slags, leadzinc smelting
Discussion
Slag from lead-zinc smelting is insoluble material. Daphnid tests, performed on an eluate of the slag made
according to DIN 384141 part 4, and tested according to OECD 202, show very limited toxicity of the slag,
lead-zinc smelting for the daphnids.
According to these data, slag, lead-zinc smelting should not be classified for aquatic toxicity.
The following information is taken into account for long-term toxicity to aquatic invertebrates for the derivation
of PNEC:
tests performed on eluate of slag, lead-zinc smelting, according to standard OECD protocol shows no long-term
toxicity to Daphnids.
7.1.1.3. Algae and aquatic plants
The results are summarised in the following table:
Table 53. Overview of effects on algae and aquatic plants
Method
Results
Remarks
Reference
Desmodesmus subspicatus (algae)
EC50 (72 h): > 100 mg/L
test mat. (nominal) based
on: growth rate
1 (reliable without
restriction)
Hydrotox (2009c)
freshwater
static
OECD Guideline 201 (Alga, Growth
Inhibition Test)
key study
NOEC (72 h): >= 100 mg/L
experimental result
test mat. (nominal) based
on: growth rate
Test material (EC
name): Slags, leadzinc smelting
Discussion
Effects on algae / cyanobacteria
Slag from lead-zinc smelting is insoluble material. Algae tests, performed on an eluate of the slag, lead-zinc
smelting made according to DIN 384141 part 4, and tested according to OECD 201, show very limited toxicity
of the slag, lead-zinc smelting for the daphnids.
According to these data, slag, lead-zinc smelting should not be classified for aquatic toxicity.
The following information is taken into account for effects on algae / cyanobacteria for the derivation of PNEC:
test performed on eluate of slag, lead-zinc smelting, according to standard OECD protocol shows no toxicity to
algae.
7.1.1.4. Sediment organisms
Data waiving
Reason: exposure considerations
Justification: Slag, lead-zinc smelting has been tested for a) acute ecotoxicity on algae, daphnids and fish, and
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b) chronic toxicity on daphnids and algae. All the test results demonstrated the lack of aquatic toxicity of this
substance, also according to EU classification criteria.
Transformation/dissolution testing on slag according to OECD standard protocol showed that the substance
releases not sufficient zinc ions to exceed classification levels for acute and chronic aquatic toxicity at pH 6
and pH 8.
Finaly, the limited amount of Zn ions released from the slag are expected to be sequestered directly into the
Acid-volatile sulphide fraction of the sediment.
For these reasons, sediment toxicity testing on slag, lead-zinc smelting is waived.
Discussion
Slag, lead-zinc smelting has been tested for a) acute ecotoxicity on algae, daphnids and fish, and b) chronic
toxicity on daphnids and algae. All the test results demonstrated the lack of aquatic toxicity of this substance,
also according to EU classification criteria.
Transformation/dissolution testing on slag, lead-zinc smelting according to OECD standard protocol showed
that the substance releases not sufficient zinc ions to exceed classification levels for acute and chronic aquatic
toxicity at pH 6 and pH 8.
Finaly, the limited amount of Zn ions released from the slag are expected to be sequestered directly into the
Acid-volatile sulphide fraction of the sediment.
For these reasons, sediment toxicity testing on slag, lead-zinc smelting is waived.
The following information is taken into account for sediment toxicity for the derivation of PNEC:
Slag, lead-zinc smelting has been tested for a) acute ecotoxicity on algae, daphnids and fish, and b) chronic
toxicity on daphnids and algae. All the test results demonstrated the lack of aquatic toxicity of this substance,
also according to EU classification criteria.
Transformation/dissolution testing on slag, lead-zinc smelting according to OECD standard protocol showed
that the substance releases not sufficient zinc ions to exceed classification levels for acute and chronic aquatic
toxicity at pH 6 and pH 8.
Finaly, the limited amount of Zn ions released from the slag, lead-zinc smelting are expected to be sequestered
directly into the Acid-volatile sulphide fraction of the sediment.
For these reasons, sediment toxicity testing on slag, lead-zinc smelting is waived.
7.1.1.5. Other aquatic organisms
In this section, whole ecosystem studies are summarised. In spite of the fact that Slag, lead-zinc smelting is
insoluble and as such not environmentally hazardous, 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 54. Overview of effects on other aquatic organisms: communities
Method
Results
macroinvertebrate communities and
NOEC (wk): > 20 — < 27
families of Ephemeroptera, Plecoptera µg/L dissolved (meas.
and Trichoptera were assessed.
