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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other:
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3.9
Dose descriptor starting point:
other: HEC-LOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.035 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Note 1. Exposures are always given in terms of mg nickel and NOT as mg substance.

Note 2. In cases where existing standards (OELs in case of workers, ambient air standards in case of general public) are used instead of DNEL/DMEL, the fields for Assessment factors and Dose descriptor Starting Points were left blank. Further information on the Standard derivation is contained in the documents referenced in the Table below.

Nickel Metal CSR Table for Workers

Exposure pattern

Route

Descriptor

DNEL / DMELa

AF

Corrected Dose descriptor

Most sensitive endpoint

Justification

Acute - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

Acute - systemic effects

Inhalation

No DNEL (Derived No Effect Level) is requiredb

 

 

 

 

 See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant, non irritant. See footnote (g)

Acute - local effects

Inhalation

DNEL (Derived No Effect Level)

11.9 mg Ni/m³

Inhalable fractionc

3.9d

HEC LOAEC: 46.6

mg Ni/m3

Inhalable fractione

repeated dose toxicity

 (lung inflammation)

 See footnotes

Long-term - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

Long-term - systemic effects

Inhalation

DNEL (Derived No Effect Level)

0.05 mg Ni/m³

Inhalable fractionf

 

 

developmental toxicity

 See footnotes

Long-term - local effects

Dermal

DNEL (Derived No Effect Level)

0.035 mg Ni/cm²

2g

NOAEL:0.07 mg Ni/cm2h

sensitisation (skin)

 See footnotes

Long-term - local effects

Inhalation

DNEL (Derived No Effect Level)

0.05 mg Ni/m³

Inhalable fractionf

 

 

carcinogenicity and repeated toxicity (respiratory tract- inhalation)

 See footnotes

a.       The approaches used in the derivation of DNELs are described in a report prepared by VITO Consultancy (Belgium)(Appendix C1), and in Appendices C2 (long-term DNELs), C3 (acute DNELs), and C4 (Summary DNEL table).

b.       Nickel metal is not classified for acute toxicity by inhalation, oral or dermal routes. Thus, no acute systemic inhalation DNEL is required.

c.       The derivation of the acute inhalation DNELs is described in detail in Appendix C3. Dosimetric modeling was used to calculate human equivalent air concentrations (HECs) for the points of departures based on effects associated with pulmonary retained (local effects) nickel doses in rats. This modeling accounts for differences in pulmonary deposition of different particle sizes between rats and humans, and also allowed the incorporation of inhalable workplace particle size ranges in the calculations.

d.       AF = 3.9 [AF interspecies difference (AS) = 1 local respiratory effects. AF interspecies difference in susceptibility = 1 (for respiratory toxicity effects after inhalation of particles of nickel or most metal-containing substances in the respirable range, rats seem to be more susceptible to toxicity effects than mice, primates or humans; AF intraspecies differences in susceptibility=3 for substances that do not undergo metabolism. AF for conversion of LOAEC to NAEC=3 based on steep dose-response for nickel toxicity. An AF for exposure duration = 1/2.3 was applied to extrapolate from 16 day repeated exposures to a single exposure. Overall AF= 1 X 3 X 3 X 1/2.3 = 3.9]. See Appendix C3 section C3.6.2 for more detailed justification of AF selection.

e.       The HEC-LOAEC of 46.6 mg Ni/m3 (inhalable fraction) was derived from the LOAEC of 4 mg Ni/m3 (MMAD=1.5µm) by applying a dosimetry adjustment as described in Appendix C3.

f.        The justification for the use of an inhalable OEL of 0.05 mg Ni/m3 is provided inAppendix C2. This value is based on the SCOEL proposed inhalable OEL for nickel compounds of 0.01 mg Ni/m3 (June 2011) with further adjustments for differences in particle size distributions between animal experiments and workplace exposures and differences in sampling efficiency between workplace 37-mm and inhalable samplers. The SCOEL value was based on epidemiological data on cancer effects. The registrant-derived inhalable value of 0.05 mg Ni/m3 is based on carcinogenicity effects in the respiratory tract observed in human studies, as well as toxicity local effects observed in the lungs of rats after inhalation. Both registrant and SCOEL consider nickel compounds to be genotoxic carcinogens with a practical threshold. These values are also protective against possible reproductive effects. For detailed description of the DNEL derivation and selection of AF, see Appendices C1 and C2.

g.       AF =2. For the water insoluble compounds like Ni metal, the uncertainty in the relative bioelution data compared to Ni sulphate relates to the repeatability (within labs) and reproducibility (between labs) of bioelution results and the relevance of the test conditions to the human exposure in the patch test and in the workplace. Based on good repeatability and reproducibility of bioelution data and relevancy of testing conditions to in vivo situation an assessment factor no greater than 2 is justified (see Appendix B3). The derived DNEL is protective of both acute and long-term local dermal effects. The derived DNEL is likely to overestimate risk compared to workplace 8 h exposure without occlusion.

