Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 µg/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:
DNEL (Derived No Effect Level)
Value:
104 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
7.5
Modified dose descriptor starting point:
other: HEC-NOAEC
Value:
783 mg/m³

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 µg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
4.3
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:
0.44 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Nickel Nitrate Hexahydrate: Corrected dose descriptor(s) per endpoint and endpoint-specific DNEL(s)/DMEL(s) for 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 were left blank. Further information on the air Standard derivation is contained in the documents referenced in the Table below.

Note 3. Acute systemic and local effects are relevant for short-term worker’s exposure (peak exposure of 15 minutes to a few hours). Long-term systemic and local effects are relevant to long-term worker’s exposure defined as 8 hours/day and 5 days per week for a working life.

DN(M)ELs 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

DNEL (Derived No Effect Level)

104 mg Ni/m³

Inhalable Fractionb

7.5c

HEC-NOAEC: 783 mg Ni/m3

Inhalable Fractiond

acute toxicity (mortality)

 See footnotes

Acute - local effects

Dermal

 

 

 

 

 

No available data to derive DNEL. See footnote (f)

Acute - local effects

Inhalation

DNEL (Derived No Effect Level)

1.6 mg Ni/m³

Inhalable Fractionb

4.3e

HEC-LOAEC: 6.9 mg Ni/m3

Inhalable Fractionf

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 Fractiong

 

 

developmental toxicity

 See footnotes

Long-term - local effects

Dermal

DNEL (Derived No Effect Level)

0.00044 mg Ni/cm²h

1i

NOAEL:0.00044 

mg Ni/cm²

sensitisation (skin)

 See footnotes

Long-term – local effects

Inhalation

DNEL (Derived No Effect Level)

0.05 mg Ni/m³

Inhalable Fractiong

 

 

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) and C3 (acute DNELs). DNELs for nickel nitrate are read across from nickel sulphate.

b.       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 deposited (systemic effects) or 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.

c.       Assessment Factor (AF) = 7.5. [AF interspecies differences in susceptibility (AS) = 1 for exposures expressed as concentrations mg/m3, and for lethal effects; AF interspecies remaining differences in susceptibility for respiratory tract = 2.5; AF intraspecies differences in susceptibility = 3 for substances that do not undergo metabolism, see Appendix C3 section C3.6 for more detailed justification; Overall AF = 2.5 x 3 =7.5]. Read-across to Ni nitrate from Ni sulphate for this endpoint is fully warranted by the bioelution data verified with in vivo data (see Appendix B2 for in depth discussion of read-across approach).

d.       The HEC-NOAEC of 783 mg Ni/m3 (inhalable fraction) was derived from the NOAEC of 120 mg Ni/m3 (MMAD=3µm) by applying a dosimetry adjustment as described in Appendix C3.

e.       AF = 4.3. [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 = 1/2.1 was applied to extrapolate from 16 day repeated exposures to a single exposure. Overall AF= 1 X 3 X 3 X 1/2.1 = 4.3]. See Appendix C3 section C3.6.2 for more detailed justification of AF selection.

f.        The HEC-LOAEC of 6.9 mg Ni/m3 (inhalable fraction) was derived from the LOAEC of 0.7 mg Ni/m3 (MMAD<4µm) by applying a dosimetry adjustment as described in Appendix C3.

g.       The justification for the use of an inhalable OEL of 0.05 mg Ni/m3 is provided in Appendix 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.

h.       The DNEL for dermal sensitization/elicitation for nickel nitrate is based on a patch test study with Ni sulphate where exposure lasted for 48 h under occlusion. This value is likely to overestimate risk compared to workplace 8 h exposure without occlusion.This DNEL is protective of both acute and long-term dermal exposures (Appendix B3).

i.        AF =1. Study done in humans, 48 hours under occlusion. This value is likely to overestimate risk compared to workplace 8 h exposure without occlusion. Study was done with a susceptible population.

