Registration Dossier

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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Toxicokinetic assessment
Type of information:
other: based on available studies
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)

Information on the physicochemical characteristics as well as the toxicological data available on iron oxide isostearate and its analogues were considered altogether to perform a qualitative assessment of the absorption, distribution/metabolism and elimination/excretion of this substance.

For the justification of the read-across between the substances, see the documents attached in the IUCLID section 13.2 (French CA letters and Read-across justification document).

Absorption:

•       Oral/gastro-intestinal (GI) absorption

Despite a low water solubility (0.13 +/- 0.0 mg/L), the molecular weight of iron oxide isostearate, equal to 291.27 g/mol, (that is well below 500 g/mol and thus favorable for absorption) and the size of particles (mean hydrodynamic diameter equal to 12.1 +/- 8.1 nm) could let expect a possible absorption by the oral route that could most probably occur by pinocytosis, considering the physico-chemical characteristics of the substance. With an expected significant solubility in lipids (log Pow = 6.3, with a solubility in n-octanol of 288.7 mg/L), iron oxide isostearate may also be taken up by micellular solubilisation (however LogPow is not a reliable parameter for unsoluble nanomaterials). In addition, enhanced intestinal penetration of the substance could be expected due to the fatty acid part of the molecule . Indeed, as indicated in the disseminated IUCLID dossier of stearic acid (EC number: 200-313-4, RN CAS: 57-11-4), due to the role as nutritional energy source, fatty acids are +/- readily absorbed from the intestinal lumen depending of the chain length (longer chains (> C12) showing lower absorption than shorter chains).

However, the absence of toxic effect in all toxicity studies performed with the substance and its analogues does not support any significant absorption.

Indeed, no effect was observed when cerium and iron oxide isostearates (Active matter of DPX10 and Active mater of DPX11) was administered by gavage at the limit dose of 2000 mg/kg as a suspension in corn oil, in studies performed according to OECD test guideline n° 423 and in compliance with GLP (C. Pelcot, 2001; E. Ollivier, 2004; Klimisch 1). No relevant systemic clinical sign or changes in body weight were observed and no apparent abnormalities were found in organs at the macroscopic examination.

Furthermore, following repeated oral administration of cerium and iron oxide isostearate (Active matter of DPX10)suspended in corn oil at doses up to the limit dose of 1000 mg/kg bw/d for 28 days in rats (OECD, guideline No. 407), there was no relevant sign of toxicity in all the parameters studied, including clinical signs, functional observational battery, body weight, food consumption, hematology or blood biochemistry (P. O. Guillaumat, 200; Klimisch 1). The weight of the organs was slightly increased at the end of the treatment with the substance but tended to return to control level at the end of the recovery period. In addition, no treatment–related macroscopic and microscopic findings were noted at the end of the treatment and treatment-free periods.  

Similarly, no toxicologically meaningful sign of systemic toxicity was also observed up to the highest dose of 1000 mg/kg bw/day in a reproduction/developmental toxicity screening test (similar to OECD guideline No. 421) performed as a preliminary study for a 2-generation reproduction study (R. Davies, 2010; Klimisch 2). In this study, where rats received Cerium and iron oxide isostearate (Active matter of DPX10) administered daily by oral gavage as a suspension in corn oil for at least 35 days in males and up to 53 days in females, no clinical signs were observed and no overt effect of the treatment was observed on the body weight and body weight gain as well as food consumption and at the macroscopic examination.  Furthermore, no effect of cerium and iron oxide isosterate was observed on reproductive performances of the parents: no relevant differences from controls were observed for pairing, mating, fertility and delivery parameters. The treatment with the substance did not have any effects on pup development in utero, pup survival, clinical signs or sex ratio. There were no treatment-related macroscopic abnormalities.

The absence of toxicological effect of cerium and iron oxide isostearate (Active matter of DPX10) was further observed in a 2-generation study, performed in accordance to OECD test guideline N° 416 and GLP, in which the substance was administered orally to males and females rats of the 2 generations as a suspension in corn oil, at concentrations up to the limit dose of 1000 mg/kg bw/d, for periods up to 18/19 weeks (F. Spézia, 2001; Klimisch 1). In this study, no effect was observed in the P0 and P1 parents on mortality, clinical signs, overall body weight, body weight gain and food consumption, oestrous cyclicity and sperm parameters, reproductive parameters and indices, sex ratio and pup mortality. No adverse finding attributable to the substance was observed in macroscopic and microscopic examinations of P0 and P1 parents and their pups, including in reproductive organs. There were no substance-related effects on clinical sign, body weight and body weight gain or on physical or reflex development in F1 et F2 pups during lactation period as well as on sexual and neurobehavioral development of the F1 animals. The No Observed Adverse Effect Level for reproductive performance and systemic toxicity of P0 and P1 generations was therefore considered to be 1000 mg/kg bw/day. Cerium and iron oxide isostearate was also not found to cause delayed or impaired development in the F1 or F2 generations following treatment of the parents. Therefore, the No Observed Effect Level for peri- and post-natal development of F1 and F2 generations was considered 1000 mg/kg bw/day.

