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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:
680 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEC

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:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor starting point:
LOAEC

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:
0.07 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

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

DNEL (Derived No Effect Level)

680 mg Ni/m³

(MMAD < 12 µm)b

15c

NOAEC: > 10,200 mg Ni/m3

(MMAD < 12 µm)

acute toxicity (mortality)

 See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant, non irritant. See footnote (g)

Acute - local effects

Inhalation

DNEL (Derived No Effect Level)

4 mg Ni/m³

(MMAD= 1.5 µm)b

1d

LOAEC: 4

mg Ni/m3

(MMAD = 1.5 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)

0.070 mg Ni/cm²

1f

NOAEL:0.07mg Ni/cm²g

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 () and included inAppendices C1andC3. 

b.     Acute DNELs based on animal inhalation studies are reported as mg Ni/m3of an aerosol of the same particle size as used in the animal studies. These DNELs cannot be directly compared to workplace aerosols of different particle size. The proper comparisons should take into account the equivalent deposited doses per unit surface area in the respiratory tract of rats exposed to experimental aerosols and in humans exposed to workplace aerosols. For more details see Appendix C2.Therefore this respirable size DNEL provides a very conservative estimate for an inhalable size DNEL. When this acute respirable DNEL is compared to an inhalable exposure, a conservative risk characterization ratio (RCR) will be derived.

c.      Assessment Factor (AF) = 15. [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), see Appendix C2 section C2.3.3 for more detailed justification; AF for uncertainty in database = 2 since study had 1 hour duration instead of 4 hours. Overall AF = 1 x 2.5 x 2 x 3= 15]. Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (1 versus 4 hours), particle size of animal aerosol (<12 um versus recommended 2-3 um), differences in particle size between animal aerosol (< 12 um) and human exposure (< 100 um), 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 15. No mortality was observed in a rat 28 day study with nickel metal powder at 24 mg/m3(1.5 um diameter) (WIL 2002). This confirms that a much acute higher exposure could be tolerated and this result is consistent with present DNEL calculation.

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 C1 and C3 and Appendix C2 section C2.3.3); AF intraspecies differences in susceptibility=3 for substances that do not undergo metabolism, ECETOC (2003, 2010), see Appendix C2 section C2.3.3 for more detailed justification. AF for conversion of LOAEC to NOAEC=3, ECHA Guidance recommends a factor between 1 and 10, 3 was selected for local respiratory effects and based on steep dose-response for nickel toxicity. AnAF for exposure duration= 1/9 was applied (as used in the European Union Risk Assessment for Nickel Sulphate, 2008-2009), since the duration of the 28-day study with nickel metal is longer than in an acute study (20 exposures of 6 hours each during 28 days versus a single 4-hour exposure in an acute guidance study). [In their calculations, the European Union Risk Assessment applied LOAEC to NOAEC, intra, and interspecies uncertainty factors to the LOAEC from the nickel sulphate 16-day study. Then they multiplied them by 1/9 to calculate a final factor, after balancing all the study duration considerations. Overall AF= 1 X 3 X 3 X 1/9 = 1.] Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (28 days versus 4 hours), differences in particle size between animal aerosol 1.5 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 respirable OEL for nickel metal of 0.005 mg Ni/m3(June 2011) based on toxicity effects observed in rats inhalation studies, with further adjustments for differences in particle size distributions between animal experiments and workplace exposures. The SCOEL value and the registrant-revised value are based exclusively on toxicity local effects observed on the lungs of rats after inhalation and do not consider nickel metal to be a carcinogen (consistent negative animal and human respiratory cancer results). The registrant’s DNEL incorporates comparisons of doses at the deposited and retained level and includes a reality-check with the available human toxicity data. These values are also protective against possible reproductive effects. See Appendix C2 for detailed description of this DNEL derivation

f.       AF =1. Study done in humans.The DNEL for dermal sensitization/elicitation 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.

g.     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/cm2x 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. SeeAppendix 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= 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:
20 ng/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
408 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
25

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 ng/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1.7
Dose descriptor starting point:
LOAEC

General Population - 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:
0.07 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.02 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12 µg/kg bw/day
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
LOAEL

General Population - Hazard for the eyes

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

DNEL (Derived No Effect Level)

408 mg Ni/m³ b

 

25c

NOAEC: >10,200 mg Ni/m3

 

acute toxicity (mortality)

 See footnotes

 

Oral

 

0.012 mg Ni ion/kgbw/dayd

 

0.012 mg Ni ion/kgbw/day

[soluble Ni]

Exacerbation of existing dermatitis

See footnotes

Acute - local effects

Dermal

 

 

 

 

 

Not relevant; not irritant. See footnote (j)

 

Inhalation

DNEL (Derived No Effect Level)

2.4 mg Ni/m³b

 

1.7e

LOAEC: 4

mg Ni/m3

 

repeated dose toxicity

(lung inflammation)

 See footnotes

Long-term - systemic effects

Dermal

 

 

 

 

 

Not relevant, negligible absorption

 

Inhalation

DNEL (Derived No Effect Level)

0.00002mg Ni/m3f

 

 

reproductive developmental toxicity

See footnotes

 

Oral

 

