Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Theoretical assessment based on available data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Principles of method if other than guideline:
A theoretical assessment was done based on all available data according to "Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 2.0, November 2014".
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Results and discussion

Any other information on results incl. tables

A substance can enter the body via the lungs, the gastrointestinal tract, and the skin. In general, a compound needs to be dissolved before it can be taken up, for example from the gastrointestinal tract after oral administration (1). Bismuth oxy-iodide bromide (BiOI/OBr) is insoluble in water at neutral pH. However, in acidic aqueous environments, the substance solubilizes according to the following reaction:

BiOI/OBr + 2 H+ <---> Bi3+ + I-/Br- + H2O

In acidic conditions bismuth oxy-iodide bromide is solubilized and the solid re-appears as soon as the acidity is insufficient. Indeed the water solubility at pH 1 was found to be 154 μg/L (calculated solubility based on analysis of dissolved bismuth ions), whereas at pH 7 no dissolved bismuth could be detected (< 5 μg Bi3+/L). As the target substance is limitedly soluble at pH 1, some bismuth-, bromide- and iodide ions are expected to be formed in the stomach after oral uptake of bismuth oxy-iodide bromide. These ions can be taken up, in part via passive diffusion, in part through active transport mechanisms (2). Bismuth oxy-iodide bromide has a moderate molecular weight (323.7 – 344.8 g/mol), which will not limit uptake as substances with a molecular weight below 500 are favourable for absorption. In spite of its moderate molecular weight, the low water solubility of bismuth oxy-iodide bromide will largely prevent uptake. Therefore, for risk assessment purposes the oral absorption of bismuth oxy-iodide bromide is set at 10% as a worst case assumption. Once absorbed, distribution of the ions of bismuth oxy-iodide bromide throughout the body is possible; bismuth may be found in all body tissues after absorption (3) and bromide and iodide are naturally present in human blood and are rapidly excreted in urine (4,5). Since only particles with an aerodynamic diameter below 15 μm reach the alveolar region of the respiratory tract, the test substance is not expected to enter these regions as no particles < 20 μm were detected in the test substance. Particles with an aerodynamic diameter below 50 μm may reach the thoracic regions upon inhalation, thus maximally 3.27% (fraction smaller than 63 μm) of the test substance can potentially reach this area after inhalation. The water insolubility of bismuth oxy-iodide bromide at neutral pH indicates that the substance will not dissolve into the mucus lining of the respiratory tract and the deposits in the nasopharyngeal region are likely to be coughed or sneezed out of the body, or swallowed. Especially since the test substance particles are not expected to reach the deeper regions of the lungs, it is likely that inhaled particles will be removed via this mechanism. For risk assessment purposes the inhalation absorption of bismuth oxy-iodide bromide is therefore set at 10%.

Bismuth oxy-iodide bromide is a crystalline powder which is considered to be insoluble in water at pH 5, the pH of the skin. Dermal integrity is not influenced by the bismuth oxyiodide bromide as it does not have irritating or corrosive properties. Its molecular weight below 500 g/mol (323.7 – 344.8 g/mol) does not favour dermal absorption.

Based on these physical/chemical properties of bismuth oxy-iodide bromide, dermal absorption is expected to be low. Although the criteria for 10% dermal absorption as given in the REACH guidance (6) (MW > 500 and log Pow <-1 or >4) are not met and data on log Pow are not available (bismuth oxy-iodide bromide is an inorganic substance), 100% dermal absorption is considered not relevant for bismuth oxy-iodide bromide as it is generally accepted that dermal absorption does not exceed oral absorption. Therefore for risk assessment purposes, 10% dermal absorption of bismuth oxy-iodide bromide as default value is considered appropriate.

References:

(1) Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620- 43;

(2) Parkinson, A. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001;

(3) Committee for veterinary medicinal products of the European Agency for the evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, EMEA/MRL/201/97-FINAL, April 1997;

(4) TOXICOLOGICAL PROFILE FOR IODINE, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Agency for Toxic Substances and Disease Registry (April 2004). 5. World Health Organization (2009): Bromide in Drinking-water Background document for development of WHO Guidelines for Drinking-water Quality;

(6) Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 2.0 November 2014.

Applicant's summary and conclusion

Conclusions:
For risk assessment purposes the oral, inhalation and dermal absorption of bismuth oxy-iodide/oxy-bromide is set at 10%. Once absorbed, distribution of the ions of bismuth oxy-iodide/oxy-bromide throughout the body is possible, rapid excretion via urine is expected.