lambda4-cerium(4+) zirconium(4+) tetraoxidandiide

Endpoint summary

Description of key information

A qualitative judgement on the toxicokinetic behaviour of the reaction mass of cerium dioxide and zirconium dioxide was performed based on the physicochemical characteristics of the substance. In addition, reliable toxicological data on the reaction mass as well as its constituents cerium dioxide (CeO₂) and zirconium dioxide (ZrO₂) are used as supporting information. It should be noted that the read across approach to cover toxicological endpoints for which no reliable data are available on the reaction mass itself is to include reliable data available for the reaction mass’ constituents cerium dioxide and zirconium dioxide (or, for zirconium dioxide, another representative zirconium compound).

The reaction mass of cerium dioxide and zirconium dioxide is a yellow powder and can be considered as a highly insoluble product as the water solubility was determined to be 0.16 µg/L at 20°C (Weissenfeld, 2008). This is in line with the water solubility of its individual constituents, as the water solubility of cerium dioxide was determined to be < 0.123 µg/L (Weissenfeld, 2007) and that of zirconium dioxide was determined to be < 55 µg/L (Paulus, 2010).

As was also supported by measurements of dissolved cerium and zirconium in the available aquatic ecotoxicity experiments for zirconium compounds, cerium dioxide, and the reaction mass of cerium dioxide and zirconium dioxide, no (zirconium) or only extremely limited (cerium) amounts of bioavailable species are to be expected in physiologically relevant media.

The reaction mass of cerium dioxide and zirconium dioxide is further characterised by a molecular weight range between 128.1 and 162.3 g/mol, a median particle size of 2.557-12.05 µm (note that the size distribution of the constituent particles in the nanoforms on the market typically shows particles in the size range of 1-20 nm, as specified in the boundary composition) and a relative density of 6.7 at 20.2°C (Demangel, 2010b). The reaction mass does not melt when heated up to 500°C (Demangel, 2010a).

 

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 the reaction mass of cerium dioxide and zirconium dioxide 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 cerium from the substance. Any dissolved zirconium or cerium is expected to be rapidly precipitated in the gut due to the presence of ligands (e.g., phosphate, carbonate). For this reason, it is expected that the bioavailability of the elements in the reaction mass will be too low for substantial uptake in the small intestine and thus the oral absorption is expected to be extremely low.

The absence of systemic toxicity in the toxicological experiments carried out with the reaction mass itself or its individual constituents cerium dioxide and zirconium dioxide (or another representative cerium or zirconium compound), supports the assumption of limited oral absorption:

- Following a single administration by oral route at the limit dose of 2000 mg/kg bw or higher (De Jouffrey, 1996a; Monnot, 1983; Lambert et al., 1993; Phycher Bio Developpement, 2008; Chemical Evaluation and Research Institute, 2001a,b,c), no relevant systemic clinical signs or changes in body weight and no gross abnormalities upon necropsy were observed for zirconium dioxide, yttrium zirconium oxide and cerium dioxide as well as for the reaction mass of cerium dioxide and zirconium dioxide itself. The reaction mass was tested using a representative nanoform.

- 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). Note that the results of this study were considered relevant for zirconium dioxide (and consequently for the reaction mass as well) because the toxicokinetic behaviour and toxicological profile of water soluble zirconium compounds such as zirconium acetate is expected to show a higher-than-expected similarity to that of insoluble zirconium compounds such as zirconium dioxide (and the reaction mass under consideration).

- Following repeated dose administration by the oral route at doses up to the limit dose of 1000 mg/kg bw cerium dioxide for up to approximately 42 days in male rats and 54 days in female rats, there was no relevant sign of toxicity in any of the parameters studied, including clinical signs, functional observational battery, body weight, food consumption, hematology or blood biochemistry (Davies, 2010a; performed according to OECD guideline 422). The absence of toxic effects indicate that the test substance and/or its degradation products or metabolites are not absorbed or devoid of toxicity following oral dosing with cerium dioxide.

- An OECD 422 study performed with nano cerium dioxide (Lee et al., 2020) did not observe any symptoms of systemic toxicity in the parent animals (including on reproductive performance) nor any adverse effects on development of the offspring up to and including at the highest dose tested, resulting in NOAELs >= 1000 mg/kg bw/day. Moreover, cerium dioxide nanoparticles were not deposited in the parental or pup internal organs after repeated oral exposure, presenting evidence of no or limited absorption.

- In an OECD 416 study performed with an organometallic nanoform of cerium dioxide (cerium and iron oxide isostearate, Spézia, 2011), no symptoms of general systemic toxicity were observed, neither were adverse effects observed on reproductive performance of the parent animals or on development of the offspring. All NO(A)ELs were considered >= 1000 mg/kg bw/day, i.e. the highest dose tested.