0.02 mg Ni ion /kg/dayg

50h

NOAEL: 1.1 mg Ni/kg/day

[soluble Ni]

reproductive developmental toxicity

See footnotes

Long-term - local effects

Dermal

DNEL (Derived No Effect Level)

0.070 mg Ni/cm²

1i

NOAEL:0.07mg Ni/cm²j

sensitisation (skin)

 See footnotes

 

Inhalation

DNEL (Derived No Effect Level)

0.00002mg Ni/m3f

 

CSTEE (ambient air standard) = 0.00002mg Ni/m3

 repeated dose toxicity (lung inflammation)

carcinogenicity

 See footnotes

  1. See Appendices C1 and C3 for more details on NOAEL identification and DNEL derivation. 
  2. This 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 C1 and C3 and D5. The long-term DNEL is protective against systemic effects like mortality, and local toxicity effects in the respiratory tract.
  3. Assessment Factor (AF) = 25. [[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 = 5 for substances that do not undergo metabolism, ECETOC (2003, 2010), see Appendix C2 section C2.3.3 for more detailed justification; AF for uncertainty in database = 2 since study had 1 hour duration instead of 4 hours. Overall AF = 1 x 2.5 x 2 x 5= 25] Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (1 versus 4 hours), particle size of animal aerosol (<12 um versus recommended 2-3 um), differences in particle size between animal aerosol (< 12 um) 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 general population are considered to be accounted for by the use of an AF of 25. No mortality was observed in a rat 28 day study with nickel metal powder at 24 mg/m3(1.5 um diameter) (WIL 2002). This confirms that a much acute higher exposure could be tolerated and this result is consistent with present DNEL calculation.              
  4. 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. This valuebased on a study with Ni sulphatewas considered byWHO (World Health Organization, 2007. Background document for development of WHO Guidelines for Drinking-water Quality. © World Health Organization,)in the derivation of the Tolerable Daily Intake for nickel. The population at risk of having an exacerbation of dermal symptoms after oral challenge consists of patients with severe nickel sensitisation. Less sensitive nickel allergic patients and the non-allergic population will not experience exacerbation of dermal symptoms or appearance of dermal symptoms after oral nickel ion intake (e.g., Ni ion release from pipes & fittings). WHO considered an AF =1 in developing drinking water guidelines for nickel based on the Nielsen study. "The LOAEL established after provocation of fasted patients with an empty stomach is 12 µg/kg of body weight (Nielsen et al., 1999). Because this is based on a highly sensitive population, it is not necessary to include an additional uncertainty factor. Based on these data, the guideline value, to allow for nickel-sensitive individuals, can be calculated as 70 µg/litre (rounded value), assuming a 60-kg adult drinking 2 litres of water per day and allocating 20% of total daily intake to drinking-water. Although this is very close to the acute LOAEL established by Nielsen et al. (1999), the absorption from drinking-water is 10- to 40-fold higher than the absorption from food, and basing the total acceptable intake for oral challenge from studies using drinking-water on an empty stomach in fasted patients can be considered a worst-case scenario. " This value was considered to be protective of sensitive subpopulations, including most nickel sensitive individuals, pregnant women and children.

e.     AF = 1.7 [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. See Appendices C1 and C3); 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=3, ECHA Guidance recommends a factor between 1 and 10, 3 was selected for local respiratory effects and based on steep dose-response for nickel toxicity. An AF for conversion of LOAEC to NOAEC=3; AF for exposure duration= 1/9 was applied (as used in the European Union Risk Assessment for Nickel Sulphate, 2008-2009), since the duration of the nickel metal study is longer than in an acute study (20 exposures of 6 hours each during 28 days versus a single 4-hour exposure in an acute guidance study). [In their calculations, the European Union Risk Assessment applied LOAEC to NOAEC, intra, and interspecies uncertainty factors to the LOAEC from the 16-day nickel sulphate study. Then they multiplied them by 1/9 to calculate a final factor, after balancing all the study duration considerations. Overall AF= 1 X 5 X 3 X 1/9 = 1.7.] Uncertainty in DNEL derivation related to different length of exposure of starting animal study compared to standard acute toxicity tests (28 days versus 4 hours), differences in particle size between animal aerosol 1.5 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 be balanced and accounted for by the use of an AF of 1.7.

f.        We used the CSTEE, EU Scientific Committee on Toxicity, Ecotoxicity and the Environment (2001) ambient air recommended nickel value of 20 ng Ni/m3for all nickel substances instead of a DNEL for metallic nickel 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 acute systemic exacerbation of dermatitis in sensitized individuals (see Appendix C1 and Appendix D5).

  1. This DNEL value does not apply to the oral consumption of nickel metal in massive or powder form. 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.
  2. AF= 50 [AF interspecies difference other =2.5; AF interspecies AS =4 (rat-human) according to 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), see Appendix C2 section C2.3.3 for more detailed justification; AF to account for differences in exposure duration=1; Overall AF = 2.5 x 4 x 5 = 50.; 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].
  3. AF =1. Study done in humans, nickel sulphate, 48 hours under occlusion.
  4. 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. See Appendix C3. This DNEL is protective of both acute and long-term local dermal 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). 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..

 

 

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= Excel Table of DNEL derivations –nickel metal

Appendix D5= Man Via the Environment Risk Assessment

 

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