Nickel(III) oxy hydroxide

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

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

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

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:

1.3 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

1

Dose descriptor:

other: NOAEL

Additional information - workers

Nickel Oxyhydroxide 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.

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)	520 mg Ni/m³ (MMAD = 2.5 -3.75 µm)^b	7.5^c	NOAEC: 3,900 mg Ni/m^3 (MMAD = 2.5 -3.75 µm)	acute toxicity (mortality)	See footnotes
Acute - local effects	Dermal						Not relevant, slightly irritating. See footnote (f)
Acute - local effects	Inhalation	DNEL (Derived No Effect Level)	3.9 mg Ni/m³ ((MMAD =2.9 µm)^b	1^d	NOAEC: 3.9 mg Ni/m^3 (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 fraction^e			developmental toxicity	See footnotes
Long-term - local effects	Dermal	DNEL (Derived No Effect Level)	1.3 mg Ni/cm²	1^f	NOAEL corrected^g: 1.3 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 fraction^e			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 in Appendix C1-C2.

b.      The DNEL based on acute toxicity-local effects (lung inflammation) read across from Ni oxide corresponds to an aerosol of MMAD = 2.9 µm. This value should be compared to workplace exposures comprised of particles of MMAD = 2.9 µm. 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 of humans exposed to workplace aerosols. If this DNEL value is used in a direct comparison to workplace exposures with MMAD ≥ 30 µm, this value is likely to overestimate risk by ≥ 4-fold. For more details see Appendix C3.

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 differences in susceptibility= 2.5; AF intraspecies differences in susceptibility =5; Overall AF = 2.5 x 5=12.5]      

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. See Appendix C1-C2); AF intraspecies differences in susceptibility=3. AF for conversion of LOAEC to NOAEC=1; AF for exposure duration= 1/9 (used in 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT), 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. Use AF of 1]

e.      The justification for the use of an inhalable OEL of 0.05 mg Ni/m³is provided in Appendix C3. This value is based on the SCOEL proposed OEL for nickel of 0.01 mg Ni/m³(March 2009) with further adjustments for differences in particle size distributions between animal experiments and workplace exposures and differences in sampling efficiency between 37-mmm and inhalable samplers. The SCOEL value and the IND-revised value are based on toxicity local effects observed on the lungs of rats after inhalation and carcinogenicity effects in the respiratory tract observed in human studies. Both values consider nickel compounds to be genotoxic carcinogens with a practical threshold. These values are also protective against possible reproductive effects.

f.        AF =1. Study done in humans, 48 hours under occlusion. The population at risk of having an exacerbation of dermal symptoms after oral challenge consists of patients with severe nickel sensitisation. 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.This DNEL is protective of both acute and long-term local dermal effects.

g.      Corrected dose descriptor = 1.3 mg Ni/cm²[0.44 µg Ni/cm²x 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 where exposure lasted for 48hs under occlusion.

 

Appendix C1 = Derivation of DNELs for 4 Reference Ni substances 

Appendix C2 = Detailed tables of DNEL derivations –nickel dihydroxide

Appendix C3 = Background document in support of use of Indicative OEL for nickel substances

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:

sensitisation (skin)

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

Additional information - General Population

Nickel Oxyhydroxide 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.

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)	312 mg Ni/m³^b	12.5^c	NOAEC: 3,900 mg Ni/m^3	acute toxicity (mortality)	See footnotes
	Oral						Not relevant, negligible oral exposure
Acute - local effects	Dermal						Not relevant, not irritant
	Inhalation	DNEL (Derived No Effect Level)	3.9 mg Ni/m³^b	^1d	NOAEC: 3.9 mg Ni/m^3	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/m^3e			exacerbation of existing dermatitis	See footnotes
	Oral						Not relevant, negligible oral exposure
Long-term - local effects	Dermal						Not relevant, negligible exposure
	Inhalation	DNEL (Derived No Effect Level)	0.00002mg Ni/m^3e		CSTEE (ambient air standard) = 0.00002mg 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 and included in Appendix C1-C2.

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 in Appendices C1-C2 and D5.

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 differences in susceptibility= 2.5; AF intraspecies differences in susceptibility =10; Overall AF = 2.5 x 5=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. See Appendices C1 and C2); AF intraspecies differences in susceptibility=5. AF for conversion of LOAEC to NOAEC=1 (Ni oxide); AF for exposure duration= 1/9 (used in 2008/2009 EU NICKEL METAL RISK ASSESSMENT), 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. Use 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 (see Appendix C1 -C2 and Appendix D5).        

 

Appendix C1 = Derivation of DNELs for 4 Reference Ni substances 

Appendix C2 = Detailed table of DNEL derivations –nickel dihydroxide

Appendix D5 = Man Via the Environment Risk Assessment

 

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 and the inhalation DNEL-DMEL value used corresponds to the ambient air guidance value derived by CSTEE for the EU general public.