No experimentally obtained data on oral absorption are available for the reaction mass of cerium dioxide and 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). As already mentioned above, higher-than-expected similarities are expected between water soluble zirconium compounds (such as zirconium dichloride oxide) and insoluble zirconium compounds (such as zirconium dioxide as well as the reaction mass under consideration).

Based on the reasoning above, the oral absorption of cerium and zirconium from the reaction mass of cerium dioxide and zirconium dioxide is expected to be extremely low and – in the absence of direct experimental evidence – 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. Therefore, inhalation of the reaction mass of cerium dioxide and zirconium dioxide as a vapour is not likely to occur.

Based on their small particle size (see above), typical grades of the substance can be considered to contain both inhalable and respirable particles. When inhaled, the reaction mass, which has a very low water solubility (Weissenfeld, 2008), 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.

This is supported by the absence of systemic toxicity in all acute and repeated dose inhalation toxicity studies performed with the reaction mass itself or its individual constituents zirconium dioxide and cerium dioxide. It should be noted that in some repeated dose toxicity studies performed with cerium dioxide, loco-regional effects were observed which were consistent with ‘portal-of-entry’ effects and a lung overload-related inflammatory response syndrome. This is however not observed for zirconium dioxide and moreover, this kind of responses was consistently found in rats, but not in mouse, for cerium dioxide. An overview of the main findings in the available studies is given below:

- Following a single inhalation (nose only) exposure assessment in rats during 4 h at the maximum technically feasible concentration of 4.3 mg/L ZrO₂ as aerosol (Smith, 2010; bulk material tested), no mortalities and no specific test item-related adverse effects in body weight, clinical signs and gross pathology were observed.

- Two acute inhalation studies were performed with bulk forms of cerium dioxide. In these studies, rats were exposed to cerium dioxide at 5.05 mg/L (Duchosal, 1993; nose only exposure) and 2.01 mg/L, the maximum technically administrable concentration (Traynard, 1983; whole body exposure), for 4 hours. No mortality occurred in both studies.

- A sub-chronic inhalation study (60 days) applying ZrO₂ (bulk test material) 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).

- Following inhalation exposure to cerium dioxide (bulk test material) for up to 90 days in rats (Viau, 1994; performed according to OECD guideline 413), the effects observed were consistent with "portal-of-entry" effects and a lung overload-related inflammatory response syndrome. No systemic effect resulting from significant absorption was evidenced. The LOAEC was set at 50.5 mg/m3, based on the incidence and severity of alveolar epithelial hyperplasia in the lungs.

- Landsiedel et al. (2014) investigated the effects of short-term inhalation of nano cerium dioxide and nano zirconium dioxide in rats following administration of test material aerosols (ranging from 0.5 to 10 mg/m3) for five consecutive days with 21-day post-exposure observation. Based on the results of this study, the NOAEC for nano zirconium dioxide was >= 10 mg/m3, based on the absence of any loco-regional effects in the lungs, whereas for nano cerium dioxide the NOAEC for loco-regional effects was set at <= 0.5 mg/m3, based on the observed increase in PMN neutrophil and lymphocyte count, and macrophage colony stimulating factor levels. Most effects were at least partially reversible during the post-exposure period. No systemic adverse effects were observed in this study.

- Dekkers et al. (2017) performed sub-acute studies (cfr. OECD 412) in mouse with nano cerium dioxide and two forms of zirconium-doped nano cerium dioxide (containing 27% and 78% zirconium, respectively). In this study, the NOAEL was observed to be > 4 mg/m3 based on the general low toxicological activity of the different test materials in mouse.

- No systemic maternal toxicity nor developmental effects in the foetuses were observed in a pre-natal developmental toxicity study in rats performed with nano cerium dioxide, in which the test material was administered following pharyngeal aspiration (Campagnolo and Pietroiusti, 2015).

Findings on accumulation supporting the macrophage-mediated clean-up mechanism are further discussed in the section on distribution.

Based on the reasoning above, and in the absence of direct experimental evidence, a worst case inhalation absorption factor of 10% is proposed.

 

Dermal absorption

Prior to penetrating the skin by diffusive mechanisms, the reaction mass of cerium dioxide and zirconium dioxide would have to dissolve in the moisture of the skin. However, as the solubility of the reaction mass 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, the reaction mass was concluded not to be irritating to skin nor skin sensitising based on reliable data on the reaction mass itself (De Jouffrey, 1996b,d; representative nanoforms tested). This is supported by available data for bulk zirconium dioxide, yttrium zirconium oxide, and both nano and bulk cerium dioxide. Also, an acute dermal toxicity study in rats performed with bulk cerium dioxide did not reveal any adverse effects up to and including at the limit test dose of 2000 mg/kg bw (Monnot, 1983).

