Tetrabutylphosphonium bromide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

November 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Materials and methods

GLP compliance:

no

Results and discussion

Main ADME results

Type:

absorption

Results:

For risk assessment purposes, 50% is used for oral and dermal absorption and 100% for inhalation absorption

Any other information on results incl. tables

A toxicant can enter the body via the gastrointestinal tract, the lungs and the skin.

In general, a substance needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration (1). The water solubility of Tetrabutylphosphonium bromide (>882 g/L) favors dissolution of the substance in the gastrointestinal fluids and hence contact with the mucosal surface. The molecular weight (MW<500) and moderate log P value (between -1 and 4) are favorable for absorption. Tetrabutylphosphonium bromide is a salt and expected to dissociate to ions in aqueous solution to form a tetrabutylphosphonium cation and a bromide anion. As it is generally assumed that ionized substances do not readily diffuse across biological membranes, absorption is considered to be limited.

Taken together, some oral absorption of Tetrabutylphosphonium bromide is expected based on its water solubility, molecular weight, and the log P. On the other hand, absorption is expected to be limited because Tetrabutylphosphonium bromide can form ions in solution. For risk assessment purposes oral absorption of Tetrabutylphosphonium bromide is set at 50% (2). The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

 

For inhaled substances the processes of deposition of the substance on the surface of the respiratory tract and the actual absorption have to be differentiated. A vapor pressure of less than 0.5 KPa and a decomposition temperature at ca. 344°C (no boiling point could be established) indicate a low volatility. Tetrabutylphosphonium bromide was visually observed to be a waxy/crystallized solid without particles. It is not likely that Tetrabutylphosphonium bromide will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapor or fine particles.

If Tetrabutylphosphonium bromide reaches the tracheobronchial region, it is likely to diffuse/dissolve into the mucus lining of the respiratory tract due to its water solubility and subsequently get absorbed due to its low molecular weight and moderate log P.

Based on the above data, for risk assessment purposes the inhalation absorption of Tetrabutylphosphonium bromide is set at 100% (2). From an exposure perspective, exposure is likely to be negligible.

 

Tetrabutylphosphonium bromide is a dry waxy particulate which will have to dissolve into the surface moisture of the skin before it can be absorped. According to the criteria given in the REACH Guidance (2), a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen. The MW (339.4) and log Pow (-0.44) of Tetrabutylphosphonium bromide indicate that absorption is to be expected. Systemic toxicity and mortality observed in an acute dermal toxicity study also indicate that absorption had occurred. In general, it is assumed that dermal absorption will not be higher that oral absorption, which for Tetrabutylphosphonium bromide is set at 50%.

Taken together, based on MW and log Pow, dermal absorption is expected. The oral absorption of Tetrabutylphosphonium bromide is set at 50%. Based on these considerations, for risk assessment purposes the dermal absorption of Tetrabutylphosphonium bromide is set at 50% (2).

 

Once absorbed, distribution of the test substance throughout the body is expected based on its water solubility and molecular weight. Absorbed Tetrabutylphosphonium bromide is most likely excreted via urine (3). Based on its partition coefficient and water solubility, Tetrabutylphosphonium bromide is not expected to accumulate in adipose tissue. It should be noted that the half-life of bromide ion in the body (3-8 days in rat, ~12 days in human) can contribute to toxicity from bromide build-up in body fluids (4).

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.      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.

3.      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.

4.      Pavelka S. Metabolism of bromide and its interference with the metabolism of iodine. Physiol Res. 2004;53 Suppl 1:S81-90.

 

Applicant's summary and conclusion

Conclusions:

Low bioaccumulation potential based on study results
For risk assessment purposes, 50% is used for oral and dermal absorption and 100% for inhalation absorption.