oxozirconium; silane

Endpoint summary

Description of key information

No 'key' information was identified, however, an assessment was made based on the physicochemical characteristics of the substance as well as on available reliable toxicological data for silicon zirconium oxide as well as zirconium dioxide and other relevant zirconium substances (see read across justification document). Preliminary (worst-case) absorption factors of 10% for the oral and inhalation pathway and 1% for the dermal pathway were put forward in the absence of key information from toxicokinetics experiments.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

10

Additional information

Toxicokinetic assessment of silicon zirconium oxide

A qualitative judgement on the toxicokinetic behaviour of the substance silicon zirconium oxide (EC 811-319-7; CAS 174633-44-4) was performed based on the physicochemical characteristics of the substance as well as on available reliable toxicological data for the substance itself as well as zirconium dioxide and other zirconium substances. No toxicological data on silicon have been added to the substance dataset as silicon is an essential micronutrient and not considered to present any physical, human health or environmental hazard, and because a comparison of the available toxicological data for silicon zirconium oxide with those available for zirconium dioxide indicated that the addition of silicon to the crystal lattice of zirconium dioxide does not alter the unhazardous character of zirconium dioxide. Therefore, no toxicokinetic or toxicological data specifically for silicon have been discussed in this assessment.

 

Silicon zirconium oxide is a white odourless powder and consists of a stabilised zirconia crystal lattice including the elements silicon, zirconium and oxygen. The substance is characterised by a molecular weight range between 107.11 and 120.25 g/mol, a median particle size of 4.959 µm (representative sample of Luxfer MEL Technologies, 2017), a very low water solubility (< 0.01 mg Zr/L at pH 6 and 20°C) (Buchholz, 2018) and a relative density of 5.706 at 21.1°C (Demangel, 2017). No melting temperature was observed for the substance below 1000°C (Dvininov, 2017). It should be noted that due to technical constraints in the water solubility study, dissolved silicon was not monitored. However, based on measurements made in the aquatic ecotoxicity experiments (daphnids and algae) for both dissolved zirconium and dissolved silicon, it became apparent that contrary to zirconium, at least some silicon can dissolve from the substance. For more details see the respective IUCLID Sections or the read across justification document attached to IUCLID Section 13.

 

Absorption

Oral absorption

The relevant pH range for the uptake in the gut after oral ingestion is 6 (at the entrance of the duodenum) to 7.4 (at the terminal ileum). Because silicon zirconium oxide is poorly soluble in water at this pH level (see above), absorption after oral exposure is expected to be very limited. During passage through the stomach, the acidic pH of the gastric environment may cause some dissolution of zirconium and/or silicon from the substance. Any dissolved zirconium however is expected to be rapidly precipitated in the gut due to the presence of ligands such as phosphate and carbonate and formation of strong, insoluble complexes with these ligands. Any silicon that may have dissolved from the substance may partly stay bioavailable for uptake in the gut, however, as dissolution is expected to be limited, uptake is also expected to be limited.

 

The absence of systemic toxicity in the experiments carried out with silicon zirconium oxide as well as the substance’s constituent zirconium dioxide or – for some endpoints – its read across compounds, supports the assumption of limited oral absorption:

- Following a single administration by oral route at the limit dose of 2000 mg/kg bw, no relevant systemic clinical signs or changes in body weight and no gross abnormalities upon necropsy were observed for silicon zirconium oxide (Appl, 2018) nor for zirconium dioxide (Phycher Bio Developpement, 2008).

- No adverse effects have been observed in an OECD 422 study performed with the read across substance zirconium acetate in rats (Rossiello, 2013), resulting in NOAEL values≥1000 mg/kg bw/day (i.e. the highest dose tested).

- No adverse effects were reported after oral administration of the read across substance zirconium basic carbonate (containing 20.9% zirconium dioxide equivalent) to rats during 17 weeks. The equivalent NOAEL for zirconium dioxide was≥3150-7080 mg/kg bw/day (Harrison et al., 1951).

 

No experimentally obtained data on oral absorption are available for silicon zirconium oxide or zirconium dioxide. Data on zirconium dichloride oxide in mouse and rat show oral absorption to be at levels of 0.01 to 0.05% of the administered dose (Delongeas et al., 1983). This well water soluble compound could be regarded as a reference for zirconium dioxide as it will instantaneously be converted to zirconium dioxide in aqueous solution (at physiologically relevant pH levels) and therefore higher-than-expected similarities between soluble and insoluble zirconium compounds are expected. 