h.       The DNEL of 0.00044 mg Ni/cm2 (x 48 h under occlusion) based on the Fischer et al. (2005) patch test studies for dermal sensitization by nickel sulphate was corrected by taking into account the relative Ni release from Ni metal in sweat. This correction was applied because the amount of Ni (II) ions released from one gram of Ni on the skin will be much lower than if the dust is made of nickel metal than it would be if the dust is made of nickel sulphate (100% dissolved). Corrected dose descriptor = 0.070 mg Ni/cm2 [0.00044 mg Ni/cm2 x 160 = 0.070 mgNi/cm2); 160-fold less release of Ni from nickel metal than from sulphate after 24 hs, 37oC in sweat, KMHC, 2010); For nickel metal, 0.006 g of Ni (II) ion/g Ni dust (100% Ni metal) were released in sweat while 1 g of Ni (II) ion would be released per g of Ni dust (100% Ni sulphate). The ratio of 1/0.006 = 167 which we rounded down to 160. See Appendix C3.This DNEL is protective of both acute and long-term local dermal effects.

 

 

Appendix C1= Derivation of DNELs for 4 Reference Ni substances 

Appendix C2= Background Document in Support of Long-term Inhalable DNELs for Nickel Metal and Nickel Compounds

Appendix C3 = Background Document in Support of Acute DNELs and Guidance Values for Nickel Metal and Nickel Compounds

Appendix C4 = Excel table of DNEL derivations –nickel metal

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
60 ng/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
By inhalation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
60 ng/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6.5
Dose descriptor starting point:
other: HEC-LOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.035 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.011 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
1.1 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.37 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
36.6 mg/kg bw/day

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Note 1. Exposures are always given in terms of mg nickel and NOT as mg substance.

Note 2. All the values (including the inhalation one) are provided in the table below.

Note 3. In cases where existing standards (OELs in case of workers, ambient air standards in case of general public) are used instead of DNEL/DMEL, the fields for Assessment factors and Dose descriptor Starting Points were left blank. Further information on the Standard derivation is contained in the documents referenced in the Table below.

Nickel Metal CSR Table for General Population

Exposure pattern

Route

Descriptor

DNEL / DMELa

AF

Corrected Dose descriptor

Most sensitive endpoint

Justification

Acute - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

 

Inhalation

No DNEL (Derived No Effect Level) is requiredb

 

 

 

 

 See footnotes

 

Oral

  

DNEL (Derived No Effect Level)

0.37 mg Ni ion/kgbw/dayc

100d

NOAEL = 36.6 mg Ni/kg/day

[soluble Ni]

acute toxicity (mortality)

See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant; not irritant. See footnote (j)

 

Inhalation

DNEL (Derived No Effect Level)

0.8 mg Ni/m³e

6.5f

HEC-LOAEC: 5.3mg Ni/m3 g

repeated dose toxicity

(lung inflammation)

 See footnotes

Long-term - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

 

Inhalation

DNEL (Derived No Effect Level)

0.00006mg Ni/m3h

 

Calculated NAEC 0.11 mg Ni/m3

reproductive developmental toxicity

See footnotes

 

Oral

  

DNEL (Derived No Effect Level)

0.011 mg Ni ion /kg/dayi

100j

NOAEL: 1.1 mg Ni/kg/day

[soluble Ni]

reproductive developmental toxicity

See footnotes

Long-term - local effects

Dermal

DNEL (Derived No Effect Level)

0.035 mg Ni/cm²

2k

NOAEL:0.07mg Ni/cm²l

sensitisation (skin)

 See footnotes

 

Inhalation

DNEL (Derived No Effect Level)

0.00006mg Ni/m3h

 

  

Calculated NAEC 0.11 mg Ni/m3

 repeated dose toxicity (lung inflammation)

carcinogenicity

 See footnotes

  1. The approaches used in the derivation of DNELs are described in a report prepared by VITO Consultancy (Belgium) (Appendix C1), and in AppendicesC2 (long-term DNELs),C3 (acute DNELs), andC4 (Summary DNEL table).
  2. Nickel metal is not classified for acute toxicity by inhalation, oral or dermal routes. Thus, no acute systemic inhalation DNEL is required.
  3. This DNEL value does not apply to the oral consumption of nickel metal in massive or powder form, since there is negligible exposure to nickel metal through the oral route. Rather, this DNEL applies to the Ni (II) ion that may be released from metallic nickel in pipes, fittings, heating elements, food contact material, etc, and becomes available in water or food. It is derived from acute toxicity data of soluble Ni and applied to any Ni ions released from Ni metal. This value was considered to be protective of the adult population but not necessary nickel-sensitive subpopulations.
  4.  AF= 100 [AF interspecies difference other =2.5; AF interspecies AS =4 (rat-human); AF intraspecies differences in susceptibility=10 for the general population according to ECHA Guidance Table R. 8-6 Default assessment factor;s AF to account for differences in exposure duration=1; Overall AF = 2.5 x 4 x 10 = 100.