(arithm. mean)) based on:
benthic macroinvertebrate
freshwater
structure and insect family
richness
field study with benthic
macroinvertebrates and insects
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Remarks
Reference
1 (reliable without
restriction)
Crane M, Kwok
KWH, Wells C,
Whitehouse P and
Lui GCS. (2007)
key study
read-across based on
grouping of
substances (category
approach)
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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.
microcosm/mesocosm
freshwater
flow-through
CAS number:
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Test material
(IUPAC name):
zinc (See endpoint
summary for
justification of
read-across)
NOEC (4 wk): 22.8 µg/L
dissolved (meas. (TWA))
based on: Phytoplakton:
community abundance,
richness and diversity
1 (reliable without
restriction)
key study
read-across based on
grouping of
substances (category
approach)
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
microcosm/mesocosm
NOEC (14 wk): 14 µg/L
dissolved (meas. (TWA))
based on: chlorophyta
eveness
2 (reliable with
restrictions)
NOEC (14 wk): 14 µg/L
dissolved (meas. (TWA))
based on: Zooplankton
eveness
read-across based on
grouping of
substances (category
approach)
NOEC (14 wk): 21 µg/L
dissolved (meas. (TWA))
based on: chlorophyll a in
periphyton
Test material (CAS
name): zinc
dichloride (See
endpoint summary
for justification of
read-across)
NOEC (18 h): >= 7 — <=
13 µg/L dissolved
(estimated) based on: C
fixation rate
2 (reliable with
restrictions)
LOEC (18 h): >= 10 — <=
15 µg/L dissolved
(nominal) based on: C
fixation rate
read-across based on
grouping of
substances (category
approach)
freshwater
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.
multispecies test
saltwater
static
Photosynthetic inhibition (C fixation)
test on phytoplancton communities in
the field, designed for dose-response
Rand GM, Hoang
TC, Brausch JM.
(2010)
Test material (CAS
name): zinc
dichloride (See
endpoint summary
for justification of
read-across)
key study
Rand GM, Hoang
TC, Brausch JM.
(2012)
Davies AG &
Sleep JA (1979)
key study
Test material
(IUPAC name):
zinc (See endpoint
summary for
justification of
read-across)
Species of macro-algae, crustaceae,
sponges, mollusca and annelids were
introduced. Zoo- and phytoplankton
and other macro invertebrates were
introduced with the water and
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No Observed Ecological
Adverse Effect
Concentration (83 d): 12
µg/L dissolved (meas.
(TWA)) based on: primary
1 (reliable without
restriction)
key study
CHEMICAL SAFETY REPORT
Foekema EM,
Kramer KJM,
Kaag NHBM,
Sneekes AC,
Bierman S,
100
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sediment.
production, grwoth of
Littorina littorea
saltwater
static
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
CAS number:
93763-87-2
read-across based on
grouping of
substances (category
approach)
Hoornsman (2012)
Test material (CAS
name): zinc
dichloride (See
endpoint summary
for justification of
read-across)
Form: powder
NOEC (24 h): 1.45 µg/L
dissolved (meas. (not
specified)) based on: C
fixation rate (growth)
static
LOEC (4 h): > 100 µg/L
dissolved (meas. (not
Field experiment on natural
specified)) based on: C
phytoplancton communities looking at fixation rate
C fixation rates as the endpoint,
designed for dose-response
2 (reliable with
restrictions)
supporting study
Wolter K, U.
Rabsch, P.
Krischker and A.
G. Davies (1984)
read-across based on
grouping of
substances (category
approach)
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, Slags, lead-zinc smelting are highly insoluble and not environmentally hazardhous; the zinc ion is
not released in sufficient quantity from Slags, lead-zinc smelting to cause aquatic toxicity. Still, the PNECs that
were derived from soluble zinc compounds are considered relevant for the Zn contained in the Slags, lead-zinc
smelting, because they are Zn-ion, not zinc substance (Slags, lead-zinc smelting) 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 55. PNEC water
PNEC
Assessment
factor
Remarks/Justification
PNEC aqua
(freshwater): 20.6
µg/L
1
Extrapolation method: statistical extrapolation
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The following considerations are made on the uncertainty around the
HC5 and for determining the size of the assessment factor: •The number
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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
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.
