Frits, chemicals

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

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:

0.05 mg/m³

DNEL related information

DNEL derivation method:

other:

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:

0.012 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

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

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.

Nickel Oxide CSR Table 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	No DNEL (Derived No Effect Level) is required^b					See footnotes
Acute - local effects	Dermal						Not relevant, negligible Ni ion release, slightly irritating
Acute - local effects	Inhalation	DNEL (Derived No Effect Level)	18.9 mg Ni/m³ Inhalable fraction^c	1.4^d	HEC-NOAEC: 26.5 mg Ni/m^3 Inhalable fraction^e	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^f			developmental toxicity	See footnotes
Long-term - local effects	Dermal	DNEL (Derived No Effect Level)	0.012 mg Ni/cm²	2^g	NOAEL corrected^h: 0.024 mg Ni/cm² from0.00044 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^f			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 C2 (long-term DNELs), C3 (acute DNELs), and C4 (Summary DNEL table).

b.       Nickel oxide is not classified for acute toxicity by inhalation, oral or dermal routes. Thus, no acute systemic inhalation DNEL is required.

c.       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.

d.       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. 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.

e.       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.

f.        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. See Appendix C2 for detailed description of this DNEL derivation.

g.       AF =2. For the water insoluble compounds like Ni oxide, 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 oxide 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.

h.       Corrected dose descriptor = 0.024 mg Ni/cm² [0.44 µg Ni/cm² x 54 = 0.024 mg Ni/cm²); where 0.44 µg Ni/cm² is 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 (Appendix B3). 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. See Appendix 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 = Background Document in Support of Acute DNELs and Guidance Values for Nickel Metal and Nickel Compounds

Appendix C4 = 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:

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:

no hazard identified

DNEL related information

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - 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 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.

Nickel Oxide CSR Table for 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	No DNEL (Derived No Effect Level) is required^b					See footnotes
	Oral						Not relevant, negligible oral exposure and absorption
Acute - local effects	Dermal						Not relevant, not irritant
	Inhalation	DNEL (Derived No Effect Level)	1.8 mg Ni/m³^c	2.3^d	HEC-NOAEC: 4.2 mg Ni/m^3 e	repeated dose toxicity (lung inflammation)	See footnotes
Long-term - systemic effects	Dermal						Not relevant, negligible exposure and absorption
	Inhalation	DNEL (Derived No Effect Level)	0.00002 mg Ni/m^3f		Calculated NAEC 0.11 mg Ni/m^3	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)	0.00002 mg Ni/m^3f		CSTEE (ambient air standard) = 0.00002 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 Appendices C2 (long-term DNELs), C3 (acute DNELs), and C4 (Summary DNEL table).

b.       Nickel oxide is not classified for acute toxicity by inhalation, oral or dermal routes. Thus, no acute systemic inhalation DNEL is required.

c.       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.

d.       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=5for substances that do not undergo metabolism. 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]. 

e.  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.

f.       We used the CSTEE, EU Scientific Committee on Toxicity, Ecotoxicity and the Environment (2001) ambient air recommended nickel value of 20 ng Ni/m³ instead 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 protectivefrom possible reproductive effects(see Appendix C1 and Appendix 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 = Background Document in Support of Acute DNELs and Guidance Values for Nickel Metal and Nickel Compounds

Appendix C4 = 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..