Taken together, the absence of systemic and reproductive toxicity after single or repeated administration of cerium and iron oxide isostearates, as reported in the above-mentioned studies, is supportive of limited absorption of the test substance itself or of its degradation products or its metabolites (even if corn oil was used as vehicle in all the studies which could have enhanced absorption since corn oil can be emulsified and digested) and/or suggests that the substance has a low toxicological potential when administered by oral route.

In addition, iron oxide isostearate is not expected to have irritant properties that could increase absorption through the gastrointestinal tract (see skin and eye irritation studies with cerium and iron oxide isostearate Active matter of DPX10, C. Pelcot, 2001; Klimisch 1).

•       Respiratory absorption

Based on the results obtained with an analogous molecule (cerium oxide isostearate: VP = 0.000002 Pa at 25°C, A.L. Comb, 1997, Klimisch 1), it can be extrapolated that iron oxide isostearate presents a negligible vapour pressure. Therefore, inhalation of the substance as a vapour is not likely to occur.

The primary particle size of the substance, as evaluated using Transmission Electronic Microscopy, (TEM, 10CRA00017, 2010) was determined to be 2.7, 3.7 and 4.8 nm, for the D10, D50 and D90, respectively. The mean hydrodynamic diameter of the particles of iron isostearate, measured using Dynamic Light Scattering (DDL, 09 CRA 01109, 2009) is 12.1 +/- 8.1 nm.  Based on this particle size information, the exposure via inhalation route should be taken into consideration for this substance.  

However, due to its poor solubility and considering its molecular formula, once deposited on the walls of the airways, the released of bioavailable forms, such as ionic forms of the metals is expected to be very low, assuming a pH of about 6.6 (for healthy individuals). Therefore, absorption from the lungs to the circulatory system is expected to be minimal.

Respired iron oxide isostearate particles may also accumulate in the lungs mainly as particulate material since this substance is poorly soluble. In that case, the particles are expected to be engulfed from the alveolar region by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Deposited material may also be transported out of the respiratory tract and swallowed through the action of mucociliary clearance mechanisms, especially material settled in the tracheobronchial region. In that case, it will contribute to the gastro-intestinal absorption rather than to the absorption via inhalation. Also as a lipophilic compound (log Pow = 6.3, with a solubility in n-octanol of 288.7 mg/L), iron oxide isostearate may also be taken up by micellular solubilisation.

However, no direct experimental evidence for this behaviour and lung clearance mechanism are available since no inhalation study was done with iron oxide isostearate because the exposure via inhalation route to this substance was not found to be the most relevant. Indeed, the handling of the registered substance (produced as a suspension in a solvent) in manufacturing processes and uses does not produce vapours, aerosols or droplets. Furthermore, for the purpose of the registration, the substance was extracted from its solvent and has formed a melting/sticky powder that prevented testing via inhalation route.

•       Dermal absorption

Studies evaluating absorption of iron oxide isostearate following dermal exposure in humans are not available. Therefore, a qualitative assessment of the dermal absorption was performed based on the physicochemical properties of iron oxide isostearate and toxicological studies that tested the substance and its analogues using dermal route.

With a molecular weight of 203.8 g/mol, a log Pow value of 6.3 and a low water solubility (0.13 mg/L at pH 6.5), the dermal absorption of iron oxide isostearate is likely to be very low. The fatty acid moiety of the molecule should not further enhanced the dermal penetration since fatty acids have been demonstrated to be poorly absorbed through the skin (see IUCLID disseminated of stearic acid).

The acute dermal toxicity of the analogue cerium and iron oxide isostearate (Active matter of DPX10) was investigated in a study performed according to OECD Test Guideline N° 402 and in compliance with GLP (C. Pelcot, 2001; Klimisch 1). The rats were exposed dermally to the substance at 2000 mg/kg and observation up to 14 days following the 24-h application. No systemic clinical sign, no effect on the body weight and body weight gain and no cutaneous reactions were observed during the study. Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Additionally, no skin and eye irritation effects of the analogue cerium and iron oxide isostearate (Active matter of DPX10) were observed in in vivo studies done according to OECD Test Guidelines 404 (for skin) and 405 (for eye) and in compliance with GLP (C. Pelcot, 2001; Klimisch 1).