 

Based on the reasoning above, the oral absorption of silicon and zirconium from silicon zirconium oxide is expected to be low and a worst case oral absorption factor of 10% is proposed.

 

Respiratory absorption

Low exposure to the substance is expected based on the inherent properties of the compound. No vapour pressure value has been determined as the product does not melt below 300°C (see above). Therefore, inhalation of silicon zirconium oxide as a vapour is not likely to occur.

 

There are no data available on the aerodynamic diameter but based on the small median particle size of a representative sample for silicon zirconium oxide, which was determined to be 4.959 µm (Luxfer MEL Technologies, 2017), typical grades of the substance can be considered to contain both inhalable and respirable particles. When inhaled, the substance, which has a very low water solubility (Buchholz, 2018), may reach the alveolar region. In the alveolar region, the particles may be engulfed by alveolar macrophages. These macrophages will then either translocate the particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. For this reason, the respiratory absorption is expected to be very low.

 

Currently there are no inhalation toxicity studies available performed on the substance itself to support the reasoning above. However, the absence of systemic toxicity in the experiments carried out with the substance’s constituent zirconium dioxide supports this assumption both after single and repeated exposure. Following a single inhalation (nose only) exposure assessment during 4 h and at the limit doses of 4.3 mg/L ZrO2 as aerosol (Smith, 2010), no mortalities and no specific test item related adverse effects in body weight, clinical signs and gross pathology were observed. A sub-chronic inhalation study (60 days) applying ZrO2 at a dose of 15.4 mg/m3 air to rats, rabbits, guinea pigs, dogs and cats and a short-term repeated dose inhalation study (30 days) applying ZrO2 at a dose of 100.8 mg/m3 air to rats, rabbits and dogs showed no significant changes in mortality rate, growth, biochemistry, hematology values or histopathology in any of the species tested (Spiegl et al., 1956). Findings on accumulation supporting the macrophage-mediated clean-up mechanism are further discussed in the section on distribution.

 

The absence of systemic effects in the available inhalation toxicity studies is supportive of the assumption of very low respiratory absorption.

 

Based on the reasoning above, a worst case inhalation absorption factor of 10% is proposed.

 

Dermal absorption

Prior to penetrating the skin by diffusive mechanisms, the test substance would have to dissolve in the moisture of the skin. However, as the solubility of silicon zirconium oxide is very low at physiologically relevant pH levels (relevant to skin), no significant dermal uptake is expected because the substance must be sufficiently soluble in water to partition from the lipid rich stratum corneum into the epidermis. 

Furthermore, silicon zirconium oxide was demonstrated to be not irritating to skin (Orovecz, 2017) nor skin sensitising (Tarcai, 2018) and therefore the expected low dermal absorption is not expected to be enhanced by any irritating/sensitising effects.

In the absence of measured data on dermal absorption, the ECHA guidance (2017) suggests the assignment of either 10% or 100% default dermal absorption rates. However, the currently available scientific evidence on dermal absorption of some metals (e.g. Zn sulphate, Ni acetate; based on the experience from previous EU risk assessments) indicates that lower figures than the lowest proposed default value of 10% could be expected (HERAG, 2007).

 

Based on the inherent properties of silicon zirconium oxide, the toxicological data available, demonstrating the absence of systemic toxicity, and the experience from HERAG, no significant dermal absorption is expected.

 

Based on the reasoning above, a worst case dermal absorption factor of 1% is proposed.

 

Distribution and accumulation

From the above discussion, absorption of the elements zirconium and silicon following exposure to the substance silicon zirconium oxide via the oral, respiratory or dermal pathway is expected to be (very) limited. Nevertheless, the available information on distribution and accumulation of zirconium is discussed below in order to describe its most likely behaviour once ending up in the circulatory system.

 

Oral administration

Since there are no oral toxicokinetics studies available informing directly on the distribution and/or accumulation of (zirconium and silicon from) silicon zirconium oxide or on the distribution and/or accumulation of (zirconium from) zirconium dioxide or other zirconium compounds, the findings from the available oral toxicity studies with these compounds were considered more closely.