PNEC aqua (marine 1
water): 6.1 µg/L
Extrapolation method: statistical extrapolation
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 56. PNEC sediment
PNEC
Assessment
factor
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Remarks/Justification
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PNEC sediment
(freshwater): 117.8
mg/kg sediment dw
Slags, lead-zinc smelting
1
PNEC sediment
1
(marine water): 56.5
mg/kg sediment dw
CAS number:
93763-87-2
Extrapolation method: statistical extrapolation
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
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 (IUCLID 5.6.) and of the aquatic toxicity
tests documented in this section 6 all consistently demonstrate the very limited solubility of slag, lead-zinc
smelting. For this reason, the testing for soil toxicity is waived, because exposure to zinc ions in the pore water
is anticipated to be very limited. Slag, lead-zinc smelting is very stable also in soils. The results on soil toxicity
obtained with soluble or slightly soluble zinc compounds are not considered relevant for slag, lead-zinc
smelting.
7.2.1.1. Toxicity to soil macro-organisms
The results are summarised in the following table:
Table 57. Overview of effects on soil macro-organisms
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Method
Results
Remarks
Reference
Eisenia sp. (annelids)
LC50 (14 d): > 50000
mg/kg soil dw test mat.
(nominal) based on:
mortality
2 (reliable with
restrictions)
Hygiene-Institüt
des Ruhrgebiets
(1999b)
short-term toxicity (laboratory study)
Substrate: "Einheitserde O"
key study
experimental result
OECD Guideline 207 (Earthworm,
Acute Toxicity Tests)
Test material (EC
name): Slags, leadzinc smelting
Data waiving
Information requirement: Toxicity to terrestrial arthropods
Reason: exposure considerations
Justification: The results of the transformation/dissolution tests in aqueous media (IUCLID 5.6.) and of the
aquatic and terrestrial toxicity tests documented in this section 6 all consistently demonstrate the very
limited solubility of slag, lead-zinc smelting. For this reason, the testing for toxicity on terrestrial arthropods
is waived, because exposure to zinc ions in the pore water is anticipated to be very limited.
Discussion of effects on soil macro-organisms except arthropods
Slags, lead -zinc smelting are very stable also in soils. There is no toxicity observed to earthworms. The results
on soil toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for slag,
lead-zinc smelting.
The following information is taken into account for effects on soil macro-organisms except arthropods for the
derivation of PNEC:
The results of the terrestrial toxicity test documented in this section demonstrate the very limited hazard of the
slag for terrestrial organisms, e. g. earthworms. Further, transformation/dissolution tests in aqueous media
(IUCLID 5.6.) and of the aquatic tests in this section 6 all consistently demonstrate the very limited solubility of
slag, lead-zinc smelting.
Discussion of effects on soil arthropods
Slag, lead-zinc smelting is very stable also in soils, as is demonstrated by results on soil toxicity tests. Data
obtained with soluble or slightly soluble zinc compounds are not considered relevant for slag, lead-zinc smelting
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 (IUCLID 5.6.) and of the aquatic and
terrestrial toxicity tests documented in this section 6 all consistently demonstrate the very limited solubility of
slag, lead-zinc smelting. For this reason, the testing for terrestrial toxicity on arthropods is waived, because
exposure to zinc ions in the pore water is anticipated to be very limited.
7.2.1.2. Toxicity to terrestrial plants
The results are summarised in the following table:
Table 58. Overview of effects on terrestrial plants
Method
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Results
Remarks
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Arabidopsis thaliana (Dicotyledonae
(dicots))
long-term toxicity (laboratory study)
early seedling growth toxicity test
Slags, lead-zinc smelting
Arabidopsis thaliana: EC50 2 (reliable with
(14 d): > 50 g/kg soil dw
restrictions)
test mat. (nominal) based
key study
on: seedling growth and
biomass
experimental result
Substrate: "Einheitserde O"
long-term toxicity (laboratory study)
early seedling growth toxicity test
Hygiene-Institüt
des Ruhrgebiets
(1999c)
Test material (EC
name): Slags, leadzinc smelting
OECD Guideline 208 (Terrestrial
Plants Test: Seedling Emergence and
Seedling Growth Test)
Hordeum vulgare (Monocotyledonae
(monocots))
CAS number:
93763-87-2
Hordeum vulgare: EC50
(14 d): > 50 g/kg soil dw
test mat. (nominal) based
on: seedling growth and
biomass
Substrate: "Einheitserde O"
2 (reliable with
restrictions)
key study
Hygiene-Institüt
des Ruhrgebiets
(1999c)
experimental result
Test material (EC
name): Slags, leadzinc smelting
OECD Guideline 208 (Terrestrial
Plants Test: Seedling Emergence and
Seedling Growth Test)
Discussion
Sags, lead-zinc smelting are very stable also in soils, and have no toxic effect on plants. The results on soil
toxicity obtained with soluble or slightly soluble zinc compounds are not considered relevant for slags, lead-zinc
smelting.
