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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
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
520 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
7.5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.024 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL

Workers - Hazard for the eyes

Additional information - workers

Nickel Oxide CSR Table forWorkers

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.

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)

520 mg Ni/m³

(MMAD = 2.5 & 3.75 µm)b

7.5c

NOAEC: 3,900 mg Ni/m3

(MMAD = 2.5-& 3.75 µm)

acute toxicity (mortality)

 See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant, negligible Ni ion release, slightly irritating

Acute - local effects

Inhalation

DNEL (Derived No Effect Level)

3.9 mg Ni/m³

((MMAD =2.9 µm)b

1d

NOAEC: 3.9

mg Ni/m3

(MMAD =2.9 µm)

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 fractione

 

 

developmental toxicity

 See footnotes

Long-term - local effects

Dermal

DNEL (Derived No Effect Level)

0.024 mg Ni/cm²

1f

NOAEL correctedg: 0.024 mg Ni/cm² from0.00044mg Ni/cm² (sulphate)

sensitisation (skin)

 See footnotes

Long-term - local effects

Inhalation

DNEL (Derived No Effect Level)

0.05 mg Ni/m³

Inhalable fractione

 

 

 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) and included inAppendices C1andC3.

b.     The DNEL based on acute toxicity-local effects (lung inflammation) was based on values observed for Ni oxide black and green and corresponds to an aerosol of MMAD = 2.5 & 3.75 µm (respirable aerosol fraction). This value is then relevant for workplace exposures comprised of particles of MMAD = 2.5-3.75 µm. The proper comparisons should take into account the equivalent deposited/retained doses per unit surface area in the respiratory tract of rats exposed to experimental aerosols and of humans exposed to workplace aerosols. If this DNEL value is used in a direct comparison to workplace exposures collected with an inhalable sampler or a 37-mm sampler, this value is likely to overestimate risk by several-fold. For more details seeAppendix C2.

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,ECHA Guidance Table R. 8-6 Default assessment factors; AF intraspecies differences in susceptibility =3 for substances that do not undergo metabolism, ECETOC (2003, 2010), seeAppendix C2section C2.3.3 for more detailed justification; Overall AF = 2.5 x 3=7.5] Uncertainty in DNEL derivation related to differences in particle size between animal aerosol (2.5-3.75 µm) and human exposure (< 100 µm), differences in susceptibility of acute toxicity effects of nickel in rats versus human, and TK and TD differences among workers, are considered to be accounted for by the use of an AF of 7.5.            

d.     AF = 1.0. [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, 1-5 µm diameter, rats seem to be more susceptible to toxicity effects than mice, primates or humans. SeeAppendices C1andC3); AF intraspecies differences in susceptibility=3for substances that do not undergo metabolism, ECETOC (2003, 2010), seeAppendix C2section C2.3.3 for more detailed justification of AF. AF for conversion of LOAEC to NOAEC=1; AF for exposure duration= 1/9 (used in 2008/2009 European Union Risk Assessment for Nickel Sulphate), since the duration is longer than in an acute study (12 exposures of 6 hours each during 16 days versus a single 4-hour exposure in an acute guidance study). Overall AF= 1 x 3 x 1 x 1/9 = 0.3. An assessment factor of 1 will be used.] Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (12x 6 hours versus 1 x 4 hours), differences in particle size between animal aerosol 2.9 um) and human exposure (< 100 um), differences in susceptibility of local respiratory toxicity effects of nickel in rats versus human, and TK and TD differences among workers are considered be balanced and accounted for by the use of an AF of 1.

e.     The justification for the use of an inhalable OEL of 0.05 mg Ni/m3is 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 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/m3is based on toxicity local effects observed in the lungs of rats after inhalation and carcinogenicity effects in the respiratory tract observed in human studies. Both registrant and SCOEL consider nickel compounds to be genotoxic carcinogens with a practical threshold. These values are also protective against possible reproductive effects. SeeAppendix C2for detailed description of this DNEL derivation.

f.       AF =1. Study done in humans, 48 hours under occlusion. The derivation of a DNEL for dermal sensitization by nickel oxide is a conservative approach since no classification appears to be warranted for this endpoint based on Ni release in sweat.

g.     Corrected dose descriptor = 0.024 mg Ni/cm2[0.44 µg Ni/cm2x 54 = 0.024 mg Ni/cm2); where 0.44 µg Ni/cm2is the DNEL for nickel sulphate based on the Fischeret al.(2005) study and 54 is the fold less release of Ni as percent of Ni content from nickel oxide-black than from Ni sulphate after 24 hours, 37C 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 oxide than it would be if the dust is made of nickel sulphate (100% dissolved). For nickel oxide, 0.0016 (green) or 0.0184 (black) g of Ni (II) ion/g Ni dust (100% Ni oxide) 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 ratios are 1/0.0184 = 54 and 1/0.0016 = 625. The most conservative value of 54 observed for NiO-black was applied to both forms of NiO. SeeAppendix C2. This DNEL is protective of both acute and long-term local dermal effects.

