Hafnium

Toxicological Summary

Workers - Hazard via inhalation 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:

other toxicological threshold

Value:

5 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

no hazard identified

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

Read across justification:

The guidance document on information requirements and chemical safety assessment deals with the specific category of metals, metal compounds and other inorganic compounds like Hf (section 6.2.5.6.). For this category, the hypothesis is that properties are likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (Hf4+ in this case). However, it is the bioavailability of the metal ion (or a redox form of this ion) at target sites that in most cases determine the occurrence and severity of the effects to be assessed for the read-across of metal substances. Supporting information to assess the bioavailability of the metal ion at the target site can include information on a number of different factors (e.g. physico-chemical properties such as water solubility, particle size and structure,in vivodata on systemic effects or toxicokinetics).

In our case, as mentioned in the literature, the chemistry of Zr and Hf is so similar that they are difficult to separate. The melting and boiling points and the solubility in solvents are the major differences in the chemistry of these two elements (cf. the following comparative table).

In addition, they both have a hexagonal crystalline structure.

Regarding their toxicological profile, it is quite similar: the oral absorption is negligible, the distribution in the organism is similar with the following gradient; squeleton > liver > spleen > lung, mainly excreted via faeces, both element show no toxicity except minor hepatic effects induced by HfO2.

 

	Hf	HfO2	Zr	ZrO2
Atomic weight	178,5	210,5	91,2	123,2
Atomic radius	155 pm	-	160 pm	-
Crystal structure	hexagonal	-	hexagonal	-
Melting point	2233 °C	2758 °C	1855 °C	2715 °C
Boiling point	4603 °C	5400 °C	4409 °C	4300 °C
Solubility in water	< 8 µg/L	< 8 µg/L	< 50 µg/L	< 55 µg/L
Oral absorption	0,04 – 0,13 %	Negligible	Very low	negligible
Dermal absorption	None	none	none	none
Distribution	Squeleton, liver, spleen, lung	Liver, spleen, lung	Squeleton, liver, spleen, lung	Squeleton, liver, spleen, lung
Excretion	faecal	faecal	faecal	faecal
Irritation	no	no	no	no
Granulometry	> 44 µm and < 0.8 mm	D10 = 0.183 µm D50 = 0.250 µm D90 = 0.533 µm	D10 = 32 µmD50 = 76 µmD90 = 141 µm	< 2 µm

Table 1: Comparison between Zr and Hf compounds parameters

 

Hf and Zr powder particles are smaller than ZrO2 or HfO2 particles, which are in any cases smaller than 4 µm, and then are able to reach lower parts of the respiratory system. This alveolar fraction particles effects are covered by studies performed with ZrO2 (mass median particle diameter: 1.5 µm), the use of these data is then toxicologically protective.

In addition, acute oral toxicity studies have been performed with Hf and HfO2 to support this read across approach. These two tests confirms the non-toxic effect of Hf and HfO2 after oral administration to rats at the dose level of 2000 mg/kg bw. These results are exactly the same as for Zr and ZrO2.

Moreover, concerning local effects, four reliable studies performed with Hf or with HfO2 and ZrO2 on skin and one study on eyes performed with ZrO2 are available. They confirmed the same behaviour of these substances related to irritation; that is to say no potential to induce any irritation.

 

So, based on all these considerations, a read across between these four similar substances is made to avoid the unnecessary use of other animals, and HfO2 or ZrO2 data are used to cover endpoints requirements.

 

Threshold values:

In this section, data from all end-points are examined and analyzed in order to determine for which it is relevant and possible to establish a DNEL value. The method followed is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration) -response for human health, November 2012).

1.   Oral toxicity

a.   Acute exposure

A single-dose oral toxicity of Hafnium was performed according to the acute toxic class method (OECD 423) in CRL:(WI) rats.

Two groups of three female rats were treated with Hafnium at a dose level of 2000 mg/kg bw by gavage.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a macroscopic examination.

Hafnium did not cause mortality at a dose level of 2000 mg/kg bw, and the treatment did not cause any test item related adverse effect during the 14 days observation period. Body weight gains of Hafnium treated animals during the study showed no indication of a treatment-related effect. There was no evidence of the test item-related macroscopic observations at a dose level of 2000 mg/kg bw.

In the conditions of this reliable study (Klimlisch 1 reliability, for a GLP study performed without any deviation), the acute oral LD 50 value of the test item Hafnium was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

Used for read across approach, HfO2 and ZrO2 were also assessed for oral toxicity in the same way, and these two similar compounds also exhibited no effect in these studies, with LD50 found above 2000 mg/kg bw.

 

b.   Repeated exposure

Ingestion of equivalent cumulative doses of 0.9 g, 9 g and 103.5 g of ZrO2 in the form of hydrated zirconium carbonate for a period of 17 weeks did not cause any death on the 60 rats submitted to the test. This indicates the absence of cumulative toxic effects. After autopsy, no abnormality was observed on heart, lungs, thyroids, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genitals organs, so it can be concluded that ingestion of hydrated zirconium carbonate (containing 20.9% ZrO2) does not induce harmful effects.