The following information is taken into account for toxicity on terrestrial plants for the derivation of PNEC:
The results of the terrestrial plant toxicity tests documented in this section, the results of the
transformation/dissolution tests in aqueous media (IUCLID 5.6.) and of the aquatic toxicity tests in section 6 all
consistently demonstrate the very limited solubility of slag, leead-zinc smelting.
7.2.1.3. Toxicity to soil micro-organisms
Data waiving
Reason: exposure considerations
Justification: The results of the terrestrial toxicity tests in this section, of the transformation/dissolution tests in
aqueous media (IUCLID 5.6.) and of the aquatic toxicity tests documented in this section 6 all consistently
demonstrate the very limited solubility of slag, lead-zinc smelting. For this reason, the testing for soil
microorganism toxicity is waived, because exposure to zinc ions in the pore water is anticipated to be very
limited.
Discussion
Slag, lead-zinc smelting is very stable also in soils, as is demonstrated by results on soil toxicity tests. Data
obtained with soluble or slightly soluble zinc compounds are not considered relevant for slag, lead-zinc
smelting.
The following information is taken into account for toxicity on soil micro-organisms for the derivation of
PNEC:
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The results of the transformation/dissolution tests in aqueous media (IUCLID 5.6.) and of the aquatic and
terrestrial toxicity tests documented in this section 6 all consistently demonstrate the very limited solubility of
slag, lead-zinc smelting. For this reason, the testing for terrestrial toxicity on soil microorganisms is waived,
because exposure to zinc ions in the pore water is anticipated to be very limited.
7.2.1.4. Toxicity to other terrestrial organisms
No data
7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil)
As indicated, Slags, lead-zinc smelting are highly insoluble and not environmentally hazardous; the zinc ion is
not released in sufficient quantity from Slags, lead-zinc smelting to cause aquatic toxicity. Still, the PNECs that
were derived from soluble zinc compounds are considered relevant for the Zn contained in the Slags, lead-zinc
smelting, because they are Zn-ion, not zinc substance (Slags, lead-zinc smelting) 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 59. PNEC soil
PNEC
Assessment
factor
Remarks/Justification
PNEC soil: 35.6
mg/kg soil dw
1
Extrapolation method: statistical extrapolation
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
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The results are summarised in the following table:
Table 60. Overview of effects on micro-organisms
Method
Results
Remarks
Reference
Pseudomonas putida
EC10 (16 h): 26.6 g/L test
mat. (nominal) based on:
Inhibition of cell
multiplication
2 (reliable with
restrictions)
Hygiene-Institüt
des Ruhrgebiets,
Gelsenkirchen,
Germany (1999)
freshwater
static
key study
experimental result
DIN 38412, part 8 (Pseudomonas
Zellvermehrungshemm-Test)
Test material (EC
name): Slags, leadzinc smelting
Discussion
Slag from lead-zinc smelting is insoluble material. Testing on aquatic bacteria, performed on an eluate of the
slag made according to DIN 384141 part 4, and tested according to DIN 38412 L8 standard protocol, shows
very limited toxicity of slag, lead-zinc smelting for the bacteria.
The following information is taken into account for effects on aquatic micro-organisms for the derivation of
PNEC:
tests performed on eluate of slag, lead-zinc smelting, according to standard OECD protocol shows no toxicity to
Aquatic bacteria.
7.4.2. PNEC for sewage treatment plant
Table 61. PNEC sewage treatment plant
Value
Assessment
factor
Remarks/Justification
PNEC STP: 100
µg/L
1
Extrapolation method: assessment factor
Considering that the nitrification inhibition test is most relevant 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
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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
Reason: other justification
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.
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 62. PNEC oral
PNEC
Assessment
factor
No potential for
bioaccumulation
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Remarks/Justification
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
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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
Based on
a) the results presented in section 4.6. on transformation /dissolution tests, demonstrating that slags, lead-zinc
smelting are insoluble to such extent that the concentration dissolved in standard aqueous media with 100mg/l
slags, lead-zinc smelting loading is lower than the reference value for aquatic toxicity of zinc at pH 6 and pH 8,
and
b) results presented under section 7, aquatic toxicity tests on fish, invertebrates and algae showing that loading
of 100mg/l of slags, lead-zinc smelting does not result in any aquatic toxicity effect,
Slags, lead-zinc smelting are not classified for environmental effects.
General discussion
Results from transformation/dissolution tests and acute aquatic toxicity testing demonstrate that slags, lead-zinc
smelting 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 slags, lead-zinc smelting.
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 slags, lead-zinc smelting, 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 slags,
lead-zinc smelting.
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. Zn slag 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
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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.
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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
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