Further, results of in vivo skin sensitization studies in guinea pigs, performed according to OECD Test Guideline 406 and GPL compliant, indicate that iron oxide isostearate and its analogues cerium and iron oxide isostearates (Active matter of DPX10 and Active matter of DP11) induced no skin sensitization response in the guinea pigs after intradermal and dermal induction and challenge exposures (C. Pelcot 2006, 2001 and 2008; Klimisch 1). No sign of systemic or local toxicity, no effect on body weight and no mortality were observed in this study.

As iron oxide isostearate does not meet the CLP criteria for classification as skin and eye irritant or skin sensitizer, the expected low dermal absorption will not be enhanced by any irritating/sensitizing effects.

Distribution and accumulation

As discussed above, the absorption of iron oxide by oral, inhalation and dermal exposures is expected to be rather limited based on the physico-chemical properties and available toxicological data on this substance. Therefore, a limited distribution and accumulation can be assumed as well.

The absence of lesions in organs, clinical signs, hematology or blood biochemistry disorders, behavioral or neurological changes and impaired development of the progeny, as observed in the acute and repeated dose toxicity studies reported above in which rats were treated with cerium and iron oxide isostearates at dose levels up to 1000 mg/kg bw/day for up to 18/19 weeks, tends to support this assumption, at least by oral and dermal route.  

Poorly soluble particles with aerodynamic diameter equal or below 1 µm, when inhaled in sufficient quantity, may have the potential to deposit in the alveolar region of the lung and be phagocytized by alveolar macrophages that could translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. No direct experimental evidence is available to evaluate the possible accumulation and distribution from the respiratory tract of iron oxide isostearate particles that have a mean primary particle size of 3.7 nm (D50) and a mean hydrodynamic diameter of 12.1 +/- 8.1  nm and a low solubility (0.13 mg/L at pH 6.5). However, the exposure via inhalation route to this substance is expected to be really low since the handling of the registered substance in manufacturing processes and uses does not produce vapours, aerosols or droplets.

Therefore, taking into consideration all the above-mentioned information, no systemic distribution and accumulation of iron oxide isostearate is expected under normal conditions of exposure.

Metabolism

The presence or absence of exogenous metabolic activation system made no difference in the results of in vitro mutagenicity and genotoxicity studies performed with iron oxide isostearate and its analogues, that has been tested negative in the 5 following studies: Ames test (OECD TG N° 471 & GLP; A. Sokolowski, 2005; H. Haddouk, 2001; G. Sire, 2004; Klimisch 1), in vitro mammalian cell gene mutation test (OECD TG N°476 & GLP; G. Sire, 2009; Klimisch 1) and in vitro chromosome aberration assay (OECD TG N° 473 & GLP; H. Haddouk, 2002; Klimisch 1). No conclusion can therefore be made regarding the transformation of the test substance and/or its degradation products or metabolites by hepatic microsomal fractions.

However, no adverse microscopic finding in the major metabolizing tissues (liver, kidneys) illustrative of metabolic activity were seen following repeated dose administration of the analogue cerium and iron oxide isostearate (Active matter of DPX10) by the oral route at doses up to the limit dose of 1000 mg/kg bw/d for up to approximately 18/19 weeks in male and female rats in a 2-generation study (OECD TG 416, GLP; F. Spézia, 2001; Klimisch 1).

Elimination/Excretion

No direct experimental evidence is available to assess the elimination/excretion of iron isostearate.

However, as discussed in this assessment, the substance is expected to have limited absorption and distribution potentials based on its physico-chemical properties and its toxicological information. For these reasons, and because of its low solubility, it can be suggested that the main part of the substance will be eliminated as such, with the faeces as the most probable route of excretion/elimination.

Executive summary:

Information on the physicochemical characteristics as well as the toxicological data available on iron oxide isostearate and its analogues cerium and iron oxide isostearates (Active matter of DPX10 - Ce:Fe ratio 0.5:0.5 and Active matter of DPX11 - Ce:Fe ratio 0.1:0.9) were considered altogether to perform a qualitative assessment of the absorption, distribution/metabolism and elimination/excretion of this substance.

