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EC number: 234-975-0 | CAS number: 12047-27-7
Assessment of the Toxicokinetic Behaviour of barium titanium trioxide (CAS-No. 12047-27-7)
There were no studies available in which the toxicokinetic properties of barium titanium trioxide were investigated.
Barium titanium trioxide (molecular weight of 233.2 g/mol) is slightly soluble in water (see chapter 4.8 water solubility). The log Pow is not required as barium titanium trioxide is an inorganic substance (see chapter 4.7 partition coefficient). These data give a first impression that accumulation of Barium titanium trioxide must be low.
In an acute oral toxicity study, rats were administered barium titanium trioxide by gavage. No mortalities were observed in all doses (1500, 3000, 6000 and 12.000 mg/kg bw) (Brown and Mastromatteo, 1962, see chapter 7.2.1 acute oral toxicity) despite extreme high dose levels. At high dose levels clinical signs of toxicity (reduced activity, temporary loss of appetite and brownish coloured discharge from the nose and eyes) were observed indicating primarily a low oral toxicity.
The evaluation of toxicokinetic information performed by a renowned scientific body (ATSDR, 2007) is as follows: The International Commission for Radiation Protection (ICRP) estimates that the gastrointestinal absorption of barium is 20% in adults, 30% for children aged 1–15 years, and 60% in infants (ICRP 1993). ”These latter values were taken forward for risk characterisation purposes.
Most likely very little ingested barium titanium trioxide is absorbed due to the slightly solubility of the substance.
In an acute dermal toxicity study a single dose level of 2000 mg/kg Barium titanium trioxide was administered to rats (TÜV SÜD PSB Pte Ltd, 2012). No signs of systemic toxicity were observed, indicating primarily no dermal toxicity as a result of poor absorption.
The experience from previous EU risk assessments on heavy metals (Zn, Ni, Pb, Co, Al, Cd, Sb, Ti) summarised that:
Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.
However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than its mass.
The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours):
From exposure to liquid/wet media: 1.0 %
From dry (dust) exposure: 0.1 %
This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007)
As barium titanium trioxide is slightly soluble dermal absorption is very unlikely.
Additionally, in an inhalation hazard test with rats with the maximum attainable concentration of dust of 4.89 mg/L, neither mortalities nor clinical signs were observed in the animals after 4 h exposure (TÜV SÜD PSB Pte. Ltd., 2012). Therefore no indication is given for systemic uptake and respective toxic effects in this test conditions.
The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.
According to ATSDR (2007) a ratio of 20% can be assumed for the gastrointestinal uptake and the material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice.
Sub chronic toxicity studies with the analogue substance barium chloride dehydrate (CAS 10326-27-9) in rats showed treatment-related effects only in the high dose (4000 ppm) of males and females (Dietz et al., 1992; Anonymous publication, 1994). Depressed body weight gains, elevated phosphorus levels, neurobehavioral effects and chemically related lesions in the kidney and lymphoid tissue were observed in the high dose group (4000 ppm). Based on these effects, the NOAEL was derived to be 2000 ppm. Calculated as Ba2+ the NOAEL for females is 80.9 mg/kg bw/day and for males 61.1 mg/kg bw/day. Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day to male and female rats respectively) were regarded as not treatment-related therefore this dose level represents the NOAEL.Therefore, based on the NOAEL of 61.1 mg Ba2+/kg bw/day for male rats, the NOAEL of barium titanium trioxide is ≥ 103 mg/kg bw/day (calculated from its molecular weight).
A treatment-related effect on impairment of fertility in rats up to the highest dose group was not indicated in the screening test with the analogous test substance barium chloride dehydrate (CAS 10326-27-9) (Dietz et al., 1992). Thus, the NOAEL was derived from 4000 ppm (to average doses of 201.5 and 179.5 mg Ba2+/kg bw/d to male and female rats, respectively). The No-observed-adverse-effect level (NOAEL) on developmental toxicity for rats of 4000 ppm (corresponds to 304.9 mg/kg bw/d barium titanium trioxide) was derived from this study. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation.
Studies on genotoxicity (Bacterial Reverse Mutation Assay, In vitro Mammalian Cell Gene Mutation Test) with the analogous test substance Barium chloride dehydrate (CAS 10326-27-9) were negative (Anonymous publication, 1994 and Lloyd, 2010).
Barium is not metabolised in the body, but it may be transported or incorporated into complexes or tissues (ATSDR, 2007).
Following ingestion in humans, barium is predominantly found in bones: approximately 90 % of the barium in the body was detected in the bone. Approximately 1–2% of the total body burden was found in muscle, adipose, skin, and connective tissue. This information is supported by a number of studies. Significant increases in the levels of barium in bone were found in rats administered barium chloride in the diet or barium as a component of Brazil nuts for 29 days, although this study did not examine other tissues. A study in which rats were exposed to barium chloride and barium carbonate in drinking water found the following non-skeletal distribution (skeletal tissue was not examined in the study) 24 hours after ingestion: heart > eye > skeletal muscle > kidney > blood > liver (ATSDR, 2007).
A study of two humans ingesting a normal diet found that faecal excretion of barium was 2–3 times higher than urinary excretion over a 30-day period. A 29-day rat study also demonstrated that the faeces were the primary route of excretion following exposure to barium chloride in the diet or barium from brazil nuts. A study in rats found that biliary excretion did not significantly contribute to the total amount of barium excreted in the faeces, suggesting that other physiological routes were responsible for faecal barium. A study of rabbits administered an intravenous injection of radio-labelled barium also found that barium was primarily excreted in the faeces. After the first day, faecal excretion was approximately twice as high as urinary excretion. The barium was primarily excreted in the first 5 days after exposure; after 9 days, approximately 50% of the dose was excreted (ATSDR, 2007).
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