 

In the 17-week oral toxicity study performed with the insoluble zirconium basic carbonate (containing 20.9% ZrO2equivalent) in rats (Harrison et al., 1951), no abnormalities were observed in heart, lungs, thyroids, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genital organs. In the OECD 422 study performed with the water soluble zirconium acetate in rats (Rossiello, 2013), no abnormal findings that could indicate accumulation of the substance in organs were made during histopathological investigation either. Finally, macroscopic investigation of rats that received a single dose of 2000 mg/kg bw silicon zirconium oxide did not show any visible accumulation of the test material in the body (Appl, 2018).

 

The findings of the studies mentioned above support the assumption that no distribution to and no accumulation of (silicon and zirconium from) silicon zirconium oxide in the organs will take place after oral ingestion.

 

Administration via inhalation

Since there are no toxicokinetics studies available informing directly on the distribution and/or accumulation of (zirconium and silicon from) silicon zirconium oxide or (zirconium from) zirconium dioxide or other zirconium compounds, the findings from the available inhalation toxicity studies with zirconium dioxide were considered more closely. In the short-term (30-day) repeated dose inhalation study in dog, rabbit and rat applying ZrO2 (Spiegl et al., 1956), an apparently granular material, brownish-black and doubly refracting, was found in the alveolar walls and in phagocytes during the histopathological examination. Occasionally, this dust was also seen in bronchi and lymph nodes. Similar findings were made in the sub-chronic (60-day) study in dogs, rabbits, rats, guinea pigs and cats.

This finding suggests that accumulation of poorly soluble ZrO2 in the lungs may occur under certain conditions, but also that the substance may at least partly be removed by a mechanism involving macrophages and consequent transport to/accumulation in the lymph nodes associated with the lungs. There is no evidence though of true absorption in the circulatory system and consequent distribution to and accumulation in organs.

 

Dermal administration

There are no dermal toxicity studies available on silicon zirconium oxide and zirconium dioxide, but based on the predicted very low dermal absorption of the substance, no accumulation or distribution is expected either.

 

Intraperitoneal administration

Olmedo et al. (2002) studied the dissemination of zirconium dioxide after intraperitoneal administration of this substance in rats. The histological analysis revealed the presence of abundant intracellular aggregates of metallic particles of zirconium in peritoneum, liver, lung and spleen.

 

Other information

Additional data show distribution of several other zirconium compounds through the body with main presence in bone and liver, but also in spleen, kidney and lungs (Spiegl et al., 1956; Hamilton, 1948; Dobson et al., 1948). Data from the latter two studies should be treated with care as substances were administered via injection and thus not only the chemical but also the physical form which becomes systemically available might be different compared to administration via the oral, dermal or inhalation route.In the study from Spiegl et al. (1956) described above for zirconium dioxide, a repeated dose inhalation study was also performed with zirconium dichloride oxide (i.e. a water soluble zirconium compound). In this study, similar observations were made as in the experiments with zirconium dioxide, but very small amounts of zirconium were also found in femur, liver and kidney. These findings can most likely be explained by further distribution throughout the body of accumulated insoluble material in the lymph nodes via fagocytic cells of the reticuloendothelial system, followed by (slow) elimination.

 

In conclusion, under normal conditions of exposure relevant under REACH, no or only limited systemic distribution of silicon zirconium oxide is expected, depending on the route of exposure.

 

Metabolism

The elements zirconium and silicon can be neither created nor destroyed within the body. In addition, there are no indications of transformation to more hazardous forms in the liver or kidney, which is also supported by the fact that silicon zirconium oxide as well as zirconium dioxide were demonstrated not to be mutagenic in vitro, both in the absence and presence of metabolic activation (Orovecz, 2018; LAUS, 2008; NOTOX, 2010a,b).

 

Excretion

Based on the substance’s insoluble nature, low absorption and distribution potential, and absence of obvious metabolism, it is probable that after oral intake, non-absorbed silicon zirconium oxide will be eliminated via the faeces, either as silicon zirconium oxide, zirconium dioxide and/or other insoluble zirconium and silicon species. After inhalation exposure, as mentioned above, distribution of particulate material may occur to the lung-associated lymph nodes, from which further distribution may occur as well as (consequent) slow excretion/elimination. No experimental data is available specifically investigating the excretion/elimination pathways and kinetics, apart from a study by Delongeas et al. (1983).In this study, zirconium dichloride oxide, a water soluble zirconium compound which is instantaneously converted to zirconium dioxide or other insoluble zirconium species in aqueous solutions at physiologically relevant pH levels, was administered to rats using a single oral dose of 450 mg/kg bw (i.e., 128 mg Zr/kg bw). In this study, 90-99% of the administered zirconium was eliminated via the faeces within 24 h. The limited absorbed fraction was (at least partly) excreted via the kidneys, with 0.0011 to 0.0015% of the total administered dose being excreted within 72 h.