             

 

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

 

 

 

 

 

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
DNEL related information
DNEL derivation method:
other:
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.8 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
other: HEC-NOAEC
Value:
109.6 mg/m³

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
60 ng/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other:
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
7.1
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:
no hazard identified
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:
medium hazard (no threshold derived)

Additional information - General Population

Nickel Nitrate Hexahydrate CSR Table for General Population (MvE)

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 were left blank. Further information on the air Standard derivation is contained in the documents referenced in the Table below.

Note 3. Acute systemic and local effects are relevant for short-term exposure (peak exposure of 15 minutes to a few hours). Long-term systemic and local effects are relevant to long-term exposure defined as 24 hours/day and 7 days per week for a life-time.

DN(M)ELs for the general population (MvE)

Exposure pattern

Route

Descriptor

DNEL / DMELa

AF

Corrected Dose descriptor

Most sensitive endpoint

Justification

Acute - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

 

Inhalation

DNEL (Derived No Effect Level)

8.8 mg Ni/m³b

12.5c

HEC-NOAEC: 109.6 mg Ni/m3 d

Acute toxicity (mortality)

 See footnotes

 

Oral

DNEL (Derived No Effect Level)

0.37 mg Ni/kg/day

100e

NOAEL= 36.6 mg Ni/kg/day

Acute toxicity (mortality)

See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant, negligible dermal exposure

 

Inhalation

DNEL (Derived No Effect Level)

0.1 mg Ni/m³b

7.1f

HEC-LOAEC: 0.8 mg 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/kg/dayi

50j

NOAEL: 1.1 mg Ni/kg/day

Reproductive Developmental toxicity

See footnotes

Long-term - local effects

Dermal

 

 

 

 

 

Not relevant, negligible exposure

 

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

a.    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)andC3 (acute DNELs).DNELs for nickel nitrate are read across from nickel sulphate.

b.       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 deposited (systemic effects) 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 correspond to the PM10aerosol fraction of ambient air.

c.       Assessment Factor (AF) = 12.5. [AF interspecies differences in susceptibility (AS) = 1 for exposures expressed as concentrations mg/m3, and for lethal effects; AF interspecies remaining differences in susceptibility for respiratory tract = 2.5; AF intraspecies differences in susceptibility =5 for substances that do not undergo metabolism, seeAppendix C3section C3.6 for more detailed justification; Overall AF = 1 x 2.5 x 5 =12.5].Read-across to Ni nitrate from Ni sulphate for this endpoint is fully warranted by the bioelution data verified with in vivo data (seeAppendix B2for in depth discussion of read-across approach).

d.       The HEC-NOAEC of 109.6 mg Ni/m3(ambient air) was derived from the NOAEC of 120 mg Ni/m3(MMAD=3µm) by applying a dosimetry adjustment as described inAppendix C3.

e.       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.

f.        AF = 7.1 [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= 1/2.1 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 1/2.1 = 7.1].Read-across to Ni nitrate from Ni sulphate for this endpoint is fully warranted by the bioelution data verified with in vivo data (seeAppendix B2for in depth discussion of read-across approach).

g.       The HEC-LOAEC of 0.8 mg Ni/m3(ambient air) was derived from the LOAEC of 0.7 mg Ni/m3(MMAD<4µm) by applying a dosimetry adjustment as described inAppendix C3.

h.       An ambient air PM10 DNEL 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).

i.         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 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.

j.    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.

 

Sensitive subpopulations.Sensitive subpopulations are not separately addressed as the oral DNEL values used correspond to the TDI calculated by WHO for the general public (this value was based on the response of a sensitive subpopulation). Although soluble nickel compounds carry a CLP classification as Resp. Sens. 1; H334, the occurrence of nickel-induced asthma among exposed workers is rare and there are only a few cases pointing to a workplace-related asthmatic disease. For this reason, deriving DNELs that protect workers or the general population from respiratory toxicity are considered to be protective of any possible sensitization effects as well.

 

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 D5=Man Via the Environment Risk Assessment