  5. The derivation of the acute inhalation DNELs is described inAppendix C3. Dosimetric modeling was used to calculate human equivalent air concentrations (HECs) for the points of departures based on effects associated with pulmonary or retained (local effects) nickel doses in rats. This modeling accounts for differences in pulmonary deposition of different particle sizes between rats and humans. HECs were calculated using particle size of animal aerosol that reasonably corresponds to the PM10aerosol fraction of ambient air.
  6. AF = 6.5 [AF interspecies difference (AS) = 1 local respiratory effects. AF interspecies difference in susceptibility = 1 (for respiratory toxicity effects after inhalation of particles of nickel or most metal-containing substances in the respirable range, rats seem to be more susceptible to toxicity effects than mice, primates or humans. AF intraspecies differences in susceptibility=5for substances that do not undergo metabolism. AF for conversion of LOAEC to NAEC=3, based on steep dose-response for nickel toxicity. An AF for exposure duration= 1/2.3 was applied to extrapolate from 16 day repeated exposures to a single exposure.SeeAppendix C3section C3.6.2 for more detailed justification of AF. Overall AF= 1 X 5 X 3 X 1/2.3 = 6.5].
  7. The HEC-LOAEC of 5.3 mg Ni/m3(ambient air) was derived from the LOAEC of 4 mg Ni/m3(MMAD=1.5µm) by applying a dosimetry adjustment as described inAppendix C3.
  8.   An ambient air PM10DNEL of 60 ng/m3was derived based on the dose descriptors reported by Oller et al., (2014) and the subsequent application of assessment factors described in Buekers et al. (2015) and described inAppendix C1andAppendix D5. The DNEL value is applied to ‘total nickel’ (including all chemical forms of nickel) because information on the speciation of emitted Ni substances is not always available. The value is applicable to typical mixtures of Ni prevailing in ambient air, at the regional and local scale. This DNEL protects from possible respiratory toxicity and reproductive effects, as well as carcinogenicity by considering nickel compounds to be indirect genotoxic carcinogens with a practical threshold similar to the approach taken by SCOEL (2011) when deriving OELs for nickel compounds (seeAppendix C1andAppendix D5).
  9. This DNEL value was derived byWHO (World Health Organization, 2007. Background document for development of WHO Guidelines for Drinking-water Quality. © World Health Organization, Geneva)as the Tolerable Daily Intake for nickel. In a well conducted two-generation study on rats, a NOAEL of 1.1 mg of soluble nickel per kg of body weight per day was identified for all the end-points studied, including the variable of post-implantation/perinatal lethality (SLI, 2000). The application of an uncertainty factor of 100 (10 to account for interspecies variation and 10 to account for intraspecies variation) gives a TDI of 11 µg/kg of body weight.
  10. AF= 100 [AF interspecies difference other =2.5; AF interspecies AS =4 (rat-human); AF intraspecies differences in susceptibility=10 for the general population according to ECHA Guidance Table R. 8-6 Default assessment factor;s AF to account for differences in exposure duration=1; Overall AF = 2.5 x 4 x 10 = 100.; the inclusion of a factor of 2-3 for severity of effects is not justified since an exposure level corresponding to 2-fold the NOAEL in the second generation study with nickel sulphate was considered by some experts as the NOAEL for the observed effects.

  11. AF =2. For the water insoluble compounds like Ni metal, the uncertainty in the relative bioelution data compared to Ni sulphate relates to the repeatability (within labs) and reproducibility (between labs) of bioelution results and the relevance of the test conditions to the human exposure in the patch test and in the workplace. Based on good repeatability and reproducibility of bioelution data and relevancy of testing conditions to in vivo situation an assessment factor no greater than 2 is justified (seeAppendix B3). The derived DNEL is protective of both acute and long-term local dermal effects. The derived DNEL is likely to overestimate risk compared to workplace 8 h exposure without occlusion.
  12. Corrected dose descriptor = 0.070 mg Ni/cm2[0.44 µg Ni/cm2x 160 = 0.070 Ni/cm2); 160-fold less release of Ni (II) ion from nickel metal than from nickel sulphate after 24 hs, 37oC in sweat, KMHC, 2010.]. This correction was applied because the amount of Ni (II) ions released from one gram of Ni on the skin will be much lower than if the dust is made of nickel metal than it would be if the dust is made of nickel sulphate (100% dissolved). For nickel metal, 0.006 g of Ni (II) ion/g Ni dust (100% Ni metal) were released in sweat while 1 g of Ni (II) ion was available per g of Ni applied in the patch test (100% Ni sulphate). The ratio of 1/0.006 = 167. SeeAppendix C4. This DNEL is protective of both acute and long-term local dermal effects.

 

 

Sensitive subpopulations. Sensitive subpopulations are not separately addressed.

 

 

Appendix C1= Derivation of DNELs for 4 Reference Ni substances 

Appendix C2= Background Document in Support of Long-term Inhalable DNELs for Nickel Metal and Nickel

          Compounds

Appendix C3= Background Document in Support of Acute DNELs and Guidance Values for Nickel Metal and

          Nickel Compounds

Appendix C4= Excel table of DNEL derivations –nickel metal

Appendix D5= Man Via the Environment Risk Assessment