Iron oxide isostearate is a solid organo-mineral substance, produced as a suspension in a solvent. This substance is poorly soluble in water but may be soluble in lipids and has a negligible vapour pressure. The molecular weight of the substance is 203.8 g/mol and its particle size averages 3.7 +/- 1.1 nm (D50 value) with a mean hydrodynamic diameter of 12.1 +/- 8.1 nm and a calculated specific surface area by volume of 1363 m2/cm3.

The toxicological effects of iron oxide isostearate were assessed using the 17 studies available on the substance itself and/or its anologues.

Iron oxide isostearate and its analogues were found to have no toxicological effect in all these studies performed according to OECD guidelines and in compliance with GLP: no systemic effect were found in acute oral and dermal toxicity studies, no skin/eye irritation and no skin sensitization was observed and no systemic and reproductive/developmental effect and no alterations in organs were seen in repeated dose toxicity studies (OECD 407 and 421) and in a reproduction study (OECD 416) performed by oral route at dose levels up to 1000 mg/kg bw/day in which rats were treated with the substance for up to 18/19 weeks. No genotoxic or clastogenic effects were observed in absence and presence of metabolic activation in 5 in vitro studies (OCD 471, 473 and 476).

Therefore, considering the physico-chemical properties of the substance and the absence of toxicity observed in all the studies mentioned above, the absorption, the distribution and the accumulation of iron oxide isostearate is expected to be really limited by oral, dermal and inhalation routes of exposure. As no overt evidence of metabolisation was observed, it can be suggested that the main part of the substance will be eliminated as such, with the faeces as the most probable route of excretion/elimination.

Description of key information

Information on the physicochemical characteristics as well as the toxicological data available on iron oxide isostearate and its analogues cerium and iron oxide isostearates (Active matter of DPX10 - Ce:Fe ratio 0.5:0.5 and Active matter of DPX11 - Ce:Fe ratio 0.1:0.9) were considered altogether to perform a qualitative assessment of the absorption, distribution/metabolism and elimination/excretion of this substance.

Iron oxide isostearate is a solid organo-mineral substance, produced as a suspension in a solvent. This substance is poorly soluble in water but may be soluble in lipids and has a negligible vapour pressure. The molecular weight of the substance is 203.8 g/mol and its particle size averages 3.7 +/- 1.1 nm (D50 value) with a mean hydrodynamic diameter of 12.1 +/- 8.1 nm and a calculated specific surface area by volume of 1363 m2/cm3.

The toxicological effects of iron oxide isostearate were assessed using the 17 studies available on the substance itself and/or its anologues.

Iron oxide isostearate and its analogues were found to have no toxicological effect in all these studies performed according to OECD guidelines and in compliance with GLP: no systemic effect were found in acute oral and dermal toxicity studies, no skin/eye irritation and no skin sensitization was observed and no systemic and reproductive/developmental effect and no alterations in organs were seen in repeated dose toxicity studies (OECD 407 and 421) and in a reproduction study (OECD 416) performed by oral route at dose levels up to 1000 mg/kg bw/day in which rats were treated with the substance for up to 18/19 weeks. No genotoxic or clastogenic effects were observed in absence and presence of metabolic activation in 5 in vitro studies (OCD 471, 473 and 476).

Therefore, considering the physico-chemical properties of the substance and the absence of toxicity observed in all the studies mentioned above, the absorption, the distribution and the accumulation of iron oxide isostearate is expected to be really limited by oral, dermal and inhalation routes of exposure. As no overt evidence of metabolisation was observed, it can be suggested that the main part of the substance will be eliminated as such, with the faeces as the most probable route of excretion/elimination.

Key value for chemical safety assessment

Additional information

Introduction

Information on the physicochemical characteristics as well as the toxicological data available on iron oxide isostearate and its analogues were considered altogether to perform a qualitative assessment of the absorption, distribution/metabolism and elimination/excretion of this substance.

For the justification of the read-across between the substances, see the documents attached in the IUCLID section 13.2 (French CA letters and Read-across justification document).

Iron oxide isostearate is a solid organo-mineral substance that is produced as a suspension in a solvent. This substance is poorly soluble in water at pH 6.5 and 21°C: the water solubility of iron oxide isostearate was determined to be 0.13 +/- 0.0 mg/L, (M. Weissenfeld, 2005). The substance is stable in water. With a log Pow value of 6.3 (M. Weissenfeld, 2005), is may be soluble in lipids; however this solubility may be limited by the low bioavailability due to very low hydrosolubility. Based on the results obtained with an analogous molecule (cerium oxide isostearate: VP = 0.000002 Pa at 25°C, A.L. Comb, 1997, Klimisch 1) and a calculated VP at < 1 x 10E-5 Pa at 25°C (M. Weissenfeld, 2005), iron oxide isostearate should present a negligible vapour pressure.