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 the reaction mass of cerium dioxide and zirconium dioxide, the toxicological data available, and the experience from HERAG, no significant dermal absorption is expected.

Based on the reasoning above, and in the absence of direct experimental evidence, a worst case dermal absorption factor of 1% is proposed.

 

Distribution and accumulation

From the above discussion, absorption of the elements zirconium and cerium following exposure to the reaction mass of cerium dioxide and zirconium dioxide via the oral, respiratory or dermal pathway is expected to be (very) limited. Nevertheless, the available information on distribution and accumulation of cerium and zirconium is discussed below in order to describe their 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 cerium from) the reaction mass of cerium dioxide and zirconium dioxide or on the distribution and/or accumulation of (zirconium from) zirconium dioxide or other zirconium compounds or (cerium from) cerium dioxide, the findings from the available oral repeated dose toxicity studies performed with zirconium acetate, zirconium basic carbonate, and (nano) cerium dioxide as well as from the acute oral toxicity studies performed with zirconium dioxide, cerium dioxide and the reaction mass of cerium dioxide and zirconium dioxide are considered more closely:

- Macroscopic investigation of rats that received a single dose of 2000 mg test substance/kg bw or higher did not show any visible accumulation of the test substance in the body (same references as mentioned in the section on oral absorption for cerium dioxide, zirconium dioxide, yttrium zirconium oxide, or the reaction mass of cerium dioxide and zirconium dioxide). In some studies, white discoloration of the faeces was observed on day 1 after administration of the test material, which may indicate that most of the test material leaves the body unchanged via the faeces.

- In the 17-week oral toxicity study performed with the insoluble zirconium basic carbonate (containing 20.9% ZrO₂ equivalent) 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. The same holds for the OECD 422 study performed with cerium dioxide (Davies, 2010a).

- In the OECD 422 study in rats performed by Lee et al. (2020) with nano cerium dioxide, tissue distribution analysis of cerium in parental and pup tissues revealed that nano cerium dioxide was not detected in almost all of the samples. Only a few samples were slightly above the mean cerium content of blank samples, but it was also observed in vehicle control and there was no correlation in cerium content among the tissues and dose groups. In conclusion, cerium dioxide nanoparticles were not deposited in the parental or pup internal organs after repeated oral exposure.

 

The findings of the studies mentioned above support the assumption that no substantial distribution to and no accumulation of (zirconium or cerium from) the reaction mass of cerium dioxide and zirconium dioxide in the organs will take place after oral ingestion.

Administration via inhalation

Since there are no respiratory toxicokinetics studies available informing directly on the distribution and/or accumulation of (zirconium and cerium from) the reaction mass of cerium dioxide and zirconium dioxide, (zirconium from) zirconium dioxide or other zirconium compounds, or (cerium from) cerium dioxide, the findings from the available repeated dose inhalation toxicity studies with these substances are considered more closely:

- In the short-term (30-day) repeated dose inhalation study in dog, rabbit and rat applying (bulk) 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.

- Following repeated dose administration of cerium dioxide by inhalation (nose only) at concentrations up to 0.5075 mg/L (507.5 mg/m3) for 13 weeks in rats (Viau, 1994), only loco-regional "portal-of-entry" effects were observed, as changes in segmented neutrophil counts, lung and spleen weights, lung and lymph node gross appearance at necropsy and respiratory tract and lymphoreticular system histopathology. These effects were illustrative of an inflammatory response subsequent to lung overloading with poorly soluble particles, without functional impairment of the immune system. No relevant systemic effects specific to cerium dioxide as such were evidenced. Microscopically, pigmented material accumulation in the lungs, bronchial, mandibular and mediastinal or pancreatic lymph nodes, trachea, bronchi, larynx, nasal cavity, liver and spleen, as well as alveolar epithelial hyperplasia in the lungs, metaplasia in larynx, and lymphoid hyperplasia in lymph nodes and lungs, correlating with the presence of pigment in these tissues, were seen in all treated groups with a clear dose-response relationship. This is also confirmative of a removal mechanism involving macrophages and consequent transport to/accumulation in the lymph nodes associated with the lungs. The presence of pigmented material accumulation in e.g. liver and spleen, may be the result of further clearance of material accumulated in the lymph nodes associated with the lungs, involving macrophages from the reticuloendothelial system, but are not thought to be the result of distribution of the material after direct uptake in the circulatory system.