 

Appendix C1= VITO report: Derivation of DNELs for 4 Ni substances 

Appendix C2= Background document in support of use of Long-term Inhalable DNELs for Nickel Metal and Nickel Compounds

Appendix C3= Excel table of DNEL derivations –nickel oxide

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 ng/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
312 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 ng/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Nickel OxideCSR Table forGeneral Population

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.

Exposure pattern

Route

Descriptor

DNEL / DMELa

AF

Corrected Dose descriptor

Most sensitive endpoint

Justification

Acute - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible exposure and absorption

 

Inhalation

DNEL (Derived No Effect Level)

312 mg Ni/m³b

 

12.5c

NOAEC: 3,900 mg Ni/m3

 

acute toxicity (mortality)

 See footnotes

 

Oral

 

 

 

 

 

Not relevant, negligible oral exposure and absorption

Acute - local effects

Dermal

 

 

 

 

 

Not relevant, not irritant

 

Inhalation

DNEL (Derived No Effect Level)

3.9 mg Ni/m³b

 

1d

NOAEC: 3.9

mg Ni/m3

 

repeated dose toxicity

(lung inflammation)

 See footnotes

Long-term - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible exposure and absorption

 

Inhalation

DNEL (Derived No Effect Level)

0.00002mg Ni/m3e

 

 

reproductive developmental toxicity

 See footnotes

 

Oral

 

 

 

 

 

Not relevant, negligible oral exposure and absorption

Long-term - local effects

Dermal

 

 

 

 

 

Not relevant, negligible exposure

 

Inhalation

DNEL (Derived No Effect Level)

0.00002mg Ni/m3e

 

CSTEE (ambient air standard) = 0.00002mg 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) and included inAppendices C1andC3.

b.     The DNEL value for acute effects after inhalation is superseded by the CSTEE, EU Scientific Committee on Toxicity, Ecotoxicity and the Environment (2001) proposed ambient air guidance value of 0.00002 mg Ni/m3as discussed inAppendices C1andC3.

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= 2.5; AF intraspecies differences in susceptibility, ECHA Guidance Table R. 8-6 Default assessment factors; AF intraspecies differences in susceptibility = 5 for substances that do not undergo metabolism, ECETOC (2003, 2010), seeAppendix C2section C2.3.3 for more detailed justification; Overall AF = 1 x 2.5 x 5=12.5] Uncertainty in DNEL derivation related to differences in particle size between animal aerosol (2.5-3.75 µm) and human exposure (PM10, PM2.5), differences in susceptibility of acute toxicity effects of nickel in rats versus human, and TK and TD differences among the general population, are considered to be accounted for by the use of an AF of 12.5.              

d.     AF = 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, 1-5 µm diameter, rats seem to be more susceptible to toxicity effects than mice, primates or humans. SeeAppendices C1andC3); AF intraspecies differences in susceptibility=5for substances that do not undergo metabolism, ECETOC (2003, 2010), seeAppendix C2section C2.3.3 for more detailed justification of AF. AF for conversion of LOAEC to NOAEC=1 (Ni oxide); AF for exposure duration= 1/9 (used in 2008/2009 European Union Risk Assessment for Nickel Sulphate), since the duration is longer than in an acute study (12 exposures of 6 hours each during 16 days versus a single 4-hour exposure in an acute guidance study). Overall AF= 1 x 5 x 1 x 1/9 = 0.6. An assessment factor of 1 will be used]. Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (12 x 6 hours versus 1 x 4 hours), differences in particle size between animal aerosol 2.9 um) and human exposure (PM10, PM2.5), differences in susceptibility of local respiratory toxicity effects of nickel in rats versus human, and TK and TD differences among workers are considered to be balanced and accounted for by the use of an AF of 1. 

e.     We used the CSTEE, EU Scientific Committee on Toxicity, Ecotoxicity and the Environment (2001) ambient air recommended nickel value of 20 ng Ni/m3instead of a DMEL based on carcinogenicity or a DNEL based on long term-local respiratory effects. The CSTEE value is based on considerations of both respiratory toxicity and carcinogenicity and it is also protective from systemic exacerbation of dermatitis in sensitized individuals (seeAppendix C1andAppendix D5). 

 

Appendix C1= Derivation of DNELs for 4 Reference Ni substances 

Appendix C2= Background document in support of use of Long-term Inhalable DNELs for Nickel Metal and Nickel Compounds

Appendix C3= Excel table of DNEL derivations –nickel oxide

Appendix D5= Man Via the Environment Risk Assessment

 

Sensitive subpopulations.Sensitive subpopulations are not separately addressed. The inhalation DNEL value used corresponds to the ambient air guidance value derived by CSTEE for the EU general public. This value was derived based on a linear extrapolation for possible cancer effects, There is now acceptance that nickel compounds have a practical threshold for carcinogenicity. Therefore, this value is very conservative and it is expected to protect the most sensitive individuals in the population..