The molecular weight of the substance is 203.8 g/mol. Its mean particle size averages 3.7 +/- 1.1 nm as measured by TEM analysis (D50 value, see report 10CRA00017, 2010) with a mean hydrodynamic diameter measured by Dynamic Light Scattering analysis (DDL, report 09 CRA 01109, 2009) equal to 12.1 +/- 8.1  nm and a calculated specific surface area by volume of 1123 m2/cm3 (report 10CRA00017, 2010).

The toxicological properties of iron oxide isostearate were assessed in the following studies:

•       In vivo skin sensitization study – Magnusson & Kligman test (OECD TG n° 406, GLP compliant, Klimisch 1): No skin sensitization was observed (report n°: 31450 TSG - C. Pelcot, 2006);

•       In-vitro bacterial reverse mutation test (Ames test) (OECD TG n° 471, GLP compliant, Klimisch 1): no effect of mutagenicity with and without metabolic activation (report n°: A13961 - A. Sokolowski, 2005)

Additionally the following toxicological data were included in a read-across approach by analogy:

Cerium and iron oxide isostearate – Active matter of DPX10 - Ce:Fe ratio 0.5:0.5:

•       Acute oral toxicity in the rat (OECD TG n° 423, GLP compliant, Klimisch 1): oral LD 50 > 2000 mg/kg bw - no mortality and no sign of local or systemic toxicity observed (report n°: 22316 TAR - C. Pelcot, 2001);

•       Acute dermal toxicity in the rat (OECD TG n° 402, GLP compliant, Klimisch 1): dermal LD 50 > 2000 mg/kg bw- no mortality and no sign of local or systemic toxicity observed (report n°: 22319 TAR - C. Pelcot, 2001);

•       In vivo skin irritation study (OECD TG n° 404, GLP compliant, Klimisch 1): the substance was not classified as a skin irritant (report n°: 22320 TAL - C. Pelcot, 2001);

•       In vivo eye irritation study (OECD TG n° 405 , GLP compliant, Klimisch 1): the substance was not classified as an eye irritant (report n°: 22321 TAL - C. Pelcot, 2001);

•       In vivo skin sensitization study – Magnusson & Kligman test (OECD TG n° 406, GLP compliant, Klimisch 1): No skin sensitization was observed (report n°: 22322 TSG - C. Pelcot, 2001);

•       In-vitro bacterial reverse mutation test (Ames test) (OECD TG n° 471, GLP compliant, Klimisch 1): no effect of mutagenicity with and without metabolic activation (report n°: 22323 MMT - H. Haddouk, 2001);  

•       In-vitro mammalian chromosome aberration test (OECD TG n° 473, GLP compliant, Klimisch 1): no effect of clastogenicity with and without metabolic activation (report n°: 22632 MLH - H.Haddouk, 2002);

•       In-vitro mammalian cell gene mutation test (OECD TG n° 476, GLP compliant, Klimisch 1): no effect of mutagenicity with and without metabolic activation (report n°: 34518 MLY – G. Sire, 2009);

•       Repeated dose toxicity study in rats – oral route (OECD TG n° 407, Klimisch 1): No systemic and local effects were seen - NOEL = 1000 mg/kg bw/day (report n°: 22314 TSR – P.O Guillaumat, 2002);

•       Reproduction / Developmental toxicity screening test in rats (used as a dose range finding study for a 2-generation reproduction study) – oral route (OECD TG n° 421, Klimisch 2): No systemic and reproductive effects were seen in parents (NOEL = 1000 mg/kg bw/day). No developmental effects were seen in pups, except a slightly lower mean body weight  (NOAEL = 450 mg/kg bw/day) (report n°: 34759 RSR – R. Davies, 2010);

•       Two-generation reproduction toxicity study in rats – oral route (OECD TG n° 416, Klimisch 1): No systemic effect and no alteration of the reproductive performance were seen in the P0 and P1 parents - NOAEL P0/P1 (systemic and reproductive performance) = 1000 mg/kg bw/day. No delayed or impaired development were seen in the F1 or F2 generations – NOEL F1/F2 (development) = 1000 mg/kg bw/day (report n°: 34760 RSR – F. Spézia, 2011).