 

References

Appl A. Silicon zirconium oxide: Acute Oral Toxicity Study in Rats. 17/233-001P, Citoxlab Hungary Ltd., Szabadságpuszta, Hungary, 2018.

 

Buchholz V. Solubility in water of one batch of Silicon zirconium oxide (CAS N°. 174633-44-4). R B7331, ANADIAG, Haguenau, France, 2018.

 

Delongeas JL et al. Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la souris et chez le rat. J. Pharmacol (Paris) 1983, 14, 4, 437-447.

 

Demangel B. Relative density of solids by stereopycnometer method on Silicon zirconium oxide (CAS No. 174633-44-4). 17-913031-004, Défitraces, Brindas, France.

 

Dobson et al. Studies with Colloids Containing Radioisotopes of Yttrium, Zirconium, Columbium and Lanthanum: 2. The Controlled Selective Localization of Radioisotopes of Yttrium, Zirconium, Columbium in the Bone Marrow, Liver and Spleen. University of California, Radiation Laboratory, W-7405-eng-48A, 1948.

Dvininov E. Melting point determination for Silicon Zirconium Oxide. MEL Chemicals, Manchester, 2017.

 

ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, Version 3.0, November 2017.

 

Hamilton JG. The Metabolic Properties of the Fission Products and Actinide Elements. University of California, Radiation Laboratory, W-7405-eng-48A-I, 1948.

 

Harrison JWE, Trabin B, Martin EW. The acute, chronic and topical toxicity of zirconium carbonate. Journal of Pharmacology and Experimental Therapeutics 102, 179-184, 1951.

 

Health risk assessment guidance for metals (HERAG) fact sheet (2007). Assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds. EBRC Consulting GmbH (2007).

 

LAUS. Determination of the mutagenic potential of CC10 Zirconium oxide with the Bacterial Reverse Mutation Test following OECD 471 and EU B.13/14. LAUS GmbH, Kirrweiler, Germany, 2008.

 

Luxfer MEL Technologies. Technical data sheet: Particle size analysis Microtrac - X100, F2261. Luxfer MEL Technologies, Manchester, United Kingdom, 2017.

 

NOTOX. Evaluation of the ability of zirconium dioxide to induce chromosome aberrations in cultured peripheral human lymphocytes (with repeat experiment). NOTOX B.V., ‘s Hertogenbosch, The Netherlands, 2010a.

 

NOTOX. Evaluation of the mutagenic activity of zirconium dioxide in an in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells (with independent repeat). NOTOX B.V., ‘s Hertogenbosch, The Netherlands, 2010b.

 

Olmedo et al. An experimental study of the dissemination of titanium and zirconium in the body. Journal of Materials Science: Materials in Medicine 13, 793-796, 2002.

 

Orovecz B. Silicon zirconium oxide: In Vitro Skin Irritation Test in the EPISKINTM (SM) Model. 17/233-043B, CiToxLAB Hungary Ltd., 2017.

 

Orovecz B. Silicon zirconium oxide: Bacterial Reverse Mutation Assay. 17/233-007M, CiToxLAB Hungary Ltd., 2018.

 

Phycher Bio Developpement. CC10 Zirconium Oxide: Acute Oral Toxicity in the Rat Acute Toxic Class Method. TAO423-PH-08/0062, Phycher Bio Developpement, Cestas, France, 2008.

 

Rossiello. Zirconium acetate solution combined repeated dose toxicity study with the reproduction/developmental toxicity screening study test in rats. Report 92620, Research Toxicology Centre S.p.A., Rome, Italy, 2013.

 

Smith AJ. Acute Inhalation Toxicity Study of Zirconium Dioxide in Albino Rats. WIL-594010, WIL Research Laboratories, Ashland, USA, 2010.

 

Spiegl CJ, Calkins MC, De Voldre JJ, Scott JK. Inhalation Toxicity of Zirconium Compounds: Short-Term Studies. Atomic Energy Commission Project, Rochester, 1956.

 

Tarcai Z. Silicon zirconium oxide: A Skin Sensitisation Study in the Guinea Pig using the Magnusson and Kligman Method. Citoxlab Hungary, 2018.