Nickel bis(sulphamidate)

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:

repeated dose toxicity

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:

0.05 mg/m³

DNEL related information

DNEL derivation method:

other:

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:

no hazard identified

Additional information - workers

Nickel Sulfamate Tetrahydrate: DN(M)ELs 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 / 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)	104 mg Ni/m³ Inhalable Fraction^b	7.5^c	HEC-NOAEC: 783 mg Ni/m^3 Inhalable Fraction^d	acute toxicity (mortality)	See footnotes
Acute - local effects	Dermal						Not relevant. See footnote (f)
Acute - local effects	Inhalation	DNEL (Derived No Effect Level)	1.6 mg Ni/m³ Inhalable Fraction^b	4.3^e	HEC-LOAEC: 6.9 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)	0.00044   mg Ni/cm^2h	1^i	NOAEL:0.00044  mg Ni/cm^2	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 local effect, dermal), C2 (long-term DNELs) and C3 (acute DNELs). DNELs for nickel sulphamate 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 sulphamate 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 nickel sulphamate is read across from Ni sulphate without further correction since both compounds have similar Ni release in synthetic sweat (KMHC, 2010). 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. This DNEL is protective of both acute and long-term local dermal effects (Appendix B3).

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

 

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:

0.013 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 Sulfamate Tetrahydrate 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 general population (MvE)

Exposure pattern	Route	Descriptor	DNEL / DMEL^a	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/m³^b	12.5^c	HEC-NOAEC: 109.6 mg Ni/m^3 d	acute toxicity (mortality)	See footnotes
	Oral	DNEL (Derived No Effect Level)	0.37 mg Ni/kg/day	100^e	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/m³^b	7.1^f	HEC-LOAEC: 0.8 mg Ni/m^3 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/m^3h		Calculated NAEC 0.11 mg Ni/m^3	reproductive developmental toxicity	See footnotes
	Oral	DNEL (Derived No Effect Level)	0.013 mg Ni/kg/day^i	100^j	BMDL10: 1.3 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/m^3h		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)andC3 (acute DNELs).DNELs for nickel sulphamate 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 sulphamate 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 sulphamate 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 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).

i.      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.

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