Cerium and iron oxide isostearate – Active matter of DPX11 - (Ce:Fe ratio 0.1:0.9):

•       Acute oral toxicity in the rat (OECD TG n° 423, GLP compliant, Klimisch 1): oral LD 50 > 2000 mg/kg bw - no mortality and no sign of local or systemic toxicity observed (report n°: 28266 TAR – E. Ollivier, 2004);

•       In vivo skin sensitization study – Magnusson & Kligman test (OECD TG n° 406, GLP compliant, Klimisch 1): No skin sensitization was observed (report n°: 30801 TSG - C. Pelcot, 2008);

•       In-vitro bacterial reverse mutation test (Ames test) (OECD TG n° 471, GLP compliant, Klimisch 1): no effect of mutagenicity with and without metabolic activation (report n°: 27881 MMT - G. Sire, 2004)

Absorption:

•       Oral/gastro-intestinal (GI) absorption

Despite a low water solubility (0.13 +/- 0.0 mg/L), the molecular weight of iron oxide isostearate, equal to 291.27 g/mol, (that is well below 500 g/mol and thus favorable for absorption) and the size of particles (mean hydrodynamic diameter equal to 12.1 +/- 8.1 nm) could let expect a possible absorption by the oral route that could most probably occur by pinocytosis, considering the physico-chemical characteristics of the substance. With an expected significant solubility in lipids (log Pow = 6.3, with a solubility in n-octanol of 288.7 mg/L), iron oxide isostearate may also be taken up by micellular solubilisation (however LogPow is not a reliable parameter for unsoluble nanomaterials). In addition, enhanced intestinal penetration of the substance could be expected due to the fatty acid part of the molecule . Indeed, as indicated in the disseminated IUCLID dossier of stearic acid (EC number: 200-313-4, RN CAS: 57-11-4), due to the role as nutritional energy source, fatty acids are +/- readily absorbed from the intestinal lumen depending of the chain length (longer chains (> C12) showing lower absorption than shorter chains).

However, the absence of toxic effect in all toxicity studies performed with the substance and its analogues does not support any significant absorption.

Indeed, no effect was observed when cerium and iron oxide isostearates (Active matter of DPX10 and Active mater of DPX11) was administered by gavage at the limit dose of 2000 mg/kg as a suspension in corn oil, in studies performed according to OECD test guideline n° 423 and in compliance with GLP (C. Pelcot, 2001; E. Ollivier, 2004; Klimisch 1). No relevant systemic clinical sign or changes in body weight were observed and no apparent abnormalities were found in organs at the macroscopic examination.

Furthermore, following repeated oral administration of cerium and iron oxide isostearate (Active matter of DPX10)suspended in corn oil at doses up to the limit dose of 1000 mg/kg bw/d for 28 days in rats (OECD, guideline No. 407), there was no relevant sign of toxicity in all the parameters studied, including clinical signs, functional observational battery, body weight, food consumption, hematology or blood biochemistry (P. O. Guillaumat, 200; Klimisch 1). The weight of the organs was slightly increased at the end of the treatment with the substance but tended to return to control level at the end of the recovery period. In addition, no treatment–related macroscopic and microscopic findings were noted at the end of the treatment and treatment-free periods.  

Similarly, no toxicologically meaningful sign of systemic toxicity was also observed up to the highest dose of 1000 mg/kg bw/day in a reproduction/developmental toxicity screening test (similar to OECD guideline No. 421) performed as a preliminary study for a 2-generation reproduction study (R. Davies, 2010; Klimisch 2). In this study, where rats received Cerium and iron oxide isostearate (Active matter of DPX10) administered daily by oral gavage as a suspension in corn oil for at least 35 days in males and up to 53 days in females, no clinical signs were observed and no overt effect of the treatment was observed on the body weight and body weight gain as well as food consumption and at the macroscopic examination.  Furthermore, no effect of cerium and iron oxide isosterate was observed on reproductive performances of the parents: no relevant differences from controls were observed for pairing, mating, fertility and delivery parameters. The treatment with the substance did not have any effects on pup development in utero, pup survival, clinical signs or sex ratio. There were no treatment-related macroscopic abnormalities.

