Nickel dihydroxide

Toxicological Summary

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: See Appendix C2 to CSR

Explanation for the modification of the dose descriptor starting point:

See Appendices C1 and C2

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 403 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

15

Modified dose descriptor starting point:

other: HEC-NOAEC

Value:

21 049 mg/m³

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: See Appendix C2 to CSR

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

1.4

Dose descriptor starting point:

other: HEC-NOAEC

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:

0.65 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

other:

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

Nickel Dihydroxide CSR Table 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 Corrected 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 / DMEL^a	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)	1403 mg Ni/m³ Inhalable Fraction^b	15^c	HEC-NOAEC: 21,049 mg Ni/m^3 Inhalable Fraction^d	acute toxicity (mortality)	See footnotes
Acute - local effects	Dermal						No available data to derive DNEL
Acute - local effects	Inhalation	DNEL (Derived No Effect Level)	18.9 mg Ni/m³ Inhalable Fraction^b	1.4^e	HEC-NOAEC: 26.5 mg Ni/m^3 Inhalable Fraction^f	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 Fraction^g			developmental toxicity	See footnotes
Long-term - local effects	Dermal	DNEL (Derived No Effect Level)	0.65 mg Ni/cm²	2^h	NOAEL corrected^i: 1.3 mg Ni/cm² from 0.00044   mg Ni/cm² (sulphate)	sensitisation (skin)	See footnotes
Long-term - local effects	Inhalation	DNEL (Derived No Effect Level)	0.05 mg Ni/m³ Inhalable Fraction^g			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 B3 (long-term dermal DNEL), C2 (long-term DNELs) and C3 (acute DNELs).

b.       The DNEL based on acute toxicity-local effects (lung inflammation) is read across from Ni oxide.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

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; AF intraspecies differences in susceptibility = 3 for substances that do not undergo metabolism, see Appendix C3 section C3.6 for more detailed justification; AF of 2 to account for the uncertainty of reading across from a compound not classified for acute toxicity (Ni Oxide) to one classified for acute toxicity (Ni Dihydroxide). Overall AF = 2.5 x 3 x 2 =15]. Read-across to Ni dihydroxide from Ni oxide 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 21,049 mg Ni/m³ (inhalable fraction) was derived from the NOAEC of 3,900 mg Ni/m³ (MMAD =3.75µm) by applying a dosimetry adjustment as described in Appendix C3.

e.       AF = 1.4. [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. Reading across from Ni oxide, 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 1/2.1 = 1.4]. See Appendix C3 section C3.6.2 for more detailed justification of AF selection.

f.        The HEC-NOAEC of 26.5 mg Ni/m³ (inhalable fraction) was derived from the NOAEC of 3.9 mg Ni/m³ (MMAD=2.9µm) 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 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 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. For detailed description of the DNEL derivation based on developmental reproductive effects, see Appendix C1.

h.       AF =2. For the water insoluble compounds like Ni dihydroxide, 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 derivation of a DNEL for dermal sensitization by nickel hydroxide is a conservative approach since no classification appears to be warranted for this endpoint based on Ni release in sweat. 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.

i.        Corrected dose descriptor = 1.3 mg Ni/cm² [0.44 µg Ni/cm² x 3,000 = 1.3 mg Ni/cm²); 3,000-fold less release of Ni from nickel hydroxide than from Ni sulphate after 24 hours, 37C in sweat, KMHC, 2010. The DNEL for dermal sensitization/elicitation is based on a patch test study with Ni sulphate where exposure lasted for 48hs under occlusion. A correction was applied because the amount of Ni (II) ions released from one gram of Ni on the skin will be much lower if the dust is made of nickel dihydroxide than it would be if the dust is made of nickel sulphate (100% dissolved). For nickel dihydroxide, 0.03 g of Ni (II) ion/g Ni dust (100% Ni dihydroxide) 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 100/0.03 = 3,000. 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

 

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:

Oral

DNEL related information

DNEL derivation method:

other:

Explanation for the modification of the dose descriptor starting point:

See Appendices C1 and C2.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

159 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):

25

Modified dose descriptor starting point:

other: HEC-NOAEC

Value:

3 970 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:

1.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2.3

Dose descriptor starting point:

other: HEC-NOAEC

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:

0.013 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:

BMDL10

Value:

1.3 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

Nickel Dihydroxide CSR Table for General 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 Starting Points were left blank. Further information on the 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

Exposure pattern	Route	Descriptor	DNEL / DMEL^a	AF	Corrected Dose descriptor	Most sensitive endpoint	Justification
Acute - systemic effects	Dermal						Not relevant, negligible exposure and absorption
	Inhalation	DNEL (Derived No Effect Level)	159 mg Ni/m³^b	25^c	HEC-NOAEC: 3,970 mg Ni/m^3 d	acute toxicity (mortality)	See footnotes
	Oral	DNEL (Derived No Effect Level)	^0.37 mg Ni ion/kg/day e	100^f	NOAEL = 36.6 mg Ni/kg/day [soluble Ni]	acute toxicity (mortality)	See footnotes
Acute - local effects	Dermal						Not relevant, negligible exposure
	Inhalation	DNEL (Derived No Effect Level)	1.8 mg Ni/m³^b	2.3^g	HEC-NOAEC: 4.2 mg Ni/m^3 h	repeated dose toxicity (lung inflammation)	See footnotes
Long-term - systemic effects	Dermal						Not relevant, negligible exposure and absorption
	Inhalation	DNEL (Derived No Effect Level)	0.00006mg Ni/m^3i		Calculated NAEC 0.11 mg Ni/m^3	reproductive developmental toxicity	See footnotes
	Oral	DNEL (Derived No Effect Level)	0.013 mg Ni ion /kg/day^j	100^k	BMDL10: 1.3 mg Ni/kg/day [soluble Ni]	reproductive developmental toxicity	See footnotes
Long-term - local effects	Dermal						Not relevant, negligible exposure
	Inhalation	DNEL (Derived No Effect Level)	0.00006mg Ni/m^3^i		Calculated NAEC 0.11 mg Ni/m^3	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) and C3 (acute DNELs).

b.       The derivation of the acute inhalation DNELs is described 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. HECs were calculated using particle size of animal aerosol that reasonably correspond to the PM₁₀ aerosol fraction of ambient air.

c.       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; AF intraspecies differences in susceptibility =5 for substances that do not undergo metabolism, seeAppendix C3section C3.6 for more detailed justification; AF of 2 to account for the uncertainty of reading across from a compound not classified for acute toxicity (Ni Oxide) to one classified for acute toxicity (Ni Dihydroxide); Overall AF = 1 x 2.5 x 5 x 2 =25]. Read-across to Ni dihydroxide from Ni oxide 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 3,970 mg Ni/m³ (ambient air) was derived from the NOAEC of 3,900 mg Ni/m³ (MMAD = 3.75µm) by applying a dosimetry adjustment as described in Appendix C3.

e. This DNEL value applies to the Ni (II) ion that may be released from nickel compounds 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 compounds. This value is considered to be protective of the adult population but not necessary nickel-sensitive subpopulations.

f. 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.

g.       AF = 2.3 [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=5 for substances that do not undergo metabolism. Reading across from Ni oxide, an AF for exposure duration= 1/2.1 was applied to extrapolate from 16 day repeated exposures to a single exposure.See Appendix C3 section C3.6.2 for more detailed justification of AF. Overall AF= 1 X 5 X 1/2.1 = 2.3].

h.        The HEC-NOAEC of 4.2 mg Ni/m³ (ambient air) was derived from the NOAEC of 3.9 mg Ni/m³ (MMAD=2.9µm) by applying a dosimetry adjustment as described in Appendix C3.

i.       An ambient air PM10 DNEL of 60 ng/m³ was 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 in Appendix C1 and Appendix 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).  

J. The oral DNEL for long-term systemic effects (0.013 mg Ni/kg/day) is based the tolerable daily intake (TDI) for nickel derived by EFSA (2020). An increased incidence of post-implantation loss in rats in SLI (2000) was identified as the critical effect for the risk characterisation of chronic oral exposure and a BMDL10 of 1.3 mg Ni/kg body weight (bw) per day was selected as the reference point for the establishment of a TDI. 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 13 µg/kg of body weight.

k. 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.

 

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= Risk Assessment of Man via the Environment

 

Sensitive subpopulations.Sensitive subpopulations are not separately addressed.