- Following repeated dose administration of nano cerium dioxide or nano zirconium dioxide by inhalation (nose only) at concentrations up to 0.1 mg/L (10 mg/m3) for 5 days in rats (Landsiedel et al., 2014), inhaled nano cerium dioxide was found in the lung, in alveolar macrophages, and more rarely in the draining lymph nodes, but none was found in extrapulmonary organs. Inhaled nano zirconium dioxide was found in the lungs but was not detectable in the lung-draining lymph nodes at any time in any of the examined animals, and was not found in extrapulmonary organs either. An organ burden analysis revealed that the recorded pulmonary deposition was consistent with the expected deposition calculated. The decrease in lung burden during the post-exposure period was around 20% for nano cerium dioxide, reflecting a clearance rate with a half-life of about two months. For nano zirconium dioxide, the decrease rates were markedly higher: decreases of up to 75% were observed.

- Dekkers et al.(2017), in their sub-acute repeated dose inhalation toxicity studies in mouse, reported observations of particle-loaded alveolar macrophages in all animals exposed to pure nano cerium dioxide but not in the control group nor in mice exposed to Zr-doped nano cerium dioxide (27 or 78% zirconium), indicating that Zr-doping may influence particle loading of alveolar macrophages in the mice under consideration. In the bronchoalveolar lavage fluid, particle-loaded macrophages were seen in all the nano-particle exposed animals but not in the control group. In tissues, significantly higher cerium and zirconium levels compared to the control were only observed in lungs and liver but not in other organs. These findings are in line with those of the other available studies.

Overall, the studies described above are all confirmative of the involvement of a macrophage-mediated clean-up mechanism and the absence of distribution as a result of direct absorption in the circulatory system after repeated inhalation exposure. The material is expected to distribute (via macrophages) to the lymph nodes associated with the lungs, and may be redistributed therefrom (also macrophage-mediated) to other organs of the reticuloendothelial system, in view of elimination from the body.

Dermal administration

There are no dermal toxicity studies available except for the acute dermal toxicity study with cerium dioxide (see above). Based on the predicted very limited dermal absorption of (zirconium and cerium from) the reaction mass of cerium dioxide and zirconium dioxide, no accumulation or distribution is expected either after dermal exposure.

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 the reaction mass of cerium dioxide and zirconium dioxide is expected, depending on the route of exposure.

 

Metabolism

The elements zirconium and cerium 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 zirconium dioxide (ZrO₂), yttrium zirconium oxide (YZrO), cerium dioxide (CeO₂), as well as the reaction mass of cerium dioxide (CeO₂) and zirconium dioxide (ZrO₂) were demonstrated not to be mutagenic in vitro, both in the absence and presence of metabolic activation (Haddouk, 2007; Shimizu, 1985; Park et al., 2007; LAUS, 2008; Chemical Inspection and Testing Institute, 1997; NOTOX, 2010a,b; Wollny, 2006), nor in vivo (Molinier, 1993).

Although no conclusion can be made regarding the transformation by hepatic microsomal fractions, no microscopic finding in the major metabolising tissues (liver, kidneys) illustrative of metabolic activity were seen following repeated dose administration of cerium dioxide by the oral route at doses up to the limit dose of 1000 mg/kg bw/day for up to approximately 42 days in male rats and 54 days in female rats (Davies, 2010a) or by inhalation (nose only) at concentrations up to 0.5075 mg/L for 13 weeks in rats (Viau, 1994).

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 reaction mass will be eliminated via the faeces, either as unchanged reaction mass of cerium dioxide and zirconium dioxide or as other insoluble zirconium and cerium 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

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

Demangel B. Melting point (DSC method) of reaction mass of cerium dioxide and zirconium dioxide. Défitraces, Brindas, France, 2010a.

Demangel B. Relative density – stereopycnometer method on reaction mass of cerium dioxide and zirconium dioxide.Défitraces, Brindas, France, 2010b.

Dobson EL 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.

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, Radioation Laboratory, W-7405-eng-48A-I, 1948.

Harrison JWE, Trabin B, Marin 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. Assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds. EBRC Consulting GmbH, 2007.

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.

Paulus J. Determination of the solubility in water of CC10 zirconium oxide according to OECD 105 resp. EU A.6. Laus Gmbh, Kirrweiler, Germany, 2010.

Weissenfeld M. Determination of the water solubility of opaline de polissage (cerium oxide). RCC Ltd., Zelgliweg 1, 4452 Itingen, Switzerland, 2007.

Weissenfeld M. Actalys LISA: Determination of the Water Solubility. RCC Ltd., Zelgliweg 1, 4452 Itingen, Switzerland, 2008.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

10