The absence of toxicological effect of cerium and iron oxide isostearate (Active matter of DPX10) was further observed in a 2-generation study, performed in accordance to OECD test guideline N° 416 and GLP, in which the substance was administered orally to males and females rats of the 2 generations as a suspension in corn oil, at concentrations up to the limit dose of 1000 mg/kg bw/d, for periods up to 18/19 weeks (F. Spézia, 2001; Klimisch 1). In this study, no effect was observed in the P0 and P1 parents on mortality, clinical signs, overall body weight, body weight gain and food consumption, oestrous cyclicity and sperm parameters, reproductive parameters and indices, sex ratio and pup mortality. No adverse finding attributable to the substance was observed in macroscopic and microscopic examinations of P0 and P1 parents and their pups, including in reproductive organs. There were no substance-related effects on clinical sign, body weight and body weight gain or on physical or reflex development in F1 et F2 pups during lactation period as well as on sexual and neurobehavioral development of the F1 animals. The No Observed Adverse Effect Level for reproductive performance and systemic toxicity of P0 and P1 generations was therefore considered to be 1000 mg/kg bw/day. Cerium and iron oxide isostearate was also not found to cause delayed or impaired development in the F1 or F2 generations following treatment of the parents. Therefore, the No Observed Effect Level for peri- and post-natal development of F1 and F2 generations was considered 1000 mg/kg bw/day.

Taken together, the absence of systemic and reproductive toxicity after single or repeated administration of cerium and iron oxide isostearates, as reported in the above-mentioned studies, is supportive of limited absorption of the test substance itself or of its degradation products or its metabolites (even if corn oil was used as vehicle in all the studies which could have enhanced absorption since corn oil can be emulsified and digested) and/or suggests that the substance has a low toxicological potential when administered by oral route.

In addition, iron oxide isostearate is not expected to have irritant properties that could increase absorption through the gastrointestinal tract (see skin and eye irritation studies with cerium and iron oxide isostearate Active matter of DPX10, C. Pelcot, 2001; Klimisch 1).

•       Respiratory absorption

Based on the results obtained with an analogous molecule (cerium oxide isostearate: VP = 0.000002 Pa at 25°C, A.L. Comb, 1997, Klimisch 1), it can be extrapolated that iron oxide isostearate presents a negligible vapour pressure. Therefore, inhalation of the substance as a vapour is not likely to occur.

The primary particle size of the substance, as evaluated using Transmission Electronic Microscopy, (TEM, 10CRA00017, 2010) was determined to be 2.7, 3.7 and 4.8 nm, for the D10, D50 and D90, respectively. The mean hydrodynamic diameter of the particles of iron isostearate, measured using Dynamic Light Scattering (DDL, 09 CRA 01109, 2009) is 12.1 +/- 8.1 nm.  Based on this particle size information, the exposure via inhalation route should be taken into consideration for this substance.  

However, due to its poor solubility and considering its molecular formula, once deposited on the walls of the airways, the released of bioavailable forms, such as ionic forms of the metals is expected to be very low, assuming a pH of about 6.6 (for healthy individuals). Therefore, absorption from the lungs to the circulatory system is expected to be minimal.

Respired iron oxide isostearate particles may also accumulate in the lungs mainly as particulate material since this substance is poorly soluble. In that case, the particles are expected to be engulfed from the alveolar region by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Deposited material may also be transported out of the respiratory tract and swallowed through the action of mucociliary clearance mechanisms, especially material settled in the tracheobronchial region. In that case, it will contribute to the gastro-intestinal absorption rather than to the absorption via inhalation. Also as a lipophilic compound (log Pow = 6.3, with a solubility in n-octanol of 288.7 mg/L), iron oxide isostearate may also be taken up by micellular solubilisation.

However, no direct experimental evidence for this behaviour and lung clearance mechanism are available since no inhalation study was done with iron oxide isostearate because the exposure via inhalation route to this substance was not found to be the most relevant. Indeed, the handling of the registered substance (produced as a suspension in a solvent) in manufacturing processes and uses does not produce vapours, aerosols or droplets. Furthermore, for the purpose of the registration, the substance was extracted from its solvent and has formed a melting/sticky powder that prevented testing via inhalation route.

•       Dermal absorption

Studies evaluating absorption of iron oxide isostearate following dermal exposure in humans are not available. Therefore, a qualitative assessment of the dermal absorption was performed based on the physicochemical properties of iron oxide isostearate and toxicological studies that tested the substance and its analogues using dermal route.

With a molecular weight of 203.8 g/mol, a log Pow value of 6.3 and a low water solubility (0.13 mg/L at pH 6.5), the dermal absorption of iron oxide isostearate is likely to be very low. The fatty acid moiety of the molecule should not further enhanced the dermal penetration since fatty acids have been demonstrated to be poorly absorbed through the skin (see IUCLID disseminated of stearic acid).