 

2.   Inhalation toxicity

 

a.   Acute exposure

For inhalation acute toxicity, as this test is technically impossible, due to pyrophoricity of Hf powder, a read across with ZrO2 is realized. An OECD guideline 436 study was available: 3 male and 3 female were exposed nose-only to 4.3 mg/L of ZrO2 for 4 hours. The mean mass median aerodynamic diameter was 2 µm (+/- 1.75 µm). With this particle size, ZrO2 could reach lower parts of respiratory tract, like the bronchioles. No mortality was observed during the test, all animals were considered clinically normal and no macroscopic findings were noted at the scheduled necropsy. The CL50 equivalent for Zr was > 3.18 mg/L.

 

b.   Repeated exposure

Two reliable studies were available (Klimisch 2): a 30 day repeated dose inhalation test in dog, rabbit and rat and a 60 day repeated dose toxicity test in cat, dog, guinea pig, rabbit and rat. No effects were reported in any of the species studied after inhalation of ZrO2 dust. NOAEC > 75 mg Zr/m3 air in the 30 day study and NOAEC > 11 mg Zr/m3 air in the 60 day study.

 

3.   Dermal toxicity

 

On the basis of column 2 of annex VIII, in addition to the oral route, for substances other than gases, the information mentioned under acute toxicity sections shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. Based on the properties of the substance (inorganic inert chemical), the dermal route of exposure is not considered to be relevant, compared to inhalation one.

 

4. Irritation / sensibilisation

 

Four reliable studies are identified to assess the irritant potential of Hf. These studies are performed with HfO2 or with Hf and ZrO2 used for read across. All these studies showed no potential for skin or eyes irritation.

Zirconium dioxide was found to be not sensitizing to the skin at level up to 25% in a maximization test

(similar to OECD 406).

 

5. Genetic toxicity

 

Tests in bacterial systems are not appropriate for metal due to a lack of sensitivity related to either probable mechanism of action or lack of metal uptake. The high prevalence of false negatives for metal compounds might suggest that mutagenesis essay with mammalian cells, as opposed to bacterial cells, would be preferred starting point.

 

Although no data is available on the genotoxic potential of metallic hafnium, one may safely assume that metallic hafnium as such cannot cross cellular membranes, but instead only the hafnium cation, the active form. Therefore, read across with reference to information on the mutagenicity of other similar substances (like ZrO2) is clearly warranted.

 

An in vitro cytogenicity study in mammalian cells with ZrO2 (according to OECD 473 guideline) and vitro gene mutation study in mammalian cells with ZrO2 (OECD 476 guideline) were realized. The result of the two tests performed with ZrO2 (the soluble Zr cation, the active form, was tested) was negative: under the experimental conditions, no chromosome aberration or gene mutation was induced in mammalian cells.

 

6.   Reprotoxicity

 

Based on the same behavior and toxicological effects, and their very low systemic absorption, a read across with Zr/ZrO2 is performed.

Overall, the available repeated dose toxicity data indicate that Zr is a metal with an extremely poor potential for causing long-term toxicity. Further, the available results do not suspect Zr of being toxic for reproduction, as no long-term effects on reproductive organs have been observed in any of the available studies.

A testing proposal according to OECD 414 was judged relevant by ECHA. Once the results of the ZrO2 test are available, an update of the Hf dossier will be made.

 

7.   Carcinogenicity

 

No data was found for carcinogenicity potential of hafnium compounds.

 

Conclusion:

As showed by all available data on Hf or HfO2 and ZrO2 for read across, no human health effect was observed in any of the tests by any of the routes and with any of the doses tested. No threshold value was then derived.

Nevertheless, an occupational value for hafnium of 0.5 mg/m³was drawn up in 1987, but no document is available that could explain how this value was elaborated. Moreover, this occupational value was set for several countries; it is not a European Occupational Value and is only recommended, not indicative or binding value.

This very low value seems not relevant, but to be protective for the Hf worker, it is decided to keep a threshold value for inhalation potential of Hf as dust. This value is the limit value for generic dust, alveolar fraction: 5 mg/m3 for France (no European value available). As no systemic effect was seen in any of the data available for Hf or read across compounds, and no epidemiological data showed any Hf effect on respiratory system, this value of 5 mg/m3 is chosen as inhalation DNEL for local effect and is the bases for risk characterization work.

 

Classification:

As showed by all available data on Hf or HfO2 and ZrO2 for read across, no human health effect was observed in any of the tests by any of the routes and with any of the doses tested.

Hafnium is then not classified at all for human health.

General Population - Hazard via inhalation 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

DNEL related information

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

As showed by all available data on Hf or HfO2 and ZrO2 for read across (see discussion fiel for workers above), no human health effect was observed in any of the tests by any of the routes and with any of the doses tested. No threshold value was then derived.

The occupational value for hafnium is not relevant for general population and except workers in specific industrial plant, there is no reason for general population to be in contact with hafnium. For these reasons, it is decided to not derive any threshold value, even for inhalation. The risk assessment also shows that only industrial manufacture and use of hafnium has to be assessed.