The acute dermal toxicity of the analogue cerium and iron oxide isostearate (Active matter of DPX10) was investigated in a study performed according to OECD Test Guideline N° 402 and in compliance with GLP (C. Pelcot, 2001; Klimisch 1). The rats were exposed dermally to the substance at 2000 mg/kg and observation up to 14 days following the 24-h application. No systemic clinical sign, no effect on the body weight and body weight gain and no cutaneous reactions were observed during the study. Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Additionally, no skin and eye irritation effects of the analogue cerium and iron oxide isostearate (Active matter of DPX10) were observed in in vivo studies done according to OECD Test Guidelines 404 (for skin) and 405 (for eye) and in compliance with GLP (C. Pelcot, 2001; Klimisch 1).

Further, results of in vivo skin sensitization studies in guinea pigs, performed according to OECD Test Guideline 406 and GPL compliant, indicate that iron oxide isostearate and its analogues cerium and iron oxide isostearates (Active matter of DPX10 and Active matter of DP11) induced no skin sensitization response in the guinea pigs after intradermal and dermal induction and challenge exposures (C. Pelcot 2006, 2001 and 2008; Klimisch 1). No sign of systemic or local toxicity, no effect on body weight and no mortality were observed in this study.

As iron oxide isostearate does not meet the CLP criteria for classification as skin and eye irritant or skin sensitizer, the expected low dermal absorption will not be enhanced by any irritating/sensitizing effects.

Distribution and accumulation

As discussed above, the absorption of iron oxide by oral, inhalation and dermal exposures is expected to be rather limited based on the physico-chemical properties and available toxicological data on this substance. Therefore, a limited distribution and accumulation can be assumed as well.

The absence of lesions in organs, clinical signs, hematology or blood biochemistry disorders, behavioral or neurological changes and impaired development of the progeny, as observed in the acute and repeated dose toxicity studies reported above in which rats were treated with cerium and iron oxide isostearates at dose levels up to 1000 mg/kg bw/day for up to 18/19 weeks, tends to support this assumption, at least by oral and dermal route.  

Poorly soluble particles with aerodynamic diameter equal or below 1 µm, when inhaled in sufficient quantity, may have the potential to deposit in the alveolar region of the lung and be phagocytized by alveolar macrophages that could translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. No direct experimental evidence is available to evaluate the possible accumulation and distribution from the respiratory tract of iron oxide isostearate particles that have a mean primary particle size of 3.7 nm (D50) and a mean hydrodynamic diameter of 12.1 +/- 8.1  nm and a low solubility (0.13 mg/L at pH 6.5). However, the exposure via inhalation route to this substance is expected to be really low since the handling of the registered substance in manufacturing processes and uses does not produce vapours, aerosols or droplets.

Therefore, taking into consideration all the above-mentioned information, no systemic distribution and accumulation of iron oxide isostearate is expected under normal conditions of exposure.

Metabolism

The presence or absence of exogenous metabolic activation system made no difference in the results of in vitro mutagenicity and genotoxicity studies performed with iron oxide isostearate and its analogues, that has been tested negative in the 5 following studies: Ames test (OECD TG N° 471 & GLP; A. Sokolowski, 2005; H. Haddouk, 2001; G. Sire, 2004; Klimisch 1), in vitro mammalian cell gene mutation test (OECD TG N°476 & GLP; G. Sire, 2009; Klimisch 1) and in vitro chromosome aberration assay (OECD TG N° 473 & GLP; H. Haddouk, 2002; Klimisch 1). No conclusion can therefore be made regarding the transformation of the test substance and/or its degradation products or metabolites by hepatic microsomal fractions.

However, no adverse microscopic finding in the major metabolizing tissues (liver, kidneys) illustrative of metabolic activity were seen following repeated dose administration of the analogue cerium and iron oxide isostearate (Active matter of DPX10) by the oral route at doses up to the limit dose of 1000 mg/kg bw/d for up to approximately 18/19 weeks in male and female rats in a 2-generation study (OECD TG 416, GLP; F. Spézia, 2001; Klimisch 1).

Elimination/Excretion

No direct experimental evidence is available to assess the elimination/excretion of iron isostearate.

However, as discussed in this assessment, the substance is expected to have limited absorption and distribution potentials based on its physico-chemical properties and its toxicological information. For these reasons, and because of its low solubility, it can be suggested that the main part of the substance will be eliminated as such, with the faeces as the most probable route